# 32 - 416 Diabetes Mellitus- Management and Therapies

### 416 Diabetes Mellitus: Management and Therapies

Diabetes Mellitus: 

Management and 

Therapies
Alvin C. Powers, Kevin D. Niswender, 

Michael R. Rickels
OVERALL GOALS
The goals of therapy for all forms of diabetes mellitus (DM) are to (1) 
eliminate symptoms related to hyperglycemia, (2) reduce or eliminate 
the long-term microvascular and macrovascular complications of DM 
(Chap. 417), and (3) allow the patient to achieve as normal a lifestyle 
as possible. To reach these goals, the physician and health care team 
should identify a target level of glycemic control for each patient, pro­
vide the patient with the educational and pharmacologic resources nec­
essary to reach this target, avoid hypoglycemia, and monitor/prevent/
treat DM-related complications. Symptoms of diabetes usually resolve 
when the plasma glucose is <11.1 mmol/L (200 mg/dL), and thus most 
DM treatment focuses on achieving the second and third goals.
The care of an individual with either type 1 or type 2 DM requires 
a multidisciplinary team. Central to the success of this team are the 
patient’s participation, input, and enthusiasm, all of which are essential 
for optimal diabetes management. Members of the health care team 
usually include the primary care provider and/or the endocrinologist 
or diabetologist, an advanced practice provider (APP), a pharmacist, 
a certified diabetes educator, a nutritionist, a behavioral health pro­
fessional, and possibly a social worker. In addition, when the com­
plications of DM arise, subspecialists (including ophthalmologists, 
neurologists, podiatrists, nephrologists, cardiologists, and cardiovascu­
lar and transplant surgeons) with experience in DM-related complica­
tions are essential. The American Diabetes Association (ADA) suggests 
applying the Chronic Care Model to diabetes with an emphasis on 
these elements: a proactive, team-based delivery and health system 
design that involves self-management, decision support with evidencebased guidelines for person-specific and population-based approaches, 
and community resources and policies that support healthy lifestyles. 
Space limitations do not allow a discussion of all these elements, so this 
chapter first reviews the ongoing treatment of diabetes in the outpa­
tient setting and then discusses the treatment of severe hyperglycemia, 
as well as the treatment of diabetes in hospitalized patients.
ONGOING ASPECTS OF COMPREHENSIVE 
DIABETES CARE
A number of names are sometimes applied to different approaches to 
diabetes care, such as intensive insulin therapy or intensive glycemic 
control. The current chapter, and other sources, uses the term Compre­
hensive diabetes care to emphasize the fact that optimal diabetes therapy 
involves much more than glucose management and medications and 
that individualized, patient-centered care is essential. Although glyce­
mic control is central to optimal diabetes therapy, comprehensive dia­
betes care of both type 1 and type 2 DM should also detect and modify 
risk factors for DM-associated disorders and manage DM-specific 
complications (Chap. 417). The key elements of comprehensive diabe­
tes care are summarized in Table 416-1. The morbidity and mortality 
of DM can be greatly reduced by timely and consistent surveillance, 
including the detection, prevention, and management of DM-related 
complications (Table 416-1 and Chap. 417). Such approaches are indi­
cated for all individuals with DM, but many individuals with diabetes 
do not receive these or comprehensive diabetes care. The social deter­
minants of health and family, financial, cultural, and employmentrelated issues may negatively impact diabetes care. This chapter, while 
recognizing that resources available for diabetes care vary widely 
throughout the world, provides guidance for comprehensive diabe­
tes care in health care settings with considerable societal resources. 

TABLE 416-1  Guidelines for Ongoing, Comprehensive Medical Care for 
Individuals with Diabetes
• Individualized glycemic goal and therapeutic plan with an emphasis on shared 
decision-making
• Blood glucose measurement using continuous glucose monitoring (CGM) or 
capillary fingerstick device
• HbA1c testing (2–4 times/year)
• Lifestyle management in the care of diabetes, including:
• Diabetes self-management education and support
• Nutrition therapy
• Physical activity
• Psychosocial care, including evaluation for depression, anxiety, diabetes 
Diabetes Mellitus: Management and Therapies  
CHAPTER 416
distress
• Detection, prevention, or management of diabetes-related complications, 
including:
• Diabetes-related eye examination (annual or biannual; Chap. 417)
• Diabetes-related foot examination (1–2 times/year by provider; daily by 
patient; Chap. 415)
• Diabetes-related neuropathy examination (annual; Chap. 415)
• Diabetes-related kidney disease testing (annual; Chap. 417)
• Screen for other diabetes-related complications (annual; see Table 417-1)
• Assessment of fracture risk in older adults with diabetes (consider 
measurement of bone mineral density)
• Manage or treat diabetes-relevant conditions, including:
• Blood pressure (assess 2–4 times/year; Chap. 417)
• Lipids (1–2 times/year; Chap. 417)
• Consider screening individuals with type 2 diabetes or prediabetes for 
metabolic dysfunction–associated steatotic liver disease if other risk 
factors are present
• Consider antiplatelet therapy with low-dose aspirin (Chap. 417)
• Immunizations, including influenza, pneumococcal, hepatitis B, 
coronavirus, and respiratory syncytial virus (>60 years of age) (Chap. 6)
Abbreviation: HbA1c, glycated hemoglobin A1c.
Patient-oriented websites also offer important resources for patients 
and their caregivers. Examples of these resources include: https://www.
tidepool.org/about; https://diatribe.org/understanding-diabetes/diabetestechnology; and https://pro.diabeteswise.org/en/.
Lifestyle Management in Diabetes Care 
The patient with type 1 
or type 2 DM should receive education about nutrition, physical activity, 
psychosocial support, care of diabetes during illness, medications used 
to control the glucose, methods for glucose monitoring, and strategies 
to prevent diabetes-related complications. Patient education allows and 
encourages individuals with DM to assume greater responsibility for 
their care, leading to improved compliance.
Diabetes Self-Management Education and Support 
(DSMES) 
DSMES refers to ways to improve the patient’s knowl­
edge, skills, and abilities necessary for diabetes self-care and should 
also emphasize psychosocial issues and emotional well-being. Patient 
education is a continuing process with regular visits for reinforcement; 
it is not a process completed after one or two visits. It should receive 
special emphasis at the diagnosis of diabetes, annually, or at times 
when diabetes treatment goals are not attained, and during transitions 
in life or medical care. DSMES is delivered by a diabetes educator who 
is a health care professional (nurse, dietician, or pharmacist) with 
specialized patient-education skills and who is certified in diabetes 
education (e.g., Association of Diabetes Care and Education Specialists 
or Certification Board for Diabetes Care and Education). Education 
topics important for optimal diabetes self-care include continuous 
glucose monitoring (CGM) or blood glucose monitoring (BGM); 
urine or blood ketone monitoring (type 1 DM); insulin administra­
tion; guidelines for diabetes management during illnesses; prevention 
and management of hypoglycemia (Chap. 418); foot and skin care; 
diabetes management before, during, and after exercise; and risk 
factor–modifying activities. The focus is providing patient-centered, 
individualized education. More frequent contact between the patient

and the diabetes management team (e.g., electronic, telephone, video) 
improves glycemic control.

Nutrition Therapy 
Medical nutrition therapy (MNT) is a term 
used by the ADA to describe the optimal coordination of caloric 
intake with other aspects of diabetes therapy (e.g., insulin, exercise, 
and weight loss). Some aspects of MNT are directed at preventing or 
delaying the onset of type 2 DM in high-risk individuals (obese or with 
prediabetes) by promoting weight reduction. Other measures of MNT 
are directed at improving glycemic control through monitoring car­
bohydrate intake, avoiding simple sugars and fructose, and managing 
diabetes-related complications (atherosclerotic cardiovascular disease 
[ASCVD], nephropathy). Medical treatment of obesity, including phar­
macologic approaches that facilitate weight loss and metabolic surgery, 
should be considered in some patients (Chaps. 413 and 414).
PART 12
Endocrinology and Metabolism
In general, the components of optimal MNT are similar for individ­
uals with type 1 or type 2 DM—high-quality, nutrient-dense foods with 
limits on carbohydrate intake and weight management (Table 416-2). 
The data are currently inconclusive about various eating patterns 
(e.g., intermittent fasting). Sleep deprivation and shift work are risk 
factors for weight gain and insulin resistance. Dietary advice should 
be individualized, acknowledging personal preferences, cultural, and 
religious traditions. Use of the glycemic index, an estimate of the post­
prandial rise in the blood glucose when a certain amount of that food 
is consumed, may reduce postprandial glucose excursions and improve 
glycemic control.
The goal of MNT in type 1 DM is to coordinate and match the car­
bohydrate intake, both temporally and quantitatively, with the appro­
priate amount of insulin. MNT in type 1 DM is informed by CGM 
and/or BGM that should be integrated to define the optimal insulin 
regimen. Based on the patient’s estimate of the carbohydrate content of 
TABLE 416-2  Nutritional Recommendations for Adults with Diabetes 
or Prediabetesa
General dietary guidelines
• Vegetables, fruits, whole grains, legumes, low-fat dairy products and food 
higher in fiber and lower in glycemic content; optimal diet composition and 
eating pattens are not known.
Fat in diet (optimal percentage of diet is not known; should be individualized)
• Encourage Mediterranean-style diet rich in monounsaturated and 
polyunsaturated fatty acids.
• Minimal or no trans fat consumption.
Carbohydrate in diet (optimal percentage of diet is not known; should be 
individualized)
• Monitor carbohydrate intake in regard to calories and set limits for meals to 
reduce postprandial glycemia.
• Consider limiting overall carbohydrate intake in adults with diabetes as this 
may improve glycemia.
• Avoid fructose- and sucrose-containing beverages and minimize consumption 
of foods with added sugar that may displace healthier, more nutrient-dense 
food choices and elevate postprandial glycemia.
• Estimate grams of carbohydrate in diet for flexible insulin dosing (type 1 
diabetes and insulin-dependent type 2 diabetes).
• Consider using glycemic index to predict how consumption of a particular 
food may affect blood glucose.
Protein in diet (optimal percentage of diet is not known; should be individualized)
Other components
• Reduced-calorie and nonnutritive sweeteners may be useful.
• Routine supplements of vitamins, antioxidants, or trace elements not 
supported by evidence.
• Vitamin D and calcium supplemental as recommended to promote bone 
health.
• Sodium intake as advised for general population (<2300 mg/d).
• Minimize disruption to sleep and eating patterns (chrononutrition), and note 
risk of hypoglycemia associated with religious fasting.
aSee text for differences for patients with type 1 or type 2 diabetes.
Source: Data from American Diabetes Association: Facilitating positive health 
behaviors and well-being to improve health outcomes: Standards of care in 
diabetes—2024. Diabetes Care 47:S77, 2024.

a meal, an insulin-to-carbohydrate ratio determines the bolus insulin 
dose for a meal or snack. MNT must be flexible enough to allow for 
exercise, and the insulin regimen must allow for variations in caloric 
intake. An important component of MNT in type 1 DM is to minimize 
the weight gain often associated with intensive insulin therapy and is 
best achieved by placing limits on carbohydrate intake.
The goals of MNT in type 2 DM should focus on weight loss and 
address the greatly increased prevalence of cardiovascular risk factors 
(hypertension, dyslipidemia, obesity) and disease in this population. 
The majority of these individuals are obese, and weight loss is strongly 
encouraged. Very-low-carbohydrate diets that induce weight loss may 
result in rapid and dramatic glucose lowering in individuals with 
new-onset type 2 DM. MNT for type 2 DM should emphasize mod­
est caloric reduction, increased physical activity, and weight loss (goal 
of at least 5–10% loss). Weight loss and exercise each independently 
improve insulin sensitivity.
Fasting for religious reasons, such as during Ramadan, presents a chal­
lenge for individuals with diabetes, especially those taking medications 
to lower the plasma glucose. Under most guidelines for fasting during 
Ramadan, individuals are risk-stratified based on a pre-Ramadan risk 
assessment for people with diabetes as those who can safely fast with medi­
cal evaluation and supervision and those in whom fasting is not advised. 
Thus, patient education and regular glucose monitoring are critical.
Physical Activity 
Exercise has multiple positive benefits, including 
cardiovascular risk reduction, reduced blood pressure, maintenance of 
muscle mass, reduction in body fat, and weight loss. For individuals with 
type 1 or type 2 DM, exercise is also useful for lowering plasma glucose 
(during and following exercise) and increasing insulin sensitivity. In 
patients with diabetes, the ADA recommends 150 min/week (distributed 
over at least 3 days) of moderate aerobic physical activity with no gaps 
longer than 2 days. Resistance exercise, flexibility and balance training, 
and reduced sedentary behavior throughout the day are also advised.
Despite its benefits, exercise may present challenges for some 
individuals with DM because they lack the normal glucoregulatory 
mechanisms (normally, insulin falls and glucagon rises during exer­
cise). Skeletal muscle is a major site for metabolic fuel consumption 
in the resting state, and the increased muscle activity during vigorous 
aerobic exercise greatly increases fuel requirements. Individuals with 
type 1 DM are prone to either hyperglycemia or hypoglycemia during 
exercise, depending on the pre-exercise plasma glucose, the circulating 
insulin level, lactate, and the level of exercise-induced catecholamines. 
If the insulin level is too low, the delivery of lactate to the liver and 
rise in catecholamines may increase the plasma glucose excessively, 
promote ketone body formation, and possibly lead to ketoacidosis. 
Conversely, if the circulating insulin level is excessive, this relative 
hyperinsulinemia may reduce hepatic glucose production (decreased 
glycogenolysis, decreased gluconeogenesis) and increase glucose entry 
into muscle, leading to hypoglycemia.
To avoid exercise-related hyper- or hypoglycemia, individuals with 
type 1 DM should (1) monitor blood glucose before, during, and after 
exercise (see below related to CGM and possible blood glucose dis­
cordance); (2) delay exercise if blood glucose is >14 mmol/L (250 mg/
dL) and ketones are present; (3) if the blood glucose is <5.0 mmol/L 
(90 mg/dL), ingest carbohydrate before exercising; (4) monitor glu­
cose during exercise and ingest carbohydrate as needed to prevent 
hypoglycemia; (5) decrease insulin doses (based on previous experi­
ence) before and after exercise and inject insulin into a nonexercising 
area; and (6) learn individual glucose responses to different types of 
exercise. In individuals with type 2 DM, exercise-related hypoglycemia 
is less common but can occur in individuals taking either insulin or 
insulin secretagogues. Untreated proliferative retinopathy is a relative 
contraindication to vigorous exercise because this may lead to vitreous 
hemorrhage or retinal detachment (Chap. 417).
Psychosocial Care 
Because the individual with DM faces chal­
lenges that affect many aspects of daily life, psychosocial assessment 
and support are a critical part of comprehensive diabetes care. The 
patient should view himself/herself/themself as an essential member 
of the diabetes care team and not as someone who is cared for by the

diabetes management team. Even with considerable effort, normo­
glycemia can be an elusive goal, and solutions to worsening glycemic 
control may not be easily identifiable. Depression, anxiety, or “diabetes 
distress,” defined by the ADA as “negative psychological reactions 
related to emotional burdens … in having to manage a chronic dis­
ease like diabetes,” should be recognized and may require the care of 
a mental health specialist. Emotional stress may provoke a change in 
behavior so that individuals no longer adhere to a dietary, exercise, or 
therapeutic regimen. Eating disorders, including binge eating disor­
ders, bulimia, and anorexia nervosa, appear to occur more frequently 
in individuals with type 1 or type 2 DM.
■
■MONITORING THE LEVEL OF 
GLYCEMIC CONTROL
Optimal monitoring of glycemic control involves CGM or BGM (blood 
collected by fingerstick) by the patient and an assessment of long-term 
control by providers using measurement of hemoglobin A1c (HbA1c). 
These measurements are complementary: the patient’s measurements 
provide a picture of short-term glycemic control, whereas the HbA1c 
reflects average glycemic control over the previous 2–3 months. By 
integrating glycemic measurements with diet and exercise history into 
comprehensive diabetes care, the diabetes management team and patient 
can improve glycemic control and reduce diabetes-related complications.
Assessment of Short-Term Glycemic Control 
All individu­
als with diabetes should be offered a device to assess their short-term 
patterns of glycemia. CGM technology utilizes a sensor or electrode 
to detect interstitial glucose, which is in equilibrium with the blood 
glucose but may lag when the blood glucose changes rapidly or during 
exercise. Glucose sensors are placed subcutaneously by the patient and 
replaced every 10–14 days; a different device can be placed subcutane­
ously by a minor surgical procedure and replaced every 6–12 months. 
Some CGMs require calibration by fingerstick blood glucose measure­
ment. CGM provides glucose data every 5 minutes, and the device’s 
output can be provided in an ambulatory glucose profile (AGP) that 
is a standardized, single page summary that includes the percentage 
of time in the desired glycemic range (TIR, or time in range), the per­
centage of time above the target range, the percentage of time below 
the target range, the glucose management indicator (GMI), which 
correlates with HbA1c (Table 416-3), and glucose variability. CGM in 
real time also allows the patient to monitor the trend of glucose change 
(upward or downward), with this trend being used to avoid predicted 
hyper- or hypoglycemia.
CGM device technology is rapidly evolving with the number of 
available CGM devices increasing and features expanding. This chapter 
uses the term CGM to encompass both real-time CGM and intermit­
tently scanned CGM, with real-time CGM being more effective. Most 
CGMs require a provider’s prescription, but CGM devices are approved 
for purchase without a provider’s prescription. The selection of CGM 
type should consider the implications for the individual with diabetes 
(e.g., cost, convenience, insurance coverage), the provider (e.g., access 
to patient’s CGM data), and the health system (e.g., integration of 
patient CGM data into the electronic medical record). Selection is 
best optimized by the involvement of a certified diabetes educator 
TABLE 416-3  Relationship of HbA1c and Estimated Average Glucose (eAG)
ESTIMATED AVERAGE GLUCOSE (AVERAGE, RANGE)
HEMOGLOBIN 
A1C (%) 
mmol/L
mg/dL

5.4 (4.2–6.7)
97 (76–120)

7.0 (5.5–8.5)
126 (100–152)

8.6 (6.8–10.3)
154 (123–185)

10.2 (8.1–12.1)
183 (147–217)

11.8 (9.4–13.9)
212 (170–249)

13.4 (10.7–15.7)
240 (193–282)

14.9 (12.0–17.5)
269 (217–314)

16.5 (13.3–19.3)
298 (240–347)
Source: Data adapted from Diabetes Care 31:1473, 2008.

knowledgeable about these technologies. Unfortunately, certified dia­
betes educators are not available in all care settings, so the individual 
with diabetes and the provider may need to investigate CGM options 
using online resources and see suggestions in the reference list. Many 
are vendor specific; some resources provide information on multiple 
vendors, technologies, and devices. The selection of a CGM device 
should be individualized based on patient preference and skill level, 
capability to collect and use the data, and ability to upload data to 
adjust therapy. CGM may be used in individuals whose diabetes is 
partially or completely managed by someone else, such as a caregiver 
(e.g., in a child or an individual with cognitive impairment). After the 
selection of a CGM device, the individual with diabetes (and/or the 
caregiver) should receive education and training on a regular basis.

Diabetes Mellitus: Management and Therapies  
CHAPTER 416
BGM devices use a small drop of blood (<2 μL) and an enzymatic 
reaction to rapidly measure the capillary blood glucose. It is critical 
that individuals using CGM also have a capillary (fingerstick) device 
for times when the CGM technology is malfunctioning, CGM results 
are questionable, or for CGM calibration (if required or desired). 
Substances can interfere with the accuracy of measurements by CGM 
devices (e.g., hydroxyurea, acetaminophen, ascorbic acid, mannitol, 
and sorbitol) and BGM devices (e.g., uric acid, galactose, xylose, acet­
aminophen, L-DOPA, or ascorbic acid).
Individuals with type 1 DM or individuals with type 2 DM taking 
insulin injections each day should monitor their blood glucose by 
CGM. CGM in type 1 DM, especially in those with hypoglycemia 
unawareness, can decrease the frequency of serious hypoglycemia 
(especially nocturnal hypoglycemia). The combination of an insulininfusion device (discussed below) and a CGM can automate insulin 
delivery with either predictive suspension of insulin delivery to avoid 
hypoglycemia or closed-loop control that automatically adjusts insulin 
delivery by a predictive algorithm (Fig. 416-1). Some CGM/insulin 
pump manufacturers offer the patient a way to upload glucose data 
into the manufacturer’s server, which can then be securely accessed 
by the provider’s staff. It is critical for the patient’s glycemic data to be 
securely accessible to the provider and uploaded into the electronic 
health record of the provider and health system, but approaches and 
systems to accomplish this need further improvement.
Individuals with type 2 DM treated on oral therapy and/or only 
with diet/lifestyle require less intense glycemic monitoring and can use 
CGM or BGM to measure the glucose at a lower frequency (e.g., 3–5 
times/week). Many individuals with type 1 or type 2 DM report that 
real-time access to glycemic information via CGM assists in lifestyle 
choices, diet, and activity in addition to insulin or medication manage­
ment, thereby improving control.
Assessment of Long-Term Glycemic Control 
Measurement 
of glycated hemoglobin (HbA1c) is the standard method for assess­
ing long-term glycemic control. When plasma glucose is consistently 
elevated, there is an increase in nonenzymatic glycation of hemo­
globin; this alteration reflects the glycemic history over the previous 
2–3 months, because erythrocytes have an average life span of ∼120 days 
(glycemic level in the preceding month contributes about 50% to the 
HbA1c value). Laboratory standards for the HbA1c test should be corre­
lated to the reference assay of the Diabetes Control and Complications 
Trial (DCCT). Measurement of HbA1c at the “point of care” allows for 
more rapid feedback and may therefore assist in adjustment of therapy.
As the primary predictor of long-term complications of DM, the 
HbA1c should mirror the short-term measurement by CGM or BGM. 
HbA1c should be measured in all individuals with DM during their 
initial evaluation and as part of their comprehensive diabetes care. In 
patients achieving their glycemic goal, the ADA recommends measure­
ment of the HbA1c at least twice per year. More frequent testing (every 
3 months) is warranted when glycemic control is inadequate or when 
therapy has changed. The HbA1c correlates with the average plasma 
glucose value or estimated average glucose (eAG) (Table 416-3) but 
does not detect glycemic variability or recent intercurrent illnesses as 
CGM or BGM can. There is interindividual variability in the HbA1c to 
mean glucose relationship, likely genetically determined; there is con­
troversy and some uncertainty about the influence of race or ancestry

PART 12
Endocrinology and Metabolism
A
B
FIGURE 416-1  Glycemic monitoring and insulin administration options for treatment of diabetes. A. Continuous glucose monitoring (CGM) profile and delivery of rapidacting insulin analogue by continuous subcutaneous insulin infusion pump involves a basal rate (light purple line) and prandial and correction boluses (purple circles) 
based on estimated carbohydrate intake (orange squares) and an insulin sensitivity factor. B. CGM profile with sensor-communicating insulin pump that automates insulin 
delivery by suspending delivery for predicted hypoglycemia and increasing basal delivery for predicted hyperglycemia (light purple curves) while still requiring user input 
for estimated carbohydrate intake (orange squares) to provide prandial insulin boluses (purple circles). C. CGM profile is used to generate an estimate of time-in-range with 
glycemic goal shown on the left side of the bar and target percent time in that glycemic range shown on the right side of the bar. D. Pharmacokinetic profile of selected 
insulin formulations. The duration of action of an insulin may vary among individuals. (Part C: Reproduced with permission from T Battelino et al: Clinical targets for 
continuous glucose monitoring data interpretation: Recommendations from the International Consensus on Time in Range. Diabetes Care 42:1593, 2019; Part D: Reproduced 
with permission from JJ Neumiller: Insulin Update: New and Emerging Insulins, American Diabetes Association, 2018.)
on HbA1c. For example, the HbA1c in African Americans is slightly 
higher (~0.3%) than in non-Hispanic white or Hispanic individuals for 
the same mean glucose. Clinical conditions leading to abnormal red 
blood cell (RBC) parameters such as hemoglobinopathies, anemias, 
reticulocytosis, transfusions, uremia, variants in glucose-6-phosphate 
dehydrogenase, hemodialysis, erythropoietin therapy, and HIV treat­
ment may alter the HbA1c result. Glycemic control can also be assessed 
by the degree of glycation of other proteins, such as fructosamine or 
glycated albumin, that reflect glycemia over the prior 2–4 weeks.
PHARMACOLOGIC TREATMENT 
OF DIABETES
Comprehensive care of type 1 and type 2 DM requires an emphasis on 
nutrition, exercise, and monitoring of glycemic control in addition to 
glucose-lowering medication(s). Medications to prevent and man­
age diabetes-related complications are discussed in Chap. 417. 
This chapter discusses classes of such medications but does not 
describe all glucose-lowering agents available worldwide. The initial 
step is to select an individualized glycemic goal for the patient.
■
■ESTABLISHMENT OF TARGET LEVEL OF 
GLYCEMIC CONTROL
Because the complications of DM are related to glycemic control, nor­
moglycemia or near-normoglycemia is the desired, but often elusive, 
goal for most patients. Normalization or near-normalization of the 
plasma glucose for long periods of time had been extremely difficult, as 
demonstrated by the DCCT and United Kingdom Prospective Diabetes 
Study (UKPDS), but new technologies and medications are making this 
goal more feasible. Regardless of the level of hyperglycemia, improve­
ment in glycemic control will lower the risk of diabetes-related com­
plications, most notably the microvascular complications (Chap. 417).
The target for glycemic control (as reflected by the HbA1c) should be 
individualized, and the goals of therapy should be developed in consul­
tation with the individuals with diabetes after considering a number of 
medical, social, and lifestyle issues (ADA terms this patient-centered 
care) such as age, ability to understand and implement a treatment 

Type 1 & Type 2
Diabetes
Target
<5%
<250 mg/dL
(13.9 mmol/L)
>180 mg/dL
(10.0 mmol/L)
<25%
Target Range:
70–180 mg/dL
(3.9–10.0 mmol/L)
>70%
<70 mg/dL (3.9 mmol/L)
<54 mg/dL (3.0 mmol/L)
C
<4%
<1%
Rapid (aspart, lispro, glulisine, inhaled human insulin)
Short (regular U-100)
Mixed short/intermediate (regular U-500)
Intermediate (NPH)
Plasma Insulin Levels
Long (U-100 glargine)
Ultra-long (degludec)

10 12 14 16 18
Time (hr)
20 22 24 26 28 30 32 34 36
D
regimen, presence and severity of complications of diabetes such as 
ASCVD, ability to recognize hypoglycemic symptoms, presence of 
other medical conditions or treatments that might affect survival or 
the response to therapy, lifestyle and occupation (e.g., possible conse­
quences of experiencing hypoglycemia on the job), and level of support 
available from family and friends.
In general, the ADA suggests that the goal is to achieve an HbA1c as 
close to normal as possible without significant hypoglycemia. In most 
individuals, the target HbA1c should be <7% (Table 416-4) with a more 
stringent (≤6.5%) target for some patients. With current treatment 
and devices, the level of HbA1c is no longer inversely related to the 
frequency and severity of hypoglycemia as seen in the DCCT. A higher 
HbA1c target of <7.5 or 8% is appropriate for individuals with cognitive 
impairment, those with reduced ability to sense hypoglycemia, or those 
with limited life span, realizing that these factors represent a spectrum 
across individuals (Table 416-4). Approximately one in four individuals 
over the age of 65 years has diabetes. Thus, the glycemic goal in elderly 
individuals (>65 years) should be individualized and consider the over­
all clinical state of the individual. For example, in an elderly individual 
with robust cognition and few major health issues, the glycemic goal 
may be the same as in younger individuals (HbA1c target <7.0%), while 
in an individual with impaired cognition or a resident of a long-term 
facility, the major goal is avoidance of hypoglycemia and severe hyper­
glycemia (Table 416-4).
Large clinical trials (UKPDS, Action to Control Cardiovascular Risk 
in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: 
Preterax and Diamicron MR Controlled Evaluation [ADVANCE], 
Veterans Affairs Diabetes Trial [VADT]; DCCT/EDIC study in type 1 
DM; see Chap. 417) examined glycemic control in type 2 DM in indi­
viduals with low risk of ASCVD, a high risk of ASCVD, or established 
ASCVD. Overall, these studies indicate that (1) improved glycemic 
control reduces microvascular complications of diabetes; (2) improved 
glycemic control in individuals early in the course of type 1 DM led to 
reduction in nonfatal myocardial infarction, stroke, and cardiovascular 
death almost two decades after the period of improved glycemic con­
trol had ended; (3) intense glycemic control is beneficial for ASCVD in

TABLE 416-4  Glycemic Goals for Adults with Diabetesa
INDEX OF GLYCEMIC CONTROL
ADULTS (NONPREGNANT)
HbA1c
<7.0% (53 mmol/mol)
<7.0–7.5% (53–57 mmol/mol)
<8.0% (64 mmol/mol)
<8.5% (64 mmol/mol) with 
avoidance of hypoglycemia
 
>70% within 3.9–10.0 
mmol/L (70–180 mg/dL)c 
CGM metrics
% Time within indicated rangec 
 
Time below 3.9 mmol/L (70 mg/dL) but 
>54 mg/dL (>3 mmol/L) indicating level 1 or 
mild hypoglycemia)c 
Time below <54 mg/dL (<3 mmol/L) indicating 
level 2 or moderate/severe hypoglycemiac 
Glucose variability, % coefficient of 
variationd
<4%
 
       
<1%
       
≤36%
Preprandial capillary blood glucose
4.4–7.2 mmol/L 
(80–130 mg/dL)
Postprandial capillary blood glucosee
<10.0 mmol/L (<180 mg/dL)
<11.1 mmol/L (200 mg/dL) 
<13.9 mmol/L (250 mg/dL) 
<13.9 mmol/L (250 mg/dL)  
aGlycemic goal should be individualized for each patient; elderly >65 years. Some suggest different glycemic targets such as the American Association of Clinical 
Endocrinology (AACE), which suggests an HbA1c goal <6.5%, and American College of Physicians (ACP), which suggests a goal of 7–8%. bMultiple chronic illnesses, 
impaired activities of daily living, or cognitive impairment. cOverall poor health with complex comorbidities, cognitive impairment, or limited life span or resident in skilled 
nursing facility or a long-term care facility. dAs determined by CGM. See Chap. 418 for hypoglycemia definitions. e1–2 h after beginning of a meal.
Abbreviations: CGM, continuous glucose monitoring; HbA1c, hemoglobin A1c; N/A, not applicable to glycemia management.
Source: Adapted from several sources, including Diabetes Care 47:S111, 2024, and Diabetes Care 47:S244, 2024.
some populations with type 2 DM; and (4) hypoglycemia in high-risk 
populations with ASCVD should be avoided as it is associated with 
cardiovascular events and mortality. Thus, near-normal glycemia is 
not the goal in this population (Table 416-4). As will be discussed 
later, these studies were conducted before the advent of glucagon-like 
peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and sodium-glucose 
cotransporter 2 (SGLT-2) inhibitors, which have greater cardiovascular 
benefit than agents utilized in these earlier clinical trials.
■
■TYPE 1 DIABETES MELLITUS
General Aspects 
The goal is to design and implement an insulin 
regimen that mimics physiologic insulin secretion. Because individu­
als with type 1 DM partially or completely lack endogenous insulin 
production, administration of basal insulin is essential for regulat­
ing glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis 
(e.g., fine-tuning hepatic and adipose metabolism). Likewise, insulin 
replacement for meals should be appropriate for the carbohydrate 
intake and insulin sensitivity, promoting normal glucose utilization 
and storage. The continued increase in insulin costs over the past 
decade has been a major challenge for individuals with diabetes. Recent 
federal and state legislative action has begun to address this; however, 
the cost of insulin continues to be a major issue in diabetes care.
Intensive Management of Glycemia 
Intensive insulin therapy 
in type 1 DM seeks to achieve normal or near-normal glycemia. This 
goal requires the integration of multiple resources and efforts, includ­
ing thorough and continuing patient education, comprehensive record­
ing of glucose measurements and nutrition intake by the patient, and a 
variable insulin regimen that matches carbohydrate intake and exercise 
and insulin dose. Insulin is delivered subcutaneously via multiple 
daily injections (MDIs), continuous subcutaneous insulin infusion 
(CSII), a sensor-augmented system, or an automated insulin delivery 
system (AID). Insulin delivery by CSII requires a manual entry into 
the pump to alter the basal infusion rate or direct an insulin bolus. 
A sensor-augmented system has a pump and a CGM device, assisted 
by an algorithm that suspends the insulin infusion when the glucose 
is low or predicted to be low in 30 min based on the glucose trajec­
tory. An AID system, using a pump, CGM, and algorithm, increases 
or decreases the basal insulin infusion rate in real time based on CGM 
data. Some AID systems deliver a correction insulin bolus, but these 

ELDERLY ADULTS WITH 
COMPLEX COMORBIDITIES, 
POOR HEALTH, OR IMPARIED 
COGNITIONc
ELDERLY ADULTS WITH 
INTACT COGNITION AND 
FUNCTIONAL STATUS
ELDERLY ADULTS 
WITH OTHER SERIOUS 
COMORBIDITIESb
 
>70% within 4.4–10.0 mmol/L 
(80–180 mg/dL)c  
 
>50% within 5.5–10.0 mmol/L 
(100–200 mg/dL)c 
 
>40% within 6.7–12.2 mmol/L 
(120–220 mg/dL)c 
Diabetes Mellitus: Management and Therapies  
CHAPTER 416
<1%
 
       
<1%
       
<33%
0%
  
      
0%
       
N/A
0%
  
      
0%
       
N/A
4.4–7.2 mmol/L 
(80–130 mg/dL)
5.0–8.3 mmol/L 
(90–150 mg/dL)
5.6–10.0 mmol/L 
(100–180 mg/dL)
TABLE 416-5  Properties of Insulin Preparationsa
TIME OF ACTION
EFFECTIVE 
DURATION, h
PREPARATION
ONSET, h
PEAK, h
Rapid-acting, injected
  Aspartb
<0.25
0.5–1.5
3–5
  Glulisine
<0.25
0.5–1.5
3–5
  Lisproc
<0.25
0.5–1.5
3–5
Short-acting, injected
 
 
 
  Regulard
0.5–1.0
2–3
4–8
Rapid-acting, inhaled
 
 
 
  Inhaled human insulin
<0.25
1–2

Intermediate-acting, injected
 
 
 
  NPH
2–4
4–10
10–16
Long-acting or Ultralong-acting, injected
  Degludec
1–9
—e
42f
  Glargineg
2–4
—e
20–24
Examples of insulin combinationsh
  75/25–75% protamine lispro, 25% lispro
<0.25
Duali
10–16
  70/30–70% protamine aspart, 30% aspart
<0.25
Duali
15–18
  50/50–50% protamine lispro, 50% lispro
<0.25
Duali
10–16
  70/30–70% NPH, 30% regular
0.5–1
Duali
10–16
Combination of long-acting insulin and 
GLP-1RA
See text
 
 
aInjectable insulin preparations (with exception of inhaled formulation) available in 
the United States; others are available in the United Kingdom and Europe. Standard 
formulations are U-100 (100 units of insulin per mL solution). Insulin detemir, a 
long-acting insulin, will soon not be available and is not included in this table. 
bFormulation with niacinamide (vitamin B3) has a slightly more rapid onset and 
offset. cLispro-aabc formulation has a slightly more rapid onset and offset. Several 
forms of insulin (e.g., degludec, insulin lispro, Lispro-aabc) are also available 
in U-200 concentration. dFormulation also available in U-500 concentration with 
delayed onset and offset. eDegludec and glargine have minimal peak activity. 
dDuration is dose-dependent. gFormulation also available in U-300 concentration, 
which has longer duration. hOther insulin combinations are available. iDual: two 
peaks—one at 2–3 h and the second one several hours later.
Abbreviations: GLP-1RA, glucagon-like peptide 1 receptor agonist; NPH, neutral 
protamine Hagedorn.

are not a completely closed-loop system as the patient must input 
carbohydrate intake data and projected activity or exercise. This is a 
rapidly evolving area of type 1 DM–related technology, algorithms, 
and artificial intelligence, with some individuals having considerable 
success using do-it-yourself (DIY) approaches that are based in the 
type 1 DM user community and not U.S. Food and Drug Administra­
tion (FDA) approved.

The benefits of intensive insulin therapy and improved glycemic 
control include a reduction in the acute metabolic and chronic micro­
vascular complications of DM. From a psychological standpoint, the 
patient experiences greater control over their diabetes and often notes 
an improved sense of well-being, greater flexibility in the timing and 
content of meals, and the capability to alter insulin dosing with exer­
cise. Intensive insulin therapy prior to and during pregnancy reduces 
the risk of fetal malformations and morbidity. Intensive insulin therapy 
is encouraged in newly diagnosed patients with type 1 DM, including 
the use of CGM. Although intensive management confers impressive 
benefits, it may not be appropriate at all times for all individuals with 
T1D (Table 416-4). Some individuals with diabetes prefer subcutane­
ous, intermittent insulin injections combined with a CGM to being 
connected continuously to an insulin infusion device, highlighting the 
need for individualized diabetes care.
PART 12
Endocrinology and Metabolism
Insulin Preparations 
Insulin preparations are generated by 
recombinant DNA technology and consist of the amino acid sequence 
of human insulin or variations thereof. In the United States, most 
insulin is formulated as U-100 (100 units/mL); short-acting insulin 
formulated as U-200 (200 units/mL; lispro) and long-acting as U-300 
(300 units/mL; glargine) are available in order to limit injection vol­
umes for patients with high insulin requirements. Regular insulin 
formulated as U-500 (500 units/mL) is sometimes used in patients with 
severe insulin resistance. Human insulin has been formulated with dis­
tinctive pharmacokinetics (regular and neutral protamine Hagedorn 
[NPH] insulin have the native insulin amino acid sequence) or geneti­
cally modified to alter insulin absorption and hence the onset and 
duration of insulin action. Insulins can be classified as rapid-acting, 
short-acting, intermediate-acting, long-acting, or ultralong-acting 
(Table 416-5; Fig. 416-1D). For example, one rapid-acting insulin 
formulation, insulin lispro, is an insulin analogue in which the 28th 
and 29th amino acids (lysine and proline) on the insulin B chain have 
been reversed. Insulin aspart and insulin glulisine are modified insulin 
analogues with properties similar to lispro. A biosimilar version of lis­
pro is available. These insulin analogues have full biologic activity but 
less tendency for self-aggregation, resulting in more rapid absorption 
and onset of action and a shorter duration of action. These character­
istics are particularly advantageous for allowing entrainment of insulin 
injection and action to the rising plasma glucose levels following meals. 
The shorter duration of action also appears to be associated with a 
decreased number of hypoglycemic episodes, primarily because the 
decay of insulin action corresponds to the decline in plasma glucose 
after a meal. Thus, insulin aspart, lispro, or glulisine is preferred over 
regular insulin for prandial coverage. Insulin glargine is a long-acting 
biosynthetic human insulin that differs from normal insulin in that 
asparagine is replaced by glycine at amino acid 21, and two arginine 
residues are added to the C terminus of the B chain, leading to the for­
mation of microprecipitates at physiologic pH in subcutaneous tissue. 
Compared to NPH insulin, the onset of insulin glargine action is later, 
the duration of action is longer (~24 h), and there is a less pronounced 
peak. A lower incidence of hypoglycemia, especially at night, has been 
reported with insulin glargine when compared to NPH insulin. A 
biosimilar version is available. Twice-daily injections of glargine are 
sometimes required to provide optimal 24-h basal insulin coverage. 
Because of modification and extension of the carboxy-terminus of 
the B chain, insulin degludec forms multihexamers in subcutaneous 
tissue and binds albumin, prolonging its duration of action (>42 h); 
it provides similar glycemic control as glargine but with less frequent 
nocturnal and severe hypoglycemia. Other modified insulins, such as 
one with a duration of action of 1 week, are in clinical trials and will 
likely soon be available.

Basal insulin requirements, largely fine-tuning hepatic glucose 
metabolism, are provided by long-acting insulin formulations (NPH 
insulin, insulin glargine, or insulin degludec) (Fig. 416-1D; Table 416-5). 
These are usually prescribed with rapid-acting insulin in an attempt to 
mimic physiologic insulin release with meals (prandial insulin require­
ment). In the past, NPH and short-acting insulin formulations were 
mixed in the same syringe, but this is not common now. The miscibil­
ity of some insulins allows for the production of combination insulins 
that contain 70% NPH and 30% regular (70/30), or equal mixtures of 
NPH and regular (50/50). By including the insulin analogue mixed 
with protamine, several additional combinations have a rapid-acting 
and long-acting profile (Table 416-5; Fig. 416-1D). Although more 
convenient for the patient (only two injections a day), combination 
insulin formulations do not allow independent adjustment of shortacting and long-acting activity and are not appropriate in type 1 DM 
management. Most insulin formulations are available as insulin “pens,” 
which are more convenient and accurate than syringes; “smart pens” 
can assist with insulin dose tracking. Insulin delivery by inhalation to 
provide mealtime insulin has a more rapid onset of action than insulin 
injected subcutaneously. Prior to its use, the forced expiratory volume 
in 1 s (FEV1) should be measured, and then monitored periodically 
during treatment. Inhaled insulin can cause bronchospasm and cough 
and should not be used by individuals with lung disease or those who 
smoke. Long-acting insulin/GLP-1RA combinations in fixed doses 
(degludec plus liraglutide or glargine plus lixisenatide) are effective and 
are associated with less weight gain.
Insulin Regimens 
There is considerable patient-to-patient varia­
tion in the peak and duration. In all regimens, long-acting insulins 
(NPH, glargine, or degludec) supply basal insulin, whereas regular, 
insulin aspart, glulisine, or lispro provide prandial insulin (Fig. 416-1D; 
Table 416-5). Rapid-acting insulin analogues should be injected just 
before (<10 min) and regular insulin 30–45 min prior to a meal. 
Sometimes rapid-acting insulin analogues are injected just after a meal 
(gastroparesis, unpredictable food intake). A consensus statement from 
ADA and the European Association for the Study of Diabetes provides 
guidance about different insulin regimens used in type 1 DM.
A shortcoming of current insulin regimens is that injected insulin 
immediately enters the systemic circulation, whereas endogenous insu­
lin is secreted into the portal venous system. Thus, exogenous insulin 
administration exposes the liver to subphysiologic insulin levels, and 
requires achieving higher peripheral levels of insulin to restrain hepatic 
glucose production. No current insulin regimen reproduces the precise 
insulin secretory pattern of the pancreatic islet. However, the most 
physiologic regimens entail more frequent insulin injections, greater 
reliance on rapid-acting insulin, and CGM or more frequent BGM. In 
general, individuals with type 1 DM require 0.4–1.0 units/kg per day of 
insulin divided into multiple doses, with 30–50% of daily insulin given 
as basal insulin with the remainder as prandial insulin. All individuals 
with type 1 DM should have a filled glucagon prescription (Chap. 416).
MDI regimens refer to the combination of basal insulin and bolus 
insulin (preprandial rapid-acting insulin). The timing and dose of 
rapid-acting, preprandial insulin are altered to accommodate the CGM 
or BGM results, anticipated food intake, and physical activity. Such 
regimens offer the patient with type 1 DM more flexibility in terms of 
lifestyle and the best chance for achieving near normoglycemia. Most 
often, basal insulin with glargine or degludec is used in conjunction 
with preprandial lispro, glulisine, or insulin aspart. The dose of longacting insulin is adjusted based on the fasting glucose. The insulin 
aspart, glulisine, or lispro dose is based on individualized algorithms 
that integrate the preprandial glucose and the anticipated carbohydrate 
intake. To determine the meal component of the preprandial insulin 
dose, the patient uses an insulin-to-carbohydrate ratio (a common 
ratio for type 1 DM is 1 unit/10–15 g of carbohydrate, but this must 
be determined for each individual). To this insulin dose is added the 
supplemental or correcting insulin based on the preprandial blood 
glucose (one formula uses 1 unit of insulin for every 1.6–3.3 mmol/L 
[30–60 mg/dL] over the preprandial glucose target; this correction 
factor can be estimated from 1500/[total daily insulin dose]). Such

TABLE 416-6  Agents Used for Treatment of Type 1 or Type 2 Diabetes
MECHANISM OF 
ACTION
EXAMPLESa
HBA1C 
REDUCTION (%)b
AGENT-SPECIFIC 
ADVANTAGES
 
Oral
 
 
 
 
 
 
Metformin
1–2
Weight neutral, do not 
cause hypoglycemia, 
inexpensive, extensive 
experience, modest 

↓ CV events
Biguanidesc*
↓ Hepatic glucose 
production, ↑ insulin 
sensitivity, influence 
gut function
Sodium-glucose 
cotransporter 2 
(SGLT-2) inhibitorsc***
Canagliflozin, 
dapagliflozin, 
empagliflozin, 
ertugliflozin, 
bexagliflozin, 
sotagliflozin 
(SGLT-1/2 
inhibitor)
0.5–1.0
Renal protective, 

↓ CV events, ↓ heart 
failure, do not cause 
hypoglycemia, modest 
↓ weight and blood 
pressure
↑ Renal glucose 
excretion
Dipeptidyl peptidase-4 
inhibitorsc***
Prolong endogenous 
GLP-1 action; 

↑ insulin, ↓ glucagon
Alogliptin, 
linagliptin, 
saxagliptin, 
sitagliptin, 
vildagliptin
0.5–0.8
Well tolerated, do not 
cause hypoglycemia
Insulin 
secretagogues: 
Sulfonylureasc*
↑ Insulin secretion
Glimepiride, 
glipizide, 
gliquidone, 
glyburide
1–2
Short onset of action, 
lower postprandial 
glucose, inexpensive
Insulin 
secretagogues: 
Nonsulfonylureasc***
↑ Insulin secretion
Nateglinide, 
repaglinide
0.5–1.0
Short onset of action, 
lower postprandial 
glucose
Thiazolidinedionesc**** ↓ Insulin resistance, 

Pioglitazone, 
rosiglitazone
0.5–1.4
Lower insulin 
requirements
↑ glucose utilization
Acarbose, 
miglitol
0.5–0.8
Reduce postprandial 
glycemia
α-Glucosidase 
inhibitorsc**
↓ GI glucose 
absorption
Parenteral/Oral (GLP-1RA-related agents)
Dulaglutide, 
exenatide, 
liraglutide, 
lixisenatide, 
semaglutide 
(oral formulation 
available)
0.5–1.0
Weight loss, do not 
cause hypoglycemia 
(unless combined 
with another insulin 
secretagogue or insulin); 
↓ CV events, modest 
renoprotection
GLP-1RAsc***
↑ Insulin, ↓ glucagon, 
slow gastric 
emptying, satiety
GLP-1/GIP receptor 
agonistc***
↑ Insulin, ↓ glucagon, 
slow gastric 
emptying, satiety
Tirzepatide
1.8-2.4
Weight loss, do not 
cause hypoglycemia 
(unless combined with 
insulin secretagogue or 
insulin); ↓ CV events
Parenteral
 
 
 
 
 
 
Amylin agonistsc,d***
Slow gastric 
emptying, ↓ glucagon
Pramlintide
0.25–0.5
Reduce postprandial 
glycemia, weight loss
See text and 
Table 416-4
Not limited
Known safety profile
Injection, weight gain, 
hypoglycemia
Insulinc,d****
↑ Glucose utilization, 
↓ hepatic glucose 
production, and other 
anabolic actions
Medical nutrition 
therapy and physical 
activityc*
Low-calorie, 
carbohydratecontrolled diet, 
exercise
1–3
Other health benefits
Compliance difficult, 
long-term success of 
sustained weight loss low
↓ Insulin resistance, 
↑ insulin secretion
aExamples are approved for use in the United States; others are available in other countries. Examples may not include all agents in the class. bHbA1c reduction (absolute) 
depends partly on starting HbA1c. cUsed for treatment of type 2 diabetes. dUsed in conjunction with insulin for treatment of type 1 diabetes. Cost of agent in the United 
States: *low, **moderate, ***high, ****variable. eDegree of risk uncertain, avoid in individuals with risk factors for pancreatitis. fRisk of euglycemic DKA in patients with insulin 
deficiency.
Note: Some agents used to treat type 2 diabetes are not included in table (see text).
Abbreviations: CHF, congestive heart failure; CV, cardiovascular; DKA, diabetic ketoacidosis; GFR, glomerular filtration rate; GI, gastrointestinal; GIP, gastric inhibitory 
polypeptide; GLP-1, glucagon-like peptide 1; GLP-1RA, glucagon-like peptide 1 receptor agonist; HbA1c, glycated hemoglobin A1c.

AGENT-SPECIFIC 
DISADVANTAGES
CONSIDERATIONS
Diarrhea, nausea, lactic 
acidosis, vitamin B12 
deficiency
Renal insufficiency (see 
text for GFR <30 mL/min), 
CHF, radiographic 
contrast studies, 
hospitalized patients, 
acidosis
Diabetes Mellitus: Management and Therapies  
CHAPTER 416
Increased risk genital 
mycotic infections and 
necrotizing fasciitis 
of perineum; polyuria, 
dehydration; increased 
risk of euglycemic DKAf 
(see text); exacerbate 
tendency to hyperkalemia
Moderate renal 
insufficiency; 
discontinue 3–4 days 
before surgery, during 
serious illness
Angioedema/urticarial 
and immune-mediated 
dermatologic effects; 
rarely associated with 
pancreatitis
Reduced dose with renal 
insufficiency
Hypoglycemia, weight 
gain
Renal/liver insufficiency
Hypoglycemia
Renal/liver insufficiency 
(except repaglinide)
Peripheral edema, CHF, 
weight gain, fractures, 
macular edema
CHF, renal/liver 
insufficiency
GI flatulence, elevated 
liver function tests
Renal/liver insufficiency
Nausea, GI intolerance; 
possibly associated with 
pancreatitise, possibly 
worsen retinopathy
Renal disease, agents 
that also slow GI motility; 
medullary carcinoma of 
thyroid, previous ileus
Nausea, GI intolerance, 
possibly associated 
pancreatitise, possibly 
worsen retinopathy
Renal disease, agents 
that also slow GI motility; 
medullary carcinoma 
of thyroid, pancreatic 
disease, history of 
gastroparesis
Agents that also slow GI 
motility
Injection, nausea, ↑ risk 
of hypoglycemia with 
insulin
Can be combined with 
most other agents
Other health benefits

calculations must be adjusted based on each individual’s sensitiv­
ity to insulin. CGM or BGM is essential for these types of insulin 
regimens.

AID is the preferred insulin delivery mechanism for most indi­
viduals with type 1 DM (Fig. 416-1), but cost and insurance coverage 
are critical considerations. To the basal insulin infusion, a prepran­
dial insulin (“bolus”) is delivered by the insulin infusion device based 
on instructions from the patient or an algorithm that incorporates 
the preprandial plasma glucose and anticipated carbohydrate intake. 
These sophisticated devices can accurately deliver small doses of 
insulin (microliters per hour) and have several advantages: (1) multi­
ple basal infusion rates can be programmed to accommodate noctur­
nal versus daytime basal insulin requirement; (2) basal infusion rates 
can be altered during periods of exercise; (3) different waveforms of 
insulin infusion with meal-related bolus allow better matching of 
insulin depending on meal composition; and (4) programmed algo­
rithms consider ongoing action of prior insulin administration and 
blood glucose values in calculating the insulin dose. As mentioned, 
the technology, algorithms, and integration of the different compo­
nents are changing rapidly, indicating the need to match these with 
patients’ desires, for instruction by a health professional with con­
siderable experience with insulin infusion devices, and for frequent 
patient interactions with the diabetes management team. Insulin 
infusion devices may present unique challenges, such as infection at 
the infusion site, unexplained hyperglycemia because the infusion 
set becomes obstructed, or diabetic ketoacidosis (DKA) if the insulin 
infusion device becomes disconnected. Because most physicians use 
lispro, glulisine, or insulin aspart in CSII or AID, the short half-life 
of these insulins quickly leads to insulin deficiency if the delivery 
system is interrupted. Essential to the safe use of infusion devices is 
thorough patient education, CGM or frequent BGM, and a backup 
plan for injecting long- and/or rapid-acting insulins in the event 
of insulin infusion device failure. CGM sensor-augmented insulin 
infusion devices integrate the information from the CGM to inform 
insulin delivery (Fig. 416-1). Currently, sensor communicating 
functions can interrupt basal insulin delivery during hypoglycemia 
(threshold suspension) or when hypoglycemia is anticipated (predic­
tive suspension), which may be particularly useful for preventing 
nocturnal hypoglycemia. Hybrid closed-loop systems can combine 
patient-directed preprandial boluses with automated adjustment 
of between-meal and basal insulin delivery based on CGM. Clini­
cal experience with closed-loop systems is rapidly increasing and 
expanding. Bihormonal infusion devices that deliver both insulin and 
glucagon are being tested.
PART 12
Endocrinology and Metabolism
Other Agents That Improve Glucose Control 
The role of 
amylin, a 37-amino-acid peptide co-secreted with insulin from pan­
creatic beta cells in normal glucose homeostasis is uncertain. However, 
based on the rationale that patients who are insulin deficient are also 
amylin deficient, an analogue of amylin (pramlintide) was created and 
found to reduce postprandial glycemic excursions in individuals with 
type 1 or type 2 DM taking insulin. Pramlintide injected just before a 
meal slows gastric emptying and suppresses glucagon but does not alter 
insulin levels. Pramlintide is approved for insulin-treated patients with 
type 1 or type 2 DM. The addition of pramlintide produces a modest 
reduction in the HbA1c and seems to dampen meal-related glucose 
excursions. In type 1 DM, pramlintide is started as a 15-μg SC injec­
tion before each meal and titrated up to a maximum of 30–60 μg as 
tolerated. In type 2 DM, pramlintide is started as a 60-μg SC injection 
before each meal and may be titrated up to a maximum of 120 μg. 
The major side effects are nausea and vomiting, and dose escalations 
should be slow to limit these side effects. Because pramlintide slows 
gastric emptying, it may influence absorption of other medica­
tions and should not be used in combination with other drugs that 
slow gastrointestinal (GI) motility. The rapid-acting insulin given 
before the meal should initially be reduced to avoid hypoglycemia 
and then titrated as the effects of the pramlintide become evident. 
Because pramlintide suppresses glucagon, it may worsen hypoglyce­
mia recovery and should not be used in patients with hypoglycemia 

Management of
Type 2 Diabetes
Screen for/manage
complications
of diabetes
• Retinopathy
• Nephropathy
• Neuropathy
• Cardiovascular
  disease
• Other complications
Treat associated 
conditions
   • Dyslipidemia
   • Hypertension
   • Obesity
Individualized
glycemic control
  • Diet/lifestyle
  • Exercise
  • Medication
FIGURE 416-2  Essential elements in comprehensive care of type 2 diabetes.
unawareness. GLP-1RAs and SGLT-2 inhibitors modestly improve 
the HbA1c in type 1 DM, but the SGLT-2 inhibitors increase the risk 
of DKA and in general should not be used.
■
■TYPE 2 DIABETES MELLITUS
General Aspects 
The goals of glucose-directed therapy for type 2 
DM are similar to those in type 1 DM and, likewise, should be individ­
ualized for each patient. Whereas glycemic control tends to dominate 
the management of type 1 DM, the care of individuals with type 2 DM 
must also include even greater attention to the treatment of conditions 
associated with type 2 DM (e.g., obesity, hypertension, dyslipidemia, 
ASCVD) and prevention/detection/management of DM-related com­
plications (Fig. 416-2; Chap. 417). Reduction in cardiovascular risk is 
of paramount importance because this is the leading cause of mortal­
ity in these individuals. One approach to pharmacology of glucosedirected therapies in type 2 DM is shown in Fig. 416-3.
Type 2 DM management should begin with MNT (discussed 
above). An exercise regimen to increase insulin sensitivity and promote 
weight loss should also be instituted. Pharmacologic approaches to 
the management of type 2 DM include oral glucose-lowering agents, 
insulin, and other agents that improve glucose control. Any therapy 
that improves glycemic control reduces “glucose toxicity” to beta cells 
and may improve endogenous insulin secretion. However, type 2 DM 
is a progressive disorder and ultimately requires multiple therapeutic 
agents and sometimes insulin.
Glucose-Lowering Agents 
Advances in the therapy of type 2 DM 
have led to glucose-lowering agents that target different pathophysi­
ologic processes in type 2 DM. Based on their mechanisms of action, 
glucose-lowering agents are subdivided into agents that increase insulin 
secretion, reduce glucose production, increase insulin sensitivity, act as a 
GLP-1 receptor agonist, or promote urinary excretion of glucose (Table 
416-6). Insulin is sometimes the initial glucose-lowering agent in type 2 
DM if there is severe hyperglycemia or the patient is catabolic.
BIGUANIDES  Metformin, representative of this class of agents, reduces 
hepatic glucose production and improves peripheral glucose utiliza­
tion slightly (Table 416-6) and is relatively low cost. Metformin acts 
in multiple tissues, but its mechanism of action remains incompletely 
defined. Metformin reduces fasting plasma glucose (FPG) and insulin 
levels, improves the lipid profile, and promotes modest weight loss. An 
extended-release form is available and may have fewer GI side effects 
(diarrhea, anorexia, nausea, metallic taste). Because of metformin’s 
relatively slow onset of action and GI symptoms with higher doses, 
the initial dose should be low and then escalated every 1–2 weeks to 
a maximally tolerated dose of 2000 mg daily. Metformin is effective 
as monotherapy and can be used in combination with other glucose 
lowering agents. The major toxicity of metformin, lactic acidosis, is 
very rare and can be prevented by careful patient selection. Vitamin 
B12 levels are lower during metformin treatment and should be moni­
tored. Metformin should not be used in patients with moderate renal 
insufficiency (glomerular filtration rate [GFR] <30 mL/min), any form 
of acidosis, unstable congestive heart failure (CHF), liver disease, or

severe hypoxemia. Metformin should be discontinued in hospitalized 
patients, in patients who can take nothing orally, and in those receiving 
radiographic contrast material. Insulin should be used as needed until 
metformin can be restarted.
INSULIN SECRETAGOGUES—AGENTS THAT AFFECT THE ATP-SENSITIVE 
K+ CHANNEL  Insulin secretagogues stimulate insulin secretion by 
interacting with the ATP-sensitive potassium channel on the beta 
cell (Chap. 415). These drugs are most effective in individuals with 
type 2 DM of relatively recent onset (<5 years) who have residual 
endogenous insulin production. Sulfonylureas reduce both fast­
ing and postprandial glucose and should be initiated at low doses 
and increased at 1- to 2-week intervals based on CGM or BGM. 
Glimepiride and glipizide can be given in a single daily dose and are 
preferred over glyburide, especially in the elderly. Repaglinide and 
nateglinide are not sulfonylureas but also interact with the ATPsensitive potassium channel. Because of their short half-life, these 
glinide agents are given immediately before each meal to reduce 
meal-related glucose excursions.
Insulin secretagogues, especially the longer-acting ones, have the 
potential to cause hypoglycemia, especially in elderly individuals. 
Hypoglycemia is usually related to delayed meals, increased physical 
activity, alcohol intake, or renal insufficiency. Individuals who ingest 
an overdose of some agents develop prolonged and serious hypogly­
cemia and should be monitored closely in the hospital (Chap. 418). 
Most sulfonylureas are metabolized in the liver to compounds (some 
of which are active, such as those of glyburide and the glinide nateg­
linide) that are cleared by the kidney. Thus, their use in individuals 
with significant hepatic or renal dysfunction is not advisable. For 
patients with chronic kidney disease the glinide repaglinide may be 
used with caution. Weight gain, a common side effect of sulfonylurea 
therapy, results from the increased insulin levels and improvement in 
glycemic control. Some sulfonylureas have significant drug interac­
tions with alcohol and some medications including warfarin, aspirin, 
ketoconazole, α-glucosidase inhibitors, and fluconazole. Sulfonylureas 
interact with some antibiotics such as fluoroquinolones, clarithromy­
cin, sulfamethoxazole-trimethoprim, metronidazole, and fluconazole, 
so the sulfonylureas should be discontinued when these antimicrobials 
are added to the patient’s medications.
GLP-1RAS ALONE OR IN COMBINATION WITH GIP RECEPTOR AGONIST 

“Incretins” amplify glucose-stimulated insulin secretion and suppress 
inappropriate glucagon secretion (Chap. 415). Agents that either act as 
a GLP-1RA or enhance endogenous GLP-1 activity are approved for the 
treatment of type 2 DM and obesity (Table 416-6). Agents in this class 
do not cause hypoglycemia because of the glucose-dependent nature of 
incretin-stimulated insulin secretion (unless there is concomitant use 
of an agent that can lead to hypoglycemia—sulfonylureas, etc.). GLP1RAs increase glucose-stimulated insulin secretion, suppress glucagon, 
and slow gastric emptying, but the GLP-1 receptor is expressed in 
several tissues, including the brain. These agents promote weight loss 
(see Chaps. 413 and 414) and reduce cardiovascular events in those 
with type 2 DM and ASCVD (see Chap. 417 for additional discussion 
about the effect on diabetes-related complications). Thus, these agents 
are particularly advantageous in type 2 DM. Long-acting GLP-1RAs 
include sustained-release exenatide, dulaglutide, lixisenatide, and sema­
glutide, all administered weekly, and are the ones most commonly used. 
Daily oral semaglutide is available that allows gastric absorption to 
avoid proteolytic degradation in the small intestine. All are modified to 
avoid enzymatic inactivation by dipeptidyl peptidase IV (DPP-4) in the 
circulation. Higher doses of liraglutide and semaglutide than used for 
glucose-lowering effects are effective for weight-loss therapy for obesity. 
Liraglutide treatment has also been associated with a decrease in cardio­
vascular disease (CVD) events in patients with type 2 DM and established 
CVD and with lower rates of diabetic kidney disease. In similar patient 
populations, semaglutide treatment has been associated with fewer 
CVD events and reduced diabetic kidney disease, but with an increased 
rate of retinopathy-related complications. Dulaglutide treatment has 
been associated with both a reduction in CVD events and a reduc­
tion in composite microvascular retinopathy and nephropathy-related 

complications primarily driven by prevention of renal events. Treatment 
with GLP-1RAs should start at a low dose to minimize initial side effects 
(nausea being the limiting one). GLP-1RAs can be used as combination 
therapy with metformin, sulfonylureas, and thiazolidinediones. Some 
patients taking insulin or an insulin secretagogue may require a reduc­
tion in those agents to prevent hypoglycemia. The major side effects are 
nausea and vomiting. Some formulations carry a black box warning from 
the FDA because of an increased risk of thyroid C-cell tumors in rodents 
and are contraindicated in individuals with medullary carcinoma of the 
thyroid or multiple endocrine neoplasia. Because GLP-1RAs slow gastric 
emptying, they may influence the absorption of other drugs. Whether 
GLP-1RAs enhance beta cell survival or promote beta cell proliferation 
is not known. It is not clear if these agents alter the natural history of 
type 2 DM.

Diabetes Mellitus: Management and Therapies  
CHAPTER 416
Tirzepatide, a once-weekly subcutaneous injectable peptide engi­
neered to have dual agoniism at both the glucose-dependent insulino­
tropic polypeptide receptor (GIPR) and the GLP-1R, promotes greater 
weight loss than a GLP-1RA alone. Additional dual-acting and tripleacting molecules are in development and clinical trials.
DPP-4 inhibitors inhibit degradation of native GLP-1 and GIP and 
thus enhance the incretin effect. DPP-4, which is widely expressed on 
the cell surface of endothelial cells and some lymphocytes, degrades a 
wide range of peptides (not incretin specific). DPP-4 inhibitors pro­
mote insulin secretion in the absence of hypoglycemia or weight gain 
and appear to have a preferential effect on postprandial blood glucose. 
The levels of GLP-1 action in the patient are greater with the GLP-1RAs 
than with DPP-4 inhibitors. DPP-4 inhibitors are used either alone or 
in combination with other oral agents in type 2 DM. Reduced doses 
should be given to patients with renal insufficiency. Allergy, including 
rash, hypersensitivity reactions (including anaphylaxis, angioedema, 
and Stevens-Johnson syndrome), and severe joint pain have been 
reported in association with DPP-4 inhibitors. There is evidence con­
cerning a potentially increased risk for acute pancreatitis with GLP1RAs and less so with DPP-4 inhibitors. It is prudent to avoid these 
agents in patients with pancreatic disease or with other significant risk 
factors for acute pancreatitis (e.g., heavy alcohol use, severely elevated 
serum triglycerides, hypercalcemia).
SGLT-2 INHIBITORS  These agents (Table 416-6) lower the blood glu­
cose by selectively inhibiting this co-transporter, which is expressed 
almost exclusively in the proximal convoluted tubule in the kidney. 
This inhibits glucose reabsorption, lowers the renal threshold for 
glucose excretion, and leads to increased urinary glucose loss. Thus, 
the glucose-lowering effect is insulin independent and not related to 
changes in insulin sensitivity or secretion. The loss of urinary glucose 
may promote modest weight reduction. Since these agents also impair 
proximal reabsorption of sodium, their use is associated with a diuretic 
effect and a 3- to 6-mmHg reduction in systolic blood pressure. Due to 
the increased urinary glucose, urinary and genital mycotic infections 
are more common in both men and women, and the diuretic effect 
can lead to reduced intravascular volume and acutely impaired kidney 
function. Inhibition of SGLT-2 may lead to increased glucagon and, 
consequently, liver production of glucose and ketones. Euglycemic 
DKA may occur during illness or when ongoing glucosuria masks 
stress-induced requirements for insulin. Patients should be educated 
about this possibility, and providers should be vigilant about detec­
tion. These agents should not be prescribed for patients with type 1 
DM or pancreatogenic forms of DM associated with insulin deficiency. 
Empagliflozin or canagliflozin reduces ASCVD events and all-cause 
cardiovascular mortality in patients with type 2 DM and established 
ASCVD. SGLT-2 inhibitors may reduce hospitalization for CHF. 
Empagliflozin, canagliflozin, and dapagliflozin have all been shown to 
reduce progression of diabetic kidney disease but should not be initi­
ated in patients with stage 3b chronic kidney disease (CKD; estimated 
GFR [eGFR] <45 mL/min per 1.73 m2) and should not be used in 
stage 4 CKD (eGFR <30 mL/min per 1.73 m2). A possible increased 
risk of bladder cancer has been seen with dapagliflozin. The impact of 
SGLT-2 inhibitors on diabetes-related complications is discussed in 
Chap. 417 and below.

THIAZOLIDINEDIONES  Thiazolidinediones (Table 416-6) reduce 
insulin resistance by binding to the peroxisome proliferator-activated 
receptor γ (PPAR-γ) nuclear receptor (which forms a heterodimer with 
the retinoid X receptor). The PPAR-γ receptor is found at highest levels 
in adipocytes but is expressed at lower levels in many other tissues. 
Agonists of this receptor regulate a large number of genes, promote 
adipocyte differentiation, reduce hepatic fat accumulation, and pro­
mote fatty acid storage. Thiazolidinediones promote a redistribution 
of fat from central to peripheral locations. Circulating insulin levels 
decrease with use of the thiazolidinediones, indicating a reduction in 
insulin resistance.

Rosiglitazone raises low-density lipoprotein (LDL), high-density 
lipoprotein (HDL), and triglycerides slightly. Pioglitazone raises HDL to 
a greater degree and LDL to a lesser degree but lowers triglycerides. The 
clinical significance of the lipid changes with these agents is not known.
PART 12
Endocrinology and Metabolism
Thiazolidinediones are associated with weight gain (2–3 kg), a small 
reduction in the hematocrit, and a mild increase in plasma volume. 
Peripheral edema and CHF are more common in individuals treated 
with these agents. These agents are contraindicated in patients with 
hepatic insufficiency or CHF (class III or IV). The FDA has issued an 
alert that rare patients taking these agents may experience a worsening 
of diabetic macular edema. An increased risk of fractures has been 
noted in postmenopausal women taking these agents. Thiazolidinedio­
nes have been shown to induce ovulation in premenopausal women 
with polycystic ovary syndrome. Women should be warned about the 
risk of pregnancy because the safety of thiazolidinediones in pregnancy 
is not established. According to an FDA review, pioglitazone may be 
associated with an increased risk of bladder cancer. In one study, pio­
glitazone lowered the risk for recurrent stroke or myocardial infarction 
in insulin-resistant individuals without diabetes who had a prior stroke 
or transient ischemic attack.
`-GLUCOSIDASE INHIBITORS  α-Glucosidase inhibitors reduce post­
prandial hyperglycemia by delaying glucose absorption (Table 416-6). 
Postprandial hyperglycemia, secondary to impaired hepatic and periph­
eral glucose disposal, contributes significantly to the hyperglycemic state 
in type 2 DM. These drugs, taken just before each meal, reduce glucose 
absorption by inhibiting the enzyme that cleaves oligosaccharides into 
simple sugars in the intestinal lumen. Therapy should be initiated at a 
low dose with the evening meal and increased to a maximal dose over 
weeks to months. The major side effects (diarrhea, flatulence, abdominal 
distention) are related to increased delivery of oligosaccharides to the 
large bowel and can be reduced somewhat by gradual upward dose titra­
tion. α-Glucosidase inhibitors may increase levels of sulfonylureas and 
increase the incidence of hypoglycemia. Simultaneous treatment with 
bile acid resins and antacids should be avoided. These agents should not 
be used in individuals with inflammatory bowel disease, gastroparesis, or 
a serum creatinine >177 μmol/L (2 mg/dL). This class of agents is not as 
potent as other oral agents in lowering the HbA1c but is unique because 
it reduces the postprandial glucose rise. If hypoglycemia from other 
diabetes treatments occurs while taking these agents, the patient should 
consume glucose because the degradation and absorption of complex 
carbohydrates will be slowed.
OTHER THERAPIES FOR TYPE 2 DM  • 
Bile Acid–Binding Resins 

Evidence indicates that bile acids, by signaling through nuclear recep­
tors, may have a role in metabolism. Bile acid metabolism is abnormal 
in type 2 DM. The bile acid–binding resin colesevelam has been 
approved for the treatment of type 2 DM (already approved for treat­
ment of hypercholesterolemia). The role of this class of drugs in the 
treatment of type 2 DM is not yet defined.
Bromocriptine  A formulation of the dopamine receptor agonist bro­
mocriptine (Cycloset) has been approved by the FDA for the treat­
ment of type 2 DM. However, its role in the treatment of type 2 DM 
is uncertain.
INSULIN THERAPY IN TYPE 2 DM  Insulin should be considered for ini­
tial therapy in type 2 DM, particularly in lean individuals or those with 
severe weight loss, in individuals with underlying renal or hepatic dis­
ease that precludes oral glucose-lowering agents, or in individuals who 

are hospitalized or acutely ill. Insulin therapy is ultimately required 
by a substantial number of individuals with type 2 DM because of the 
progressive nature of the disorder and the relative insulin deficiency 
that develops with long-standing diabetes. Both physician and patient 
reluctance often delay the initiation of insulin therapy, but glucose 
control and individual well-being are improved by insulin therapy in 
patients who have not reached their glycemic target.
Because endogenous insulin secretion is capable of providing some 
coverage of mealtime caloric intake, insulin is usually initiated in a 
single dose of long-acting insulin (0.1–0.4 U/kg per day), given in the 
evening or just before bedtime (NPH, glargine, or degludec). Because 
fasting hyperglycemia and increased hepatic glucose production are 
prominent features of type 2 DM, bedtime insulin is more effective in 
clinical trials than a single dose of morning insulin. Glargine given 
at bedtime has less nocturnal hypoglycemia than NPH insulin. Some 
physicians prefer a relatively low, fixed starting dose of long-acting 
insulin (10–15 units) or a weight-based dose (0.1 units/kg). The insulin 
dose may then be adjusted in 10–20% increments as dictated by CGM 
or BGM results. Both morning and bedtime long-acting insulin may 
be used in combination with oral glucose-lowering agents. Initially, 
basal insulin may be sufficient, but often prandial insulin coverage with 
multiple insulin injections is needed as diabetes progresses (see insulin 
regimens used for type 1 DM). Other insulin formulations that have a 
combination of rapid-acting and long-acting insulin (Table 416-5) are 
sometimes used in patients with type 2 DM because of convenience but 
do not allow independent adjustment of rapid-acting and long-acting 
insulin dose and often do not achieve the same degree of glycemic 
control as basal/bolus regimens. AID in selected individuals with type 
2 DM should be considered, especially in those who are insulindeficient. CGM should be used in all individuals taking insulin.
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT  The level of hyper­
glycemia and the patient’s individualized goal (see “Establishment 
of Target Level of Glycemic Control”) should influence the initial 
choice of therapy. Patients with mild hyperglycemia (FPG <7.0–
11.0 mmol/L [126–199 mg/dL]) often respond well to a single, oral 
glucose-lowering agent, while those with moderate hyperglycemia 
(FPG 11.1–13.9 mmol/L [200–250 mg/dL]) will usually require more 
than one oral agent or insulin. Patients with more severe hyperglyce­
mia (FPG >13.9 mmol/L [250 mg/dL]) may respond partially but are 
unlikely to achieve normoglycemia with oral therapy. Insulin can be 
used as initial therapy in individuals with severe hyperglycemia (FPG 
<13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptom­
atic from the hyperglycemia. This approach is based on the rationale 
that more rapid glycemic control will reduce “glucose toxicity” to the 
islet cells, improve endogenous insulin secretion, and possibly allow 
oral glucose-lowering agents to be more effective. If this occurs, the 
insulin may be discontinued. Treatment algorithms by several profes­
sional societies (ADA/ European Association for the Study of Diabetes 
[EASD], International Diabetes Federation, American Association of 
Clinical Endocrinology) suggest metformin as initial therapy because 
of its efficacy, known side effect profile, and low cost (Fig. 416-3). 
Initiation of pharmacologic therapy should be accompanied by an 
emphasis on lifestyle modification (e.g., MNT, increased physical activ­
ity, and weight loss). Metformin’s advantages are that it promotes mild 
weight loss, lowers insulin levels, and improves the lipid profile slightly. 
Based on CGM or BGM results and the HbA1c, the dose of metformin 
should be increased until the glycemic target is achieved or the maxi­
mum dose is reached. GLP-1RAs and SGLT-2 inhibitors are increasing 
in use as evidence accumulates for CVD and CKD benefits, in addition 
to weight loss and glucose-lowering effects.
Insulin secretagogues, biguanides, α-glucosidase inhibitors, thia­
zolidinediones, GLP-1RAs, DPP-4 inhibitors, SGLT-2 inhibitors, and 
insulin are approved for monotherapy of type 2 DM. Although each 
class of oral glucose-lowering agents has advantages and disadvantages 
(Table 416-6), certain generalizations apply: (1) insulin secretagogues, 
biguanides, GLP-1RAs, and thiazolidinediones improve glycemic con­
trol to a similar degree (1–2% reduction in HbA1c) and are more 
effective than α-glucosidase inhibitors, DPP-4 inhibitors, and SGLT-2

Individual with type 2 DM
Develop person-centered, individualized plan
• Medical nutrition therapy
• Physical activity/lifestyle
• Weight loss goal of 5–7%
• Continue or initiate metformin
Goal: Manage HbA1c + cardiorenal risk factor reduction
Goal: Manage HbA1c + weight reduction or maintenance
Heart failure,
HFrEF, or
HFpEF?
CKD?
ASCVD or
ASCVD risk
factors?
GLP-1RA or
SGLT-2
inhibitor
SGLT-2
inhibitor
SGLT-2
inhibitor
HbA1c above
target?
HbA1c above
target?
• Add GLP-
  1RA
• Add TZD
• Add SGLT-2
 inhibitor or
 GLP-1RA
HbA1c above target?
• Add insulin
• Combination of injectable and oral
• Re-emphasize lifestyle, nutrition, physical activity
FIGURE 416-3  Glycemic management of type 2 diabetes. See text for discussion of treatment of severe hyperglycemia or symptomatic hyperglycemia. In this Figure, the term 
glucagon-like peptide-1 receptor agonists (GLP-1RAs) refers to GLP-1 RAs and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RAs. Agents that can 
be combined with metformin include insulin, GLP-1RAs, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, insulin secretagogues, thiazolidinediones (TZD), α-glucosidase 
inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. Injectable refers to insulin or GLP-RA. In individuals with type 2 DM and metabolic dysfunction–associated steatotic 
liver disease (see Chap. 354) or metabolic dysfunction–associated steatohepatitis (see Chap. 354), a GLP-1 RA or a dual glucose-dependent insulinotropic polypeptide (GIP) 
and GLP-1 RA and/or TZD (pioglitazone) should be considered. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; HbA1c, 
hemoglobin A1c; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.
inhibitors; (2) insulin secretagogues, GLP-1RAs, DPP-4 inhibitors, 
α-glucosidase inhibitors, and SGLT-2 inhibitors begin to lower the 
plasma glucose immediately, whereas the glucose-lowering effects of 
the biguanides and thiazolidinediones takes several days; (3) not all 
agents are effective in all individuals with type 2 DM; (4) biguanides, 
α-glucosidase inhibitors, GLP-1RAs, DPP-4 inhibitors, thiazolidinedio­
nes, and SGLT-2 inhibitors do not directly cause hypoglycemia; (5) most 
individuals will eventually require treatment with more than one class of 
oral glucose-lowering agents or insulin, reflecting the progressive nature 
of type 2 DM; and (6) durability of glycemic control is slightly less for 
sulfonylureas compared to metformin or thiazolidinediones.
COMBINATION THERAPY WITH GLUCOSE-LOWERING AGENTS  The 
approach to type 2 DM has changed dramatically with the demon­
stration that GLP-1RAs and SGLT-2 inhibitors reduce cardiovascular 
events and slow the progression of renal disease, indicating that a 
GLP-1RA or an SGLT-2 inhibitor should be used in most individu­
als with type 2 DM. Therapy should be dictated by whether ASCVD, 
heart failure, or CKD is present or whether weight loss is a major goal 
(Fig. 416-3). A number of combinations of therapeutic agents are use­
ful in type 2 DM: metformin plus SGLT-2 inhibitor, metformin plus 
GLP-1RA, metformin plus insulin, or combinations of a long-acting 
insulin and a GLP-1RA. Because the mechanism of action of the first 
and second agents differs, the effect on glycemic control is usually 
additive. Recent results from the National Institutes of Health–funded 
Glycemia Reduction Approaches in Diabetes: A Comparative Effec­
tiveness Study (GRADE) indicated that addition of liraglutide or basal 

Diabetes Mellitus: Management and Therapies  
CHAPTER 416
Weight loss
Glycemia
• GLP-1RA
• Structured medical
  weight loss program
• Metabolic surgery
• GLP-1RA
• GLP-1RA and insulin
• Combination oral +
   injectable
• Sulfonylurea
• TZD
• DPP-4 inhibitor
insulin to metformin leads to better glycemic control than glimepiride 
or sitagliptin (SGLT-2 inhibitors were not studied). Medication costs 
vary considerably (Table 416-6), and this often factors into medication 
choice as drugs in some categories are very expensive (e.g., SGLT-2 
inhibitors, GLP-1RAs). Several fixed-dose combinations of oral agents 
are available, but evidence that they are superior to titration of a single 
agent to a maximum dose and then addition of a second agent is lack­
ing. If adequate control is not achieved with the combination of two 
agents (based on reassessment of the HbA1c every 3 months), a third 
oral agent, including basal insulin, should be considered (Fig. 416-3). 
Treatment approaches vary considerably from country to country. For 
example, α-glucosidase inhibitors are used commonly in South Asian 
patients (Indian) but infrequently in the United States or Europe. 
Whether this reflects an underlying difference in the disease or physi­
cian preference is not clear.
Treatment with insulin often becomes necessary as type 2 DM 
enters the phase of relative insulin deficiency and is signaled by inad­
equate glycemic control with one or two oral glucose-lowering agents. 
Insulin alone or in combination should be used in patients who fail 
to reach glycemic targets. For example, a single dose of long-acting 
insulin at bedtime is often effective in combination with metformin. 
As endogenous insulin production falls further, multiple injections of 
long-acting insulin together with rapid-acting insulin are necessary to 
control postprandial glucose excursions. These insulin regimens are 
identical to the long-acting and rapid-acting combination regimens 
discussed above for type 1 DM, although usually at higher doses given

insulin resistance. Weight gain and hypoglycemia are the major adverse 
effects of insulin therapy. The addition of a GLP-1RA can limit this 
and reduce the dose of insulin needed. The daily insulin dose required 
can become quite large (1–2 units/kg per day) as endogenous insulin 
production falls and insulin resistance persists, especially in the setting 
of weight gain. Insulin plus a thiazolidinedione promotes weight gain 
and may be associated with peripheral edema. Addition of a GLP-1RA 
or a thiazolidinedione may necessitate a reduction in the insulin dose 
to avoid hypoglycemia. Patients requiring large doses of insulin (>200 
units/day) can be treated with more concentrated forms of insulin to 
reduce the volume of injectate and improve absorption.

PART 12
Endocrinology and Metabolism
■
■OTHER THERAPIES FOR DIABETES
Metabolic (also referred to as bariatric) surgery for obese individuals 
with type 2 DM has shown considerable effectiveness, sometimes with 
dramatic resolution of diabetes or major reductions in the needed 
dose of glucose-lowering therapies (Chaps. 413 and 414). Several 
large, nonrandomized clinical trials have demonstrated a much greater 
efficacy of metabolic surgery compared to medical management in 
the treatment of type 2 DM, but these trials were conducted before 
the advent of recently available GLP-1RAs. The ADA clinical guide­
lines state that metabolic surgery should be considered in individuals 
with type 2 DM and a body mass index >30 kg/m2 if hyperglycemia 
is inadequately controlled despite optimal medical therapy. Metabolic 
surgery is ideally performed in certified centers with experience with 
the procedures and associated nutritional support.
Short-term intense caloric restriction (very-low-calorie diet, typi­
cally 800–1000 calories/d) can dramatically improve type 2 DM, 
sometimes leading to resolution of the diabetes. Such an approach is 
more effective in recent-onset type 2 DM and should be supervised 
by a provider with expertise and accompanied by a long-term, weightmaintenance program.
Whole-pancreas transplantation can normalize glucose control in 
type 1 DM and when performed simultaneously with or after kidney 
transplantation can prolong the life of the kidney transplant by offer­
ing protection against recurrent diabetic nephropathy. However, the 
number of whole-pancreas transplants is declining, likely reflecting 
the success with CGM and AID. Pancreatic islet transplantation is a 
less invasive form of beta-cell replacement therapy for type 1 DM; an 
islet product has received FDA approval. Despite the risks associated 
with chronic immunosuppression, whole-pancreas and pancreatic islet 
transplantation may be considered for patients with severe metabolic 
instability or already requiring immunosuppression in support of a 
kidney or other organ transplant. Patients with chronic pancreatitis 
and preserved islet function who require pancreatectomy for pain relief 
may benefit from autologous islet transplantation as this may prevent 
or ameliorate postsurgical DM.
■
■EMERGING THERAPIES
Recent clinical trials using transplantation of insulin-producing cells 
derived from human pluripotent stem cells have shown promise. 
Cost, durability, long-term safety, and patient selection remain to be 
determined. Many individuals with long-standing type 1 DM still 
produce very small amounts of insulin or have insulin-positive cells 
within the pancreas. This suggests that beta cells may slowly regen­
erate but are quickly destroyed by the autoimmune process. Efforts 
to suppress the autoimmune process, for example, with a monoclo­
nal antibody that targets T lymphocytes, may preserve beta cells 
when given at the time of new-onset hyperglycemia in type 1 DM. 
This agent, teplizumab, a humanized monoclonal antibody to CD3 
on T cells, has been approved by the FDA to delay the onset of clinical 
type 1 DM (stage 3) in patients 8 years of age or older with preclinical 
(stage 2) disease. Agents that target thioredoxin-interacting protein 
(TXNIP), especially Ca2+ channel blockers, have shown promise in 
recent-onset type 1 DM and in rodent models of diabetes.
ADVERSE EFFECTS OF THERAPY FOR DM
The benefits of efforts directed toward glycemic control must be bal­
anced against the risks of treatment (Table 416-6). Side effects of inten­
sive treatment include an increased frequency of serious hypoglycemia, 

weight gain, and greater demands on the individual with diabetes. The 
most serious complication of therapy for DM is hypoglycemia, and its 
prevention and treatment with oral glucose or glucagon administered 
intra-nasally or by injection are discussed in Chap. 418. Severe, recur­
rent, or unexplained hypoglycemia warrants reassessment of the treat­
ment regimen and glycemic goal for the individual patient and possibly 
deintensification of insulin therapy (see categories of individuals for 
this would be appropriate in Table 416-4). Weight gain occurs with 
most (insulin, insulin secretagogues, thiazolidinediones) but not all 
(metformin, α-glucosidase inhibitors, GLP-1RAs, SGLT-1 inhibitors, 
DPP-4 inhibitors) therapies. The weight gain is partially due to the 
anabolic effects of insulin and the reduction in glucosuria.
ACUTE DISORDERS RELATED TO SEVERE 
HYPERGLYCEMIA
Individuals with type 1 or type 2 DM and severe hyperglycemia should 
be assessed for clinical stability, including mentation and hydration. The 
physician should determine if the individual with diabetes is stable or if 
DKA or a hyperglycemic hyperosmolar state (HHS) is present. In DKA, 
the hyperglycemia is accompanied by increased ketone concentration 
in blood and metabolic acidosis. In HHS, the hyperglycemia is usually 
greater, leading to hyperosmolality and marked dehydration but with­
out ketosis or acidosis. Ketones bodies, an indicator of DKA, should be 
measured in individuals with type 1 DM when the plasma glucose is 
persistently >13.9 mmol/L (250 mg/dL). The possibility of DKA should 
always be considered in patients with type 1 DM during a concurrent 
illness or with symptoms such as nausea, vomiting, or abdominal pain. 
Measurement of β-hydroxybutyrate in the blood is preferred over urine 
testing with nitroprusside-based assays that measure only acetoacetate 
and acetone. Worldwide, the number of reported cases of DKA and 
HHS is increasing for unclear reasons. Both DKA and HHS are associ­
ated with potentially serious complications, including greater mortality.
Most cases of DKA are in individuals with type 1 DM, while HHS 
occurs mostly in individuals with type 2 DM. DKA, formerly consid­
ered a hallmark of type 1 DM, can also occur at diabetes diagnosis in 
obese young adults, often of Hispanic or African descent, whose labo­
ratory values are similar to those seen in DKA associated with type 1 
DM. However, after treatment of the DKA, these individuals recover 
their insulin secretory capacity, can gradually discontinue insulin treat­
ment after a few weeks or months, and remain normoglycemic with 
only diet or oral medication. The cause of this atypical form of diabetes 
is unknown; it is often termed ketosis-prone diabetes. DKA can also 
occur in the setting of treatment of type 2 DM with an SGLT-2 inhibi­
tor. Often the blood glucose is normal or just mildly elevated because 
of the glucosuria. Table 416-7 compares the features of DKA, HHS, 
and euglycemic DKA associated with SGLT-2 inhibitors. DKA and 
HHS exist along a continuum of hyperglycemia, with up to one-third 
of patients having features of both.
■
■DIABETIC KETOACIDOSIS
Clinical Features 
The symptoms and physical signs of DKA are 
listed in Table 416-8 and usually develop over 24 h. DKA may be the 
initial symptom complex that leads to a diagnosis of type 1 DM, but 
more frequently, it occurs in individuals with established diabetes. 
Nausea and vomiting are often prominent, and their presence in an 
individual with diabetes warrants laboratory evaluation for DKA. 
Abdominal pain may be severe and can resemble acute pancreatitis or 
ruptured viscus. Hyperglycemia leads to glucosuria, volume depletion, 
and tachycardia. Hypotension can occur because of volume depletion 
in combination with peripheral vasodilatation. Kussmaul respirations 
and a fruity odor on the patient’s breath (secondary to metabolic aci­
dosis and increased acetone) are classic signs of the disorder. Lethargy 
and central nervous system depression may evolve into coma with 
severe DKA but should also prompt evaluation for other reasons for 
altered mental status (e.g., infection, hypoxemia). Cerebral edema, an 
extremely serious complication of DKA, is seen most frequently in 
children. Signs of infection, which may precipitate DKA, should be 
sought on physical examination, even in the absence of fever. Failure 
to augment insulin therapy during physiologic stress often compounds

TABLE 416-7  Laboratory Values in Diabetic Ketoacidosis (DKA), Hyperglycemic Hyperosmolar State (HHS), and 
Euglycemic DKA [Representative Ranges at Presentation; mmol/L ( mg/dL)]
 
DKA
HHS
EUGLYCEMIC DKAc
Glucose,a mmol/L (mg/dL)
11.1–33.3 (250–600)
33.3–66.6 (600–1200)
5.5-13.9 (100–250)c
Sodium, meq/L
125–135
135–145
Normal
Potassiuma,b
Normal to ↑
Normal
Normal to ↑
Magnesiuma
Normal
Normal
Normal
Chloridea
Normal
Normal
Normal
Phosphatea,b
Normal
Normal
Normal
Creatinine
Slightly to moderately ↑
Moderately ↑
Slightly ↑
Osmolality (mOsm/mL)
>300
>300
Normal
Serum/urine ketonesa
>++
+/–
>++
Serum β-hydroxybutyrate, mmol/L
>3.0
<1.0
>3.0
Serum bicarbonate,a meq/L
<18
>18
<18
Arterial pH
6.8–7.3
>7.3
<7.3
Arterial Pco2,a mmHg
20–30
Normal
20–30
Anion gapa (Na – [Cl + HCO3])
↑
Normal to slightly ↑
↑
aLarge changes occur during treatment of DKA; serum level may be normal initially but then require replacement. bAlthough plasma 
levels may be normal or high at presentation, total-body stores are usually depleted. cSometimes occurs with sodium-glucose 
cotransporter 2 (SGLT-2) inhibitor treatment; disproportionate glucosuria is consistent with SGLT-2 inhibitor effect.
the problem. Tissue ischemia (heart, brain) can also be a precipitating 
factor. Omission of insulin because of an infusion pump delivery site 
occlusion or device malfunction, eating disorder, mental health disor­
ders, or an unstable psychosocial environment may each be a factor 
precipitating DKA. Complete omission or inadequate administration of 
insulin by the patient or health care team (in a hospitalized patient with 
type 1 DM) may precipitate DKA. The rising cost of insulin has been a 
major challenge and has contributed to individuals with diabetes omit­
ting or rationing their insulin, making them more vulnerable to DKA.
Pathophysiology 
DKA results from relative or absolute insulin 
deficiency combined with counterregulatory hormone excess (gluca­
gon, catecholamines, cortisol, and growth hormone). The decreased 
ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, 
and ketone body formation in the liver, as well as increases in substrate 
delivery from fat and muscle (free fatty acids, amino acids) to the liver. 
Ketosis results from a marked increase in free fatty acid release from 
adipocytes, with a resulting shift toward ketone body synthesis in the 
liver. Reduced insulin levels, in combination with elevations in cate­
cholamines and growth hormone, also increase lipolysis and the release 
of free fatty acids. Markers of inflammation (cytokines, C-reactive 
protein) are elevated in both DKA and HHS.
Laboratory Abnormalities and Diagnosis 
The timely diag­
nosis of DKA is crucial and allows for prompt initiation of therapy. 
DKA is characterized by hyperglycemia (serum glucose >13.9 mmol/L 
[250 mg/dL], ketosis, and metabolic acidosis [serum bicarbonate 
<15–18 mmol/L with increased anion gap]) along with a number of 
TABLE 416-8  Manifestations of Diabetic Ketoacidosis
Symptoms
  Nausea/vomiting
  Thirst/polyuria
  Abdominal pain
  Shortness of breath
Precipitating events
  Inadequate insulin administration
  Infection (pneumonia/UTI/
Physical Findings
  Tachycardia
  Dehydration/hypotension
  Tachypnea/Kussmaul respirations/
respiratory distress
  Abdominal tenderness (may 
resemble acute pancreatitis or 
surgical abdomen)
  Lethargy/obtundation/cerebral 
gastroenteritis/sepsis)
  Infarction (cerebral, coronary, 
edema/possibly coma
mesenteric, peripheral)
  Pancreatitis
  Drugs (cocaine)
  Pregnancy
Abbreviation: UTI, urinary tract infection.

Diabetes Mellitus: Management and Therapies  
CHAPTER 416
secondary metabolic derangements (Table 416-7). Occasionally, the 
serum glucose is only minimally elevated and may even be normal 
(euglycemic DKA). This has been noted especially in individuals 
treated with SGLT-2 inhibitors. Arterial pH usually ranges between 6.8 
and 7.3, depending on the severity of the acidosis. Despite a total-body 
potassium deficit, the serum potassium at presentation may be mildly 
elevated, secondary to the acidosis and volume depletion. Total-body 
stores of sodium, chloride, phosphorus, and magnesium are also 
reduced in DKA but are not accurately reflected by their levels in the 
serum because of hypovolemia and hyperglycemia. Elevated blood 
urea nitrogen (BUN) and serum creatinine levels reflect intravascular 
volume depletion. Leukocytosis, hypertriglyceridemia, and hyperli­
poproteinemia are commonly found as well. Hyperamylasemia may 
suggest a diagnosis of pancreatitis, especially when accompanied by 
abdominal pain. However, in DKA the amylase is usually of salivary 
origin and thus is not diagnostic of pancreatitis. Serum lipase should 
be obtained if pancreatitis is suspected.
The measured serum sodium is reduced as a consequence of the 
hyperglycemia. An estimated correction is provided by the equa­
tion: (1.6-mmol/L [1.6-meq] reduction in serum sodium for each 
5.6-mmol/L [100-mg/dL] rise in the serum glucose). A normal serum 
sodium in the setting of DKA indicates a more profound water deficit.
In DKA, the ketone body, β-hydroxybutyrate, is synthesized at 
a threefold greater rate than acetoacetate; however, acetoacetate is 
preferentially detected by a commonly used ketosis detection reagent 
(nitroprusside). The nitroprusside tablet, or stick, is often used to 
detect urine ketones; certain medications such as captopril, penicil­
lamine, or valproic acid may cause false-positive reactions. Serum or 
plasma assays for β-hydroxybutyrate are preferred because they more 
accurately reflect the true ketone body level.
The degree of acidosis and hyperglycemia do not necessarily cor­
relate closely because a variety of factors determine the level of hyper­
glycemia (oral intake, urinary glucose loss). Ketonemia is a consistent 
finding in DKA and distinguishes it from simple hyperglycemia. The 
differential diagnosis of DKA includes starvation ketosis, alcoholic 
ketoacidosis (bicarbonate usually >15 meq/L), and other forms of 
increased anion-gap acidosis (Chap. 55).
TREATMENT
Diabetic Ketoacidosis
Based on laboratory values and clinical exam, DKA can be classified 
as mild (pH 7.25–7.3, serum bicarbonate 15–18 meq/L, men­
tal status normal), moderate (pH 7.0–7.25, serum bicarbonate 
10–15 meq/L, mildly reduced mental status), or severe (pH <7.0,

serum bicarbonate <10–15 meq/L, reduced mental status, coma). 
The management of DKA is outlined in Table 416-9. After initiat­
ing IV fluid replacement and insulin therapy, the event that precipi­
tated the episode of DKA should be sought and aggressively treated. 
If the patient is vomiting or has altered mental status, a nasogastric 
tube should be inserted to prevent aspiration of gastric contents. 
Central to successful treatment of DKA is careful monitoring and 
frequent reassessment to ensure that the patient and the metabolic 
derangements are improving. A comprehensive flow sheet should 
record chronologic changes in vital signs, fluid intake and output, 
and laboratory values as a function of insulin administered.

After the initial bolus of normal saline or lactated Ringer’s, 
replacement of the sodium and free water deficit is carried out over 
the next 24 h (fluid deficit is often 3–5 L). When hemodynamic 
stability and adequate urine output are achieved, IV fluids should 
be switched to 0.45% saline or lactated Ringer’s, depending on the 
calculated volume deficit. Ringer’s lactate is associated with more 
rapid DKA resolution and a reduced trend toward hyperchloremia 
later in the course of DKA resolution.
PART 12
Endocrinology and Metabolism
A bolus of IV (0.1 units/kg) short-acting regular insulin is usu­
ally administered immediately (Table 416-9), and subsequent treat­
ment should provide continuous and adequate levels of circulating 
TABLE 416-9  Management of Diabetic Ketoacidosis (DKA)
1.	 Confirm diagnosis (↑ serum glucose, ↑ serum β-hydroxybutyrate, metabolic 
acidosis).
2.	 Admit to hospital; intensive care setting may be necessary for severe DKA 
(see text). Mild to moderate DKA can be treated in a step-down unit with 
close nursing and laboratory monitoring.
3.	 Assess:
Serum electrolytes (K+, Na+, Mg2+, Cl–, bicarbonate, phosphate)
Acid-base status—pH, HCO3
–, PCO2, β-hydroxybutyrate
Renal function (creatinine, urine output)
4.	 Replace fluids: 2–3 L of 0.9% saline or lactated Ringer’s over first 1–3 h 
(10–20 mL/kg per hour); subsequently, 0.45% saline at 250–500 mL/h; change 
to 5–10% glucose and 0.45% saline or lactated Ringer’s at 150–250 mL/h when 
blood glucose reaches 250 mg/dL (13.9 mmol/L). For treatment of euglycemic 
DKA, start 5% or 10% dextrose infusion and insulin treatment when 0.9% saline 
is started; adjust dextrose infusion to prevent hypoglycemia.
5.	 Administer short-acting regular insulin: IV (0.1 units/kg), then 0.1 units/
kg per hour by continuous IV infusion; increase two- to threefold if no 
response by 2–4 h. In mild to moderate DKA, subcutaneous rapid-acting 
insulin may be used with close monitoring (0.1 unit/kg rapid-acting insulin 
analogue subcutaneously and then 0.1 unit/kg every 1 h or 0.2 unit/kg every 
2 h). Continue insulin treatment and 5% or 10% dextrose infusion to prevent 
hypoglycemia. If the initial serum potassium is <3.3 mmol/L (3.3 meq/L), do 
not administer insulin until the potassium is corrected.
6.	 Assess patient: What precipitated the episode (noncompliance, infection, 
trauma, pregnancy, infarction, cocaine)? Initiate appropriate workup for 
precipitating event (cultures, CXR, ECG, etc.).
7.	 Measure blood glucose every 1–2 h; measure electrolytes (especially K+, 
bicarbonate, phosphate) and anion gap every 4 h for first 24 h.
8.	 Monitor blood pressure, pulse, respirations, mental status, fluid intake and 
output every 1–4 h.
9.	 Replace K+ if ECG, urine flow, and creatinine are normal. If K+ <3.5 mmol/L, 
administer 10–20 mmol/L per hour until K+ >3.5 mmol/L. If K+ 3.5–5 mmol/L, 
administer 10–20 mmol/L in each liter of IV fluid to keep serum K+ between 
4 and 5 mmol/L. If K+ >5.0 mmol/L, start insulin but hold K+. Recheck K+ every 
2 h to determine when to start K+ replacement.
10.	 Continue above until patient is stable, glucose goal is 8.3–11.1 mmol/L 
(150–200 mg/dL), normal plasma ketone and pH, and bicarbonate ≥18 mmol/L. 
Insulin infusion may be decreased to 0.02–0.1 unit/kg per hour. Resolution of 
euglycemic DKA should be based on bicarbonate, not glucose, correction; 
see text.
11.	 Administer long-acting insulin as soon as patient is eating. Allow for a 2- to 
4-h overlap in insulin infusion and SC long-acting insulin injection.
Abbreviations: CXR, chest x-ray; ECG, electrocardiogram.
Source: Adapted from multiple sources, including Nyenwe EA, Kitabchi AE: The 
evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and 
management. Metabolism 65:507, 2016; and Umpierrez GE et al: Hyperglycaemic 
crises in adults with diabetes: A consensus report. Diabetologia 67:1455, 2024.

insulin. IV administration is usually preferred (0.1 units/kg of regu­
lar insulin per h) but uncomplicated DKA can also be treated with 
SC short-acting insulin analogues. As the acidosis and insulin resis­
tance associated with DKA resolve, the insulin infusion rate can 
be decreased (to 0.02–0.1 units/kg per h). Long-acting insulin, in 
combination with SC short-acting insulin, should be administered 
as soon as the patient resumes eating, because this facilitates transi­
tion to an outpatient insulin regimen and reduces length of hospital 
stay. Hyperglycemia usually improves at a rate of 4.2–5.6 mmol/L 
(50–100 mg/dL) per h as a result of insulin-mediated glucose 
disposal, reduced hepatic glucose release, and rehydration. Rehy­
dration reduces catecholamines, increases urinary glucose loss, 
and expands the intravascular volume. The decline in the plasma 
glucose within the first 1–2 h may be more rapid and is mostly 
related to volume expansion. Ketoacidosis begins to resolve as 
insulin reduces lipolysis, increases peripheral ketone body use, sup­
presses hepatic ketone body formation, and promotes bicarbonate 
regeneration. However, the acidosis and ketosis resolve more slowly 
than hyperglycemia. Depending on the rise of serum chloride, 
the anion gap (but not bicarbonate) will normalize more quickly. 
A hyperchloremic acidosis (serum bicarbonate of 15–18 mmol/L 
[15–18 meq/L]) often follows successful treatment and gradually 
resolves as the kidneys regenerate bicarbonate and excrete chloride.
Potassium stores are depleted in DKA (estimated deficit 
3–5 mmol/kg [3–5 meq/kg]). During treatment with insulin and 
fluids, various factors contribute to the development of hypokale­
mia. These include insulin-mediated potassium transport into cells, 
resolution of the acidosis (which also promotes potassium entry 
into cells), and urinary loss of potassium salts of organic acids. 
Thus, potassium repletion should commence as soon as adequate 
urine output and a normal serum potassium are documented 
(Table 416-9).
Bicarbonate replacement has not been shown to improve out­
comes. However, in the presence of severe acidosis (arterial pH 
<7.0), sodium bicarbonate (50 mmol [meq/L] in 200 mL of sterile 
water with 10 meq/L KCl per h) may be administered for the first 
2 h until the pH is >7.0. Hypophosphatemia and hypomagnesemia 
may develop during DKA therapy, and if severe, may also require 
supplementation.
With appropriate therapy, the mortality rate of DKA is low (<1%) 
and is related more to the underlying or precipitating event, such as 
infection ((pneumonia, SARS-Co-V2, etc.) COVID-19), pregnancy, 
end-stage renal disease, or myocardial infarction. Venous throm­
bosis, upper GI bleeding, and acute respiratory distress syndrome 
occasionally complicate DKA. The major nonmetabolic complica­
tion of DKA therapy is cerebral edema, which most often devel­
ops in children as DKA is resolving. The etiology of and optimal 
therapy for cerebral edema are not well established.
Following treatment, the physician and patient should review the 
sequence of events that led to DKA to prevent future recurrences. 
Even a single episode of DKA is associated with a greatly increased 
1-year mortality rate. Foremost is patient education about the 
symptoms of DKA, its precipitating factors, and the management 
of diabetes during a concurrent illness. In some individuals, DKA 
is recurrent and may indicate underlying mental health issues. The 
structural barriers to accessing care, insulin cost, and the social 
determinants of health often play a role.
■
■HYPERGLYCEMIC HYPEROSMOLAR STATE
Clinical Features 
The most common presentation of HHS is an 
elderly individual with type 2 DM, with a several-week history of 
polyuria, weight loss, and diminished oral intake that culminates in 
mental confusion, lethargy, or coma. The physical examination reflects 
profound dehydration and hyperosmolality and reveals hypotension, 
tachycardia, and altered mental status. Notably absent are symptoms of 
nausea, vomiting, and abdominal pain and the Kussmaul respirations 
characteristic of DKA. HHS is often precipitated by a serious, concur­
rent illness such as myocardial infarction or stroke. Sepsis, pneumonia,

and other serious infections are frequent precipitants and should be 
sought. In addition, a debilitating condition (prior stroke or dementia) 
or social situation that compromises water intake usually contributes to 
the development of the disorder.
Pathophysiology 
Relative insulin deficiency and inadequate fluid 
intake are the underlying causes of HHS. Insulin deficiency increases 
hepatic glucose production (through glycogenolysis and gluconeogen­
esis) and impairs glucose utilization in skeletal muscle (see above dis­
cussion of DKA). Hyperglycemia induces an osmotic diuresis that leads 
to intravascular volume depletion, which is exacerbated by inadequate 
fluid replacement. The absence of ketosis in HHS is not understood. 
Presumably, the insulin deficiency is only relative and less severe than 
in DKA. Lower levels of counterregulatory hormones and free fatty 
acids have been found in HHS than in DKA in some studies. It is also 
possible that the liver is less capable of ketone body synthesis or that 
the insulin/glucagon ratio does not favor ketogenesis.
Laboratory Abnormalities and Diagnosis 
The laboratory fea­
tures in HHS are summarized in Table 416-7. Most notable are 
the marked hyperglycemia (plasma glucose may be >55.5 mmol/L 
[1000 mg/dL]), hyperosmolality (>300 mOsm/L), and prerenal azo­
temia. The measured serum sodium may be normal or slightly low 
despite the marked hyperglycemia. The corrected serum sodium 
is usually increased (add 1.6 meq to measured sodium for each 
5.6-mmol/L [100-mg/dL] rise in the serum glucose). In contrast to 
DKA, acidosis and ketonemia are absent or mild. A small anion-gap 
metabolic acidosis may be present secondary to increased lactic acid. 
Moderate ketonuria, if present, is secondary to starvation.
TREATMENT
Hyperglycemic Hyperosmolar State
Volume depletion and hyperglycemia are prominent features of 
both HHS and DKA. Consequently, the therapy of these disorders 
shares several elements (Table 416-9). In both disorders, careful 
monitoring of the patient’s fluid status, laboratory values, and insu­
lin infusion rate is crucial. Underlying or precipitating problems 
should be aggressively sought and treated. In HHS, fluid losses and 
dehydration are usually more pronounced than in DKA due to the 
longer duration of the illness. The patient with HHS is usually older, 
more likely to have mental status changes, and more likely to have a 
life-threatening precipitating event with accompanying comorbidi­
ties. Even with proper treatment, HHS has a substantially higher 
mortality rate than DKA (up to 15% in some clinical series).
Fluid replacement should initially stabilize the hemodynamic 
status of the patient (1–3 L of 0.9% normal saline over the first 
2–3 h). Because the fluid deficit in HHS is accumulated over a 
period of days to weeks, the rapidity of reversal of the hyperosmolar 
state must balance the need for free water repletion with the risk 
that too rapid a reversal may worsen neurologic function. If the 
serum sodium is >150 mmol/L (150 meq/L), 0.45% saline should 
be used. After hemodynamic stability is achieved, the IV fluid 
administration is directed at reversing the free water deficit using 
hypotonic fluids (0.45% saline initially, then 5% dextrose in water 
[D5W]). The calculated free water deficit (which can be as great as 
9–10 L) should be reversed over the next 1–2 days (infusion rates of 
200–300 mL/h of hypotonic solution). Potassium repletion is usu­
ally necessary and should be dictated by repeated measurements of 
the serum potassium. In patients taking diuretics, the potassium 
deficit can be quite large and may be accompanied by magnesium 
deficiency. Hypophosphatemia may occur during therapy and can 
be improved by using KPO4 and beginning nutrition.
As in DKA, rehydration and volume expansion lower the plasma 
glucose initially, but insulin is also required. A reasonable regimen 
for HHS begins with an IV insulin bolus of 0.1 unit/kg followed 
by IV insulin at a constant infusion rate of 0.1 unit/kg per h. If the 
serum glucose does not fall, increase the insulin infusion rate by 
twofold. As in DKA, glucose should be added to IV fluid when the 

plasma glucose falls to 11.1–13.9 mmol/L (200–250 mg/dL), and 
the insulin infusion rate should be decreased to 0.02–0.1 unit/kg 
per h. The insulin infusion should be continued until the patient 
has resumed eating and can be transferred to an SC insulin regi­
men. The patient should be discharged from the hospital on insulin. 
Some patients can later switch to oral glucose-lowering agents.

MANAGEMENT OF DIABETES IN A 
HOSPITAL OR FACILITY
Virtually all medical and surgical subspecialties are involved in the 
care of hospitalized patients with diabetes or individuals with diabetes 
in the perioperative setting. Hyperglycemia, whether in a patient with 
known diabetes or in someone without known diabetes, appears to be a 
predictor of poor outcome in hospitalized patients. General anesthesia, 
surgery, infection, or concurrent illness raises the levels of counter­
regulatory hormones (cortisol, growth hormone, catecholamines, and 
glucagon) and cytokines that may lead to transient insulin resistance 
and hyperglycemia. These factors increase insulin requirements by 
increasing glucose production and impairing glucose utilization and 
thus may worsen glycemic control. The concurrent illness or surgical 
procedure may lead to variable insulin absorption and also prevent 
the patient with DM from eating normally and, thus, may promote 
hypoglycemia. Glycemic control should be assessed on admission 
using the HbA1c. Electrolytes, renal function, and intravascular volume 
status should be assessed as well. The high prevalence of ASCVD in 
individuals with DM (especially in type 2 DM) may necessitate pre­
operative cardiovascular evaluation (Chap. 417). CGM in the hospital 
or intensive care unit (ICU) setting is not FDA approved. Individuals 
using CGM and/or AID prior to admission should continue to use 
these devices if the provider, the nursing staff, and the patient agree 
that this can be safely done within the context of the patient’s current 
reason for hospitalization.
Diabetes Mellitus: Management and Therapies  
CHAPTER 416
The goals of diabetes management during hospitalization or in the 
perioperative periods are near-normoglycemia, avoidance of hypogly­
cemia, and transition back to the outpatient diabetes treatment regi­
men. Upon hospital admission, frequent glycemic monitoring should 
begin, as should planning for diabetes management after discharge. 
Glycemic control appears to improve clinical outcomes in a variety 
of settings, but optimal glycemic goals for the hospitalized patient are 
incompletely defined. In a number of cross-sectional studies of patients 
with diabetes, a greater degree of hyperglycemia was associated with 
worse cardiac, neurologic, and infectious outcomes. In some studies, 
patients who do not have preexisting diabetes but who develop modest 
blood glucose elevations during their hospitalization appear to benefit 
from achieving near-normoglycemia using insulin treatment. How­
ever, a large randomized clinical trial (Normoglycemia in Intensive 
Care Evaluation Survival Using Glucose Algorithm Regulation [NICESUGAR]) of individuals in the ICU (most of whom were receiving 
mechanical ventilation) found an increased mortality rate and a greater 
number of episodes of severe hypoglycemia with very strict glycemic 
control (target blood glucose of 4.5–6 mmol/L or 81–108 mg/dL) com­
pared to individuals with a more moderate glycemic goal (target blood 
glucose of <10 mmol/L or 180 mg/dL). Currently, most data suggest 
that very strict blood glucose control in acutely ill patients likely wors­
ens outcomes and increases the frequency of hypoglycemia. The ADA 
suggests the following glycemic goals for hospitalized patients: (1) in 
critically or non-critically ill patients, glucose of 7.8–10.0 mmol/L or 
140–180 mg/dL; (2) in selected patients, glucose of 6.1–7.8 mmol/L 
or 110–140 mg/dL with avoidance of hypoglycemia; and (3) the 
target range in the perioperative period should be 80–180 mg/dL 
(4.4–10.0 mmol/L).
Critical aspects for optimal diabetes care in the hospital include the 
following: (1) A hospital-wide system approach to treatment of hyper­
glycemia and prevention of hypoglycemia is needed. Inpatient diabetes 
management teams consisting of nurse practitioners and physicians 
are increasingly common. (2) Diabetes treatment plans should focus 
on the transition from the ICU and the transition from the inpatient 
to the outpatient setting. (3) Adjustment of the discharge treatment

regimen of patients whose diabetes was poorly controlled on admission 
(as reflected by the HbA1c) is important.

The physician caring for an individual with diabetes in the peri­
operative period, during times of infection or serious physical illness, 
or simply when the patient is fasting for a diagnostic procedure must 
monitor the plasma glucose vigilantly, adjust the diabetes treatment 
regimen, and provide glucose infusion as needed. Hypoglycemia is 
frequent in hospitalized patients, and many of these episodes are avoid­
able. Hospital systems should have a diabetes management protocol to 
avoid inpatient hypoglycemia. Measures to reduce or prevent hypogly­
cemia include frequent glucose monitoring, but it is also important to 
prevent hypoglycemia by anticipating drops in insulin requirement by 
factors such as decreasing renal function, decreasing glucocorticoid 
doses, or interruption of nutrition (parenteral or enteral or PO).
PART 12
Endocrinology and Metabolism
Depending on the severity of the patient’s illness and the hospital 
setting, the physician can use either an insulin infusion or SC insulin. 
Insulin infusions are preferred in the ICU or in a clinically unstable 
setting because the half-life of the infused insulin is quite short (minutes). 
The absorption of SC insulin may be variable in such situations. Insu­
lin infusions can also effectively control plasma glucose in the peri­
operative period and when the patient is unable to take anything by 
mouth, although for relatively short (<4 h) procedures, most patients 
can remain on SC insulin. Regular insulin is used rather than insulin 
analogues for IV insulin infusion because it is less expensive and 
equally effective. The physician must consider carefully the clinical 
setting in which an insulin infusion will be used, including whether 
adequate ancillary personnel are available to monitor the blood glucose 
frequently and whether they can adjust the insulin infusion rate to 
maintain the blood glucose within the optimal range. Insulin-infusion 
algorithms should integrate the insulin sensitivity of the patient, fre­
quent blood glucose monitoring, and the trend of changes in the blood 
glucose to determine the insulin-infusion rate. Insulin-infusion algo­
rithms jointly developed and implemented by nursing and physician 
staff are advised. Because of the short half-life of IV regular insulin, it 
is necessary to administer long-acting insulin prior to discontinuation 
of the insulin infusion (2–4 h before the infusion is stopped) to avoid a 
period of insulin deficiency.
In patients who are not critically ill or not in the ICU, basal or 
“scheduled” insulin is provided by SC, long-acting insulin supple­
mented by prandial and/or “corrective” insulin using a rapid-acting 
insulin. “Sliding scale,” with short-acting or rapid-acting insulin alone, 
where no insulin is given unless the blood glucose is elevated, is inad­
equate for inpatient glucose management. The rapid-acting, prepran­
dial insulin dose should include coverage for food consumption (based 
on anticipated carbohydrate intake) plus corrective insulin based on 
the patient’s insulin sensitivity and the blood glucose. For example, if 
the patient is thin (and likely insulin-sensitive), an insulin correction 
factor might be 1 unit for each 2.7 mmol/L (50 mg/dL) over the glucose 
target. If the patient is obese and likely insulin-resistant, then the insu­
lin correction factor might be 2 units for each 2.7 mmol/L (50 mg/dL) 

over the glucose target. It is critical to individualize the regimen and 
adjust the basal and prandial insulin doses frequently based on the 
corrective insulin required. A consistent carbohydrate-controlled 
diabetes meal plan for hospitalized patients provides a predictable 
amount of carbohydrate for a particular meal each day (but not neces­
sarily the same amount for breakfast, lunch, and supper) and avoids 
concentrated sweets. Individuals with type 1 DM who are undergoing 
general anesthesia and surgery or who are seriously ill should receive 
continuous insulin, through an IV insulin infusion, their insulin infu­
sion device, or by SC administration of a reduced dose of long-acting 
insulin. Rapid-acting insulin alone is insufficient. Prolongation of a 
surgical procedure or delay in the recovery room is common and may 
result in periods of insulin deficiency leading to DKA. Insulin infusion 
is the preferred method for managing patients with type 1 DM over a 
prolonged (several hours) perioperative period or when serious con­
current illness is present (0.5–1.0 units/h of regular insulin). If the diag­
nostic or surgical procedure is brief (<4 h), a reduced dose of SC insulin 
may suffice (20–50% basal reduction, with rapid-acting correctional 
dose insulin as needed). This approach prevents interruption of insulin 

infusion device therapy or, for MDI, facilitates the transition back to 
basal/bolus insulin after the procedure. The blood glucose should be 
monitored frequently during the illness or in the perioperative period.
Individuals with type 2 DM can be managed with either an insulin 
infusion or SC long-acting insulin (20–50% reduction depending on 
clinical setting) plus preprandial, rapid-acting insulin. Oral glucoselowering agents should be discontinued upon admission (or up to a 
week prior to planned admission for SGLT-2 inhibitors) and are not 
useful in regulating the plasma glucose in clinical situations where 
the insulin requirements and glucose intake are changing rapidly. 
Moreover, these oral agents may be dangerous if the patient is fasting 
(e.g., hypoglycemia with sulfonylureas, euglycemic DKA with SGLT-2 
inhibitors) or at risk for declining kidney function due to, for example, 
radiographic contrast media or unstable CHF (lactic acidosis with 
metformin). Once clinically stable, oral glucose-lowering agents may 
be resumed in anticipation of discharge. Each patient should receive 
an individualized, structured discharge plan for diabetes management.
The principles of the care of individuals with diabetes who are in a 
rehabilitation facility or a long-term care facility are similar to those in 
a hospitalized patient with the glycemic goals individualized based on 
the patient’s overall clinical status (outlined in Table 416-4). Often the 
avoidance of hypoglycemia is the major goal with less intense glycemic 
targets.
SPECIAL CONSIDERATIONS IN DM
■
■TOTAL PARENTERAL NUTRITION (TPN)/TOTAL 
ENTERAL NUTRITION (TEN)
(See also Chap. 335) TPN or TEN greatly increases insulin require­
ments. In addition, individuals not previously known to have DM 
may become hyperglycemic during TPN or TEN and require insulin 
treatment. For TPN, IV insulin infusion is the preferred treatment for 
hyperglycemia, and rapid titration to the required insulin dose is done 
most efficiently using a separate insulin infusion. After the total insulin 
dose has been determined, a proportion of this insulin may be added 
directly to the TPN solution to cover the nutritional requirements for 
insulin and adjusted based on the need for modified dosing of rapidacting insulin. In TEN, hyperglycemia may be limited by using highprotein formulations but often requires insulin treatment. Individuals 
receiving enteral bolus feedings should receive SC, rapid-acting insulin 
prior to each bolus. As a start, 1 unit of insulin is given SC for each 
10–15 g of carbohydrate in the bolus. Patients with insulin deficiency 
(type 1 DM and pancreatogenic DM) should also receive long-acting 
insulin (0.1–0.2 units/kg per day) to cover basal insulin requirements 
should the TPN or TEN be interrupted or cycled.
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■GLUCOCORTICOIDS
Glucocorticoids increase insulin resistance, decrease glucose utiliza­
tion, increase hepatic glucose production, and impair insulin secretion. 
These changes lead to a worsening of glycemic control in individuals 
with DM and may precipitate hyperglycemia in other individuals. 
If new-onset hyperglycemia remains during chronic treatment with 
supraphysiologic doses of glucocorticoid (>5 mg of prednisone or 
equivalent), the DM may be called “steroid-induced diabetes.” The 
effects of glucocorticoids on glucose homeostasis are dose-related, 
usually reversible, most pronounced in the postprandial period, and 
dependent on the timing and type of glucocorticoid. If the FPG is near 
the normal range, oral diabetes agents (e.g., sulfonylureas, metformin) 
may be sufficient to reduce hyperglycemia. If the FPG is >11.1 mmol/L 
(200 mg/dL), oral agents are usually not sufficient, and insulin therapy 
is required. If steroids are administered in the morning, then shortacting insulin and/or NPH in the morning may be sufficient to control 
postprandial glucose excursions.
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■DIABETES MANAGEMENT IN OLDER ADULTS
Diabetes is very common in older adults, being present in ~25% 
of individuals over the age of 65 years. Increasingly, individuals 
with many years of type 1 DM are part of this patient population. 
As discussed above (Table 416-4), individualized therapeutic goals 
and modalities in older adults should consider biologic age, other