3115 Diabetes Mellitus: Management and Therapies CHAPTER 404

TABLE 404-6 Laboratory Values in Diabetic Ketoacidosis (DKA), Hyperglycemic Hyperosmolar State (HHS), and Euglycemic

DKA (Representative Ranges at Presentation)

DKA HHS EUGLYCEMIC DKAc

Glucose,a

 mmol/L (mg/dL) 13.9–33.3 (250–600) 33.3–66.6 (600–1200) <11.1-13.9 (<200–250)c

Sodium, meq/L 125–135 135–145 ~135

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) 300–320 330–380 ~300

Serum/urine ketonesa ++++ +/– ++++

Serum β-hydroxybutyrate, mmol/L >2.5 <1.0 >2.5

Serum bicarbonate,a

 meq/L <18 >18 <18

Arterial pH 6.8–7.3 >7.3 6.8–7.3

Arterial PCO2

,

a

 mmHg 20–30 Normal 20–30

Anion gapa

(Na – [Cl + HCO3

]) ↑ Normal to slightly ↑ ↑

a

Large changes occur during treatment of DKA. b

Although plasma levels may be normal or high at presentation, total-body stores are usually depleted. c

Sometimes occurs with SGLT2 inhibitor treatment; disproportionate glucosuria is consistent with SGLT2 inhibitor effect.

TABLE 404-7 Manifestations of Diabetic Ketoacidosis

Symptoms

Nausea/vomiting

Thirst/polyuria

Abdominal pain

Shortness of breath

Precipitating events

Inadequate insulin administration

 Infection (pneumonia/UTI/

gastroenteritis/sepsis)

 Infarction (cerebral, coronary,

mesenteric, peripheral)

Pancreatitis

Drugs (cocaine)

Pregnancy

Physical Findings

Tachycardia

Dehydration/hypotension

 Tachypnea/Kussmaul respirations/

respiratory distress

 Abdominal tenderness (may

resemble acute pancreatitis or

surgical abdomen)

 Lethargy/obtundation/cerebral

edema/possibly coma

Abbreviation: UTI, urinary tract infection.

occlusion or device malfunction, eating disorder, mental health disorders, or an unstable psychosocial environment may sometimes 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.

Pathophysiology DKA results from relative or absolute insulin

deficiency combined with counterregulatory hormone excess (glucagon, catecholamines, cortisol, and growth hormone). Both insulin

deficiency and glucagon excess, in particular, are necessary for DKA to

develop. 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 catecholamines 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 diagnosis 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

secondary metabolic derangements (Table 404-6). Occasionally, the

serum glucose is only minimally elevated and may even be normal

(euglycemic DKA). This has been noted especially in individuals

treated with SGLT2 inhibitors. Arterial pH usually ranges between

6.8 and 7.3, depending on the severity of the acidosis. Despite a totalbody 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 hyperlipoproteinemia 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 (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). Serum ketones are present at significant levels (usually

positive at serum dilution of ≥1:8). The nitroprusside tablet, or stick,

is often used to detect urine ketones; certain medications such as captopril or penicillamine 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 metabolic derangements of DKA exist along a spectrum,

beginning with mild acidosis with moderate hyperglycemia evolving into more severe findings. The degree of acidosis and hyperglycemia do not necessarily correlate closely because a variety of

factors determine the level of hyperglycemia (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

The management of DKA is outlined in Table 404-8. After initiating IV fluid replacement and insulin therapy, the agent or

3116 PART 12 Endocrinology and Metabolism

event that precipitated 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. The change to 0.45% saline or using lactated Ringer’s helps to reduce the trend toward hyperchloremia later

in the course of DKA.

A bolus of IV (0.1 units/kg) short-acting regular insulin is

usually administered immediately (Table 404-8), and subsequent

treatment should provide continuous and adequate levels of circulating insulin. IV administration is usually preferred (0.1 units/

kg of regular insulin per h) in patients with severe or complicated

DKA because it ensures rapid distribution and allows adjustment of

the infusion rate as the patient responds to therapy. Mild to moderate uncomplicated DKA can also be treated with SC short-acting

insulin analogues. If chosen, IV regular insulin should be continued

until the acidosis resolves and the patient is metabolically stable.

As the acidosis and insulin resistance 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 transition to an outpatient insulin

regimen and reduces length of hospital stay. It is crucial to continue

the insulin infusion or insulin SC until adequate insulin levels are

achieved by administering long-acting insulin by the SC route. Even

relatively brief periods of inadequate insulin administration in this

transition phase may result in DKA relapse. In euglycemic DKA

associated with SGLT2 inhibitors, the pharmacologic effect may

persist for 10–14 days following discontinuation of SGLT2 inhibitor

therapy as evidenced by ongoing glucosuria despite normoglycemia

(glucose <180 mg/dL), during which time relapse of ketoacidosis is

common if nutritional intake has not advanced (e.g., in the postoperative setting).

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. Rehydration 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. When the plasma glucose reaches 11.1–

13.9 mmol/L (200–250 mg/dL), glucose should be added to the

0.45% saline infusion to maintain the plasma glucose in the

8.3–11.1 mmol/L (150–200 mg/dL) range, and the insulin infusion

should be continued at a lower rate to inhibit ketogenesis. More

rapid correction of the serum glucose can precipitate the development of cerebral edema. Ketoacidosis begins to resolve as insulin

reduces lipolysis, increases peripheral ketone body use, suppresses

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. 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 hypokalemia. 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. If

the initial serum potassium level is elevated, then potassium repletion should be delayed until the potassium falls into the normal

range. Inclusion of 20–40 meq of potassium in each liter of IV

fluid is reasonable, but additional potassium supplements may

also be required. To reduce the amount of chloride administered,

potassium phosphate or acetate can be substituted for the chloride

salt. The goal is to maintain the serum potassium at >3.5 mmol/L

(3.5 meq/L).

Despite a bicarbonate deficit, bicarbonate replacement is not

usually necessary. In fact, theoretical arguments suggest that bicarbonate administration and rapid reversal of acidosis may impair

cardiac function, reduce tissue oxygenation, and promote hypokalemia. The results of most clinical trials do not support the routine

use of bicarbonate replacement, and one study in children found

that bicarbonate use was associated with an increased risk of cerebral edema. 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 may result from

increased glucose usage, but randomized clinical trials have not

demonstrated that phosphate replacement is beneficial in DKA. If

the serum phosphate is <0.32 mmol/L (1 mg/dL), then phosphate

supplement should be considered and the serum calcium monitored. Hypomagnesemia may develop during DKA therapy and

may also require supplementation.

TABLE 404-8 Management of Diabetic Ketoacidosis

1. Confirm diagnosis (↑ serum glucose, ↑ serum β-hydroxybutyrate, metabolic

acidosis).

2. Admit to hospital; intensive care setting may be necessary for frequent

monitoring, if pH <7.00, labored respiration, or impaired level of arousal.

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% 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).

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. If the initial serum potassium is <3.3 mmol/L (3.3 meq/L), do not

administer insulin until the potassium is corrected. Subcutaneous insulin may

be used in uncomplicated, mild-moderate DKA with close monitoring.

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+

: 10 meq/h when plasma K+

 <5.0–5.2 meq/L (or 20–30 meq/L of

infusion fluid), ECG normal, urine flow and normal creatinine documented;

administer 40–80 meq/h when plasma K+

 <3.5 meq/L or if bicarbonate is given.

If initial serum potassium is >5.2 mmol/L (5.2 meq/L), do not supplement K+

until the potassium is corrected.

10. See text about bicarbonate or phosphate supplementation.

11. Continue above until patient is stable, glucose goal is 8.3–11.1 mmol/L

(150–200 mg/dL), and acidosis is resolved. Insulin infusion may be decreased

to 0.02–0.1 units/kg per hour.

12. 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: Data from M Sperling, in Therapy for Diabetes Mellitus and Related

Disorders, 3rd ed. Alexandria, VA: American Diabetes Association; 1998 and EA

Nyenwe, AE Kitabchi: The evolution of diabetic ketoacidosis: An update of its

etiology, pathogenesis and management. Metabolism 65:507, 2016.

3117 Diabetes Mellitus: Management and Therapies CHAPTER 404

With appropriate therapy, the mortality rate of DKA is low (<1%)

and is related more to the underlying or precipitating event, such

as infection or myocardial infarction. Venous thrombosis, upper

GI bleeding, and acute respiratory distress syndrome occasionally

complicate DKA. The major nonmetabolic complication of DKA

therapy is cerebral edema, which most often develops in children as

DKA is resolving. The etiology of and optimal therapy for cerebral

edema are not well established, but overreplacement of free water

and rapid normalization of serum glucose should be avoided.

Following treatment, the physician and patient should review the

sequence of events that led to DKA to prevent future recurrences.

Foremost is patient education about the symptoms of DKA, its

precipitating factors, and the management of diabetes during a

concurrent illness.

■ HYPERGLYCEMIC HYPEROSMOLAR STATE

Clinical Features The prototypical patient with 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, concurrent 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 gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion 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

features in HHS are summarized in Table 404-6. Most notable are

the marked hyperglycemia (plasma glucose may be >55.5 mmol/L

[1000 mg/dL]), hyperosmolality (>350 mOsm/L), and prerenal

azotemia. 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, therapy of these disorders

shares several elements (Table 404-8). In both disorders, careful

monitoring of the patient’s fluid status, laboratory values, and insulin 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

comorbidities. 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

[D5

W]). 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

usually 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 hour. 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 regimen. The

patient should be discharged from the hospital on insulin, although

some patients can later switch to oral glucose-lowering agents.

MANAGEMENT OF DIABETES IN A

HOSPITALIZED PATIENT

Virtually all medical and surgical subspecialties are involved in the

care of hospitalized patients with diabetes. 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 counterregulatory 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

CVD in individuals with DM (especially in type 2 DM) may necessitate

preoperative cardiovascular evaluation (Chap. 405).

The goals of diabetes management during hospitalization are

near-normoglycemia, avoidance of hypoglycemia, and transition back

to the outpatient diabetes treatment regimen. Upon hospital admission,

frequent glycemic monitoring should begin, as should planning for

diabetes management after discharge. CGM in the hospital or ICU setting is not FDA-approved but is under study. Glycemic control appears

to improve the 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. However, a large

randomized clinical trial (Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation [NICE-SUGAR])

3118 PART 12 Endocrinology and Metabolism

of individuals in the intensive care unit (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) compared 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 worsens 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; (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 hyperglycemia 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

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 perioperative 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 avoidable. Hospital systems should have a diabetes management protocol to

avoid inpatient hypoglycemia. Measures to reduce or prevent hypoglycemia 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).

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.

Insulin infusions can also effectively control plasma glucose in the

perioperative 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, frequent blood glucose monitoring, and the trend of changes in the blood

glucose to determine the insulin-infusion rate. Insulin-infusion algorithms 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 supplemented by prandial and/or “corrective” insulin using a short-acting

insulin (insulin analogues preferred). “Sliding scale,” short-acting

insulin alone, where no insulin is given unless the blood glucose is

elevated, is inadequate for inpatient glucose management and should

not be used. The short-acting, preprandial 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 insulin-resistant, then the insulin 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 or “scheduled”

insulin dose 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 necessarily 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, either through an IV

insulin infusion, their insulin infusion device, or by SC administration

of a reduced dose of long-acting insulin. Short-acting insulin alone

is insufficient. Prolongation of a surgical procedure or delay in the

recovery room is not uncommon 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 concurrent illness is present

(0.5–1.0 units/h of regular insulin). If the diagnostic or surgical procedure is brief (<4 h), a reduced dose of SC insulin may suffice (20–50%

basal reduction, with short-acting bolus insulin withheld or reduced).

This approach prevents interruption of insulin infusion device therapy,

or for MDI, facilitates the transition back to long-acting 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, short-acting insulin. Oral glucose-lowering agents should be discontinued upon admission (or up

to a week prior to planned admission for SGLT2 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 SGLT2

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.

SPECIAL CONSIDERATIONS IN DM

■ TOTAL PARENTERAL NUTRITION (TPN)/TOTAL ENTERAL NUTRITION (TEN)

(See also Chap. 335) TPN or TEN greatly increases insulin requirements. 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 short-acting insulin. In TEN, hyperglycemia may be limited by

using high-protein formulations, but often requires insulin treatment.

Short-acting insulins should be used to cover bolus or continuous

enteral feeding to minimize the risk for hypoglycemia should the

TEN be interrupted or held. 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.

■ GLUCOCORTICOIDS

Glucocorticoids increase insulin resistance, decrease glucose utilization, 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

3119 Diabetes Mellitus: Management and Therapies CHAPTER 404

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 efficacious, and insulin therapy

is required. Short-acting insulin may be sufficient alone or together with

long-acting insulin in order to control postprandial glucose excursions.

■ 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 the patient population. As discussed above, individualized therapeutic goals and modalities in older

adults should consider biologic age, other comorbidities and risk

factors (hypertension, CV disease, etc.), neurocognitive and physical

functional status, living arrangements, social support, and other medications. For example, the HbA1c goal for a highly functional 80-yearold should be different from that for an individual with diabetes in

long-term care (skilled nursing facilities). In the former, the HbA1c goal

(<7.0–7.5%) and selected therapies may be similar to younger individuals whereas in an individual with complex/poor health or cognitive

impairment, an HbA1c goal of <8.0–8.5% would be reasonable. Critical

to diabetes management in all older individuals is the avoidance of

hypoglycemia, which can worsen underlying cognitive impairment

or CV disease. For individuals using CGM, <1% of time should be

spent with glucose <70 mg/dL and spending >50% of time in the target

range of 70–180 mg/dL is acceptable. Thus, medications that can cause

hypoglycemia (insulin secretagogues, insulin) should be used carefully.

In choosing medications for diabetes, the adverse effects (Table 404-5)

should be considered (especially heart failure, renal insufficiency, etc.).

Hypertension and dyslipidemia should be treated in elderly individuals

with diabetes because there is clear benefit of blood pressure control

with the benefit for lipid-lowering medications being less clearly

demonstrated.

■ REPRODUCTIVE ISSUES

Reproductive capacity in either men or women with DM appears to be

normal. Menstrual cycles may be associated with alterations in glycemic control in women with DM. Pregnancy is associated with marked

insulin resistance; the increased insulin requirements often precipitate

DM and lead to the diagnosis of gestational diabetes mellitus (GDM).

Glucose, which at high levels is a teratogen to the developing fetus,

readily crosses the placenta, but insulin does not. Thus, hyperglycemia

from the maternal circulation may stimulate insulin secretion in the

fetus. The anabolic and growth effects of insulin may result in macrosomia. GDM complicates ~7% (range 1–14%) of pregnancies. The

incidence of GDM is greatly increased in certain ethnic groups, including blacks and Latinas, consistent with a similar increased risk of type

2 DM. Current recommendations advise screening for glucose intolerance between weeks 24 and 28 of pregnancy in women not known

to have diabetes. Therapy for GDM is similar to that for individuals

with pregnancy-associated diabetes and involves MNT and insulin, if

hyperglycemia persists. Oral glucose-lowering agents are not approved

for use during pregnancy, but studies using metformin or glyburide

have shown efficacy and have not found toxicity. With current practices, the morbidity and mortality rates of the mother with GDM and

the fetus are not different from those in the nondiabetic population.

Individuals who develop GDM are at marked increased risk for developing type 2 DM in the future and should be screened periodically for

DM (see screening recommendations in Chap. 403). Most individuals

with GDM revert to normal glucose tolerance after delivery, but some

will continue to have overt diabetes or impairment of glucose tolerance

after delivery. In addition, children of women with GDM appear to be

at risk for obesity and glucose intolerance and have an increased risk of

diabetes beginning in the later stages of adolescence.

Pregnancy in individuals with known DM requires meticulous

planning and adherence to strict treatment regimens. Intensive insulin

therapy and near-normalization of the HbA1c (<6.5%) are essential

for individuals with existing DM who are planning pregnancy. Consideration should be given to insulin infusion and CGM devices that

may help to improve glycemic control prior to conception since the

most crucial period of glycemic control is soon after fertilization. The

risk of fetal malformations is increased 4–10 times in individuals with

uncontrolled DM at the time of conception, and normal blood glucose

during the preconception period and throughout the periods of organ

development in the fetus should be the goal, with more frequent monitoring of HbA1c every 2 months throughout gestation. Maintenance of

the HbA1c <6.0–6.5% reduces the incidence and severity of fetal macrosomia and neonatal hypoglycemia related to fetal hyperinsulinism

driven by elevated maternal glucose.

■ LIPODYSTROPHIC DM

Lipodystrophy, or the loss of SC fat tissue, may be generalized in certain genetic conditions such as leprechaunism, or acquired as part of

an autoimmune disorder. Generalized lipodystrophy is associated with

leptin deficiency and severe insulin resistance and is often accompanied by acanthosis nigricans, hepatic steatosis, and severe hypertriglyceridemia. Recombinant human leptin (metreleptin) may allow

for the achievement of metabolic control in generalized lipodystrophy,

but is associated with the development of neutralizing antibodies and

is available only through a restricted program under a Risk Evaluation

and Mitigation Strategy (REMS). Partial lipodystrophy may also be

caused by certain genetic or acquired (e.g., treatment of HIV infection)

conditions that produce a metabolic syndrome of insulin resistance,

ectopic fat accumulation (hepatic steatosis), and glucose intolerance

and dyslipidemia. Treatment of early childhood cancer with total-body

irradiation may affect adipose tissue development and predisposes

survivors to similar metabolic syndrome of adipose tissue dysfunction

with potentially severe insulin resistance, hepatic steatosis, hypertriglyceridemia, and diabetes.

HIV-Associated Lipodystrophy Protease inhibitors and nucleoside reverse transcriptase inhibitors used in the treatment of HIV

disease (Chap. 202) have been associated with a centripetal accumulation of fat (visceral and abdominal area), accumulation of fat in the

dorsocervical region, loss of extremity fat, decreased insulin sensitivity

(elevations of the fasting insulin level and reduced glucose tolerance

on IV glucose tolerance testing), hepatic steatosis, and dyslipidemia.

Although many aspects of the physical appearance of these individuals

resemble Cushing’s syndrome, increased cortisol levels do not account

for this appearance. The possibility remains that this is related to HIV

infection or highly active antiretroviral therapy by some undefined

mechanism, because the syndrome can be observed in individuals not

treated with protease inhibitors. Therapy for HIV-related lipodystrophy and associated metabolic dysfunction may include metformin,

especially for abdominal fat accumulation, pioglitazone, especially for

lipoatrophy and hepatic steatosis. Tesamorelin, a growth hormone–

releasing hormone analog, is effective for reducing excess abdominal

fat but requires monitoring of the serum insulin-like growth factor-1

(IGF-1) level, and may worsen glucose tolerance or exacerbate hyperglycemia in individuals with diabetes.

■ FURTHER READING

American Diabetes Association: Lifestyle management. Diabetes

Care 41:S38, 2018.

American Diabetes Association: Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in

Diabetes—2021. Diabetes Care 44(Suppl. 1):S40, 2021.

American Diabetes Association: Facilitating behavior change and

wellbeing to improve health outcomes: Standards of Medical Care in

Diabetes—2021. Diabetes Care 44(Suppl. 1):S5, 2021.

American Diabetes Association: Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care 44(Suppl. 1): S111, 2021.

American Diabetes Association: Older adults: Standards of Medical Care in Diabetes—2021. Diabetes Care 44(Suppl. 1):S168, 2021.

3120 PART 12 Endocrinology and Metabolism

American Diabetes Association: Diabetes technology: Standards

of Medical Care in Diabetes—2021. Diabetes Care 44(Suppl. 1):

S85, 2021.

Evert AB et al: Nutrition therapy for adults with diabetes or prediabetes: A consensus report. Diabetes Care 42:731, 2019.

Hirsch IB et al: The evolution of insulin and how it informs therapy

and treatment choices. Endocr Rev 41:733, 2020.

Ibrahim M et al: Recommendations for management of diabetes

during Ramadan: update 2020, applying the principles of the ADA/

EASD consensus. BMJ Open Diabetes Res Care 8:e001248, 2020.

Kalyani RR: Glucose-lowering drugs to reduce cardiovascular risk in

type 2 diabetes. N Engl J Med 384:1248, 2021.

Nyenwe EA, Kitabchi AE: The evolution of diabetic ketoacidosis: An

update of its etiology, pathogenesis and management. Metabolism

65:507, 2016.

Palmer SC et al: Sodium-glucose cotransporter protein-2 (SGLT-2)

inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists

for type 2 diabetes: Systematic review and network meta-analysis of

randomised controlled trials. BMJ 372:m4573, 2021.

Powers AC: Type 1 diabetes mellitus: Much progress, many opportunities. J Clin Invest 131:142242, 2021.

Qaseem A et al: Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline update from the American College

of Physicians. Ann Intern Med 166:279, 2017.

Rubino F et al: Metabolic surgery in the treatment algorithm for type 2

diabetes: A joint statement by international diabetes organizations.

Diabetes Care 39:86, 2016.

Satin LS et al: New aspects of diabetes research and therapeutic development. Pharmacol Rev 73:1001, 2021.

Thabit H, Hovorka R: Coming of age: The artificial pancreas for type 1

diabetes. Diabetologia 59:1795, 2016.

Young-Hyman D et al: Psychosocial care for people with diabetes: A

position statement of the American Diabetes Association. Diabetes

Care 39:2126, 2016.

Diabetes-related complications affect many organ systems and are

responsible for the majority of morbidity and mortality associated

with the disease. For many years in the United States, diabetes has

been the leading cause of new blindness in adults, renal failure, and

nontraumatic lower extremity amputation and is a leading contributor

to coronary heart disease (CHD). Diabetes-associated microvascular complications usually do not appear until the second decade of

hyperglycemia. In contrast, diabetes-associated CHD risk, related in

part to insulin resistance and its resultant dyslipidemeia, may develop

before hyperglycemia is established. Because type 2 diabetes mellitus

(DM) often has a long asymptomatic period of hyperglycemia before

diagnosis, many individuals with type 2 DM have both glucose-related

and insulin resistance–related complications at the time of diagnosis.

Fortunately, many of the diabetes-related complications can be prevented or mitigated with aggressive glycemic, lipid, and blood pressure

control, as well as efforts at early detection.

Diabetes-related complications can be divided into vascular and

nonvascular complications and are similar for type 1 and type 2 DM

(Table 405-1). The vascular complications of DM are further subdivided into microvascular (retinopathy, neuropathy, nephropathy) and

405 Diabetes Mellitus:

Complications

Alvin C. Powers, John M. Stafford,

Michael R. Rickels

TABLE 405-1 Diabetes-Related Complications

Microvascular

Eye disease

 Retinopathy (nonproliferative/proliferative)

 Macular edema

Neuropathy

 Sensory and motor (mono- and polyneuropathy)

 Autonomic

Nephropathy (albuminuria and declining renal function)

Macrovascular

Coronary heart disease

Peripheral arterial disease

Cerebrovascular disease

Other

Gastrointestinal (gastroparesis, diarrhea)

Genitourinary (uropathy/sexual dysfunction)

Dermatologic

Infectious

Cataracts

Glaucoma

Cheiroarthropathya

Periodontal disease

Hearing loss

Other comorbid conditions associated with type 1 or type 2 diabetes (relationship

to hyperglycemia is uncertain): depression, obstructive sleep apnea, fatty liver

disease, hip fracture, osteoporosis, cognitive impairment or dementia, low

testosterone in men.

a

Thickened skin and reduced joint mobility.

Mean HbA1c = 11% 10%

9%

8%

7%

Retinopathy progression, rate

24

20

16

12

8

4

0

0 2 1 3 4 5

Length of follow-up, years

6 7 8 9

FIGURE 405-1 Relationship of glycemic control and diabetes duration to diabetic

retinopathy. The progression of retinopathy in individuals in the Diabetes Control and

Complications Trial is graphed as a function of the length of follow-up with different

curves for different hemoglobin A1c (HbA1c) values. (Modified with permission from

The relationship of glycemic exposure (HbA1c) to the risk of development and

progression of retinopathy in the diabetes control and complications trial. Diabetes

44:968, 1995.)

macrovascular complications (CHD, peripheral arterial disease [PAD],

cerebrovascular disease). Microvascular complications are diabetesspecific, whereas macrovascular complications have additional pathophysiologic features that are shared with the general population. Nonvascular complications include infections, skin changes, hearing loss,

and increased risk of dementia and impaired cognitive function.

■ GLYCEMIC CONTROL AND COMPLICATIONS

The microvascular complications of both type 1 and type 2 DM result

from chronic hyperglycemia (Fig. 405-1). Evidence implicating a

causative role for chronic hyperglycemia in the development of macrovascular complications is less conclusive as other factors such as

dyslipidemia and hypertension also play important roles in macrovascular complications. CHD events and mortality rate are two to four

times greater in patients with type 2 DM, correlate with fasting and

3121 Diabetes Mellitus: Complications CHAPTER 405

One of the major findings of the UKPDS was that strict blood

pressure control significantly reduced both macro- and microvascular

complications. In fact, the beneficial effects of blood pressure control

were greater than the beneficial effects of glycemic control. Lowering

blood pressure to moderate goals (144/82 mmHg) reduced the risk of

DM-related death, stroke, microvascular endpoints, retinopathy, and

heart failure (risk reductions between 32 and 56%). The American

Diabetes Association (ADA) recommends blood pressure control

<130/80 mmHg for individuals with high cardiovascular risk and

<140/90 mmHg for individuals with lower cardiovascular risk.

Similar reductions in the risks of retinopathy and nephropathy were

also seen in a small trial of lean Japanese individuals with type 2 DM

randomized to either intensive glycemic control or standard therapy

with insulin (Kumamoto study). These results demonstrate the effectiveness of improved glycemic control in individuals of different ethnicity and, presumably, a different etiology of DM (i.e., phenotypically

different from those in the DCCT and UKPDS). The Action to Control

Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes

and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trials also found that improved glycemic control

reduced microvascular complications.

Thus, these large clinical trials in type 1 and type 2 DM indicate that

chronic hyperglycemia plays a causative role in the pathogenesis of

diabetic micro- and macrovascular complications. In both the DCCT

and the UKPDS, cardiovascular events were reduced at follow-up of

>10 years, even though the improved glycemic control was not maintained. This legacy effect for a positive impact of a period of improved

glycemic control on later diabetes complications has been attributed to

the benefits of metabolic memory. Of note, despite long-standing DM,

some individuals never develop retinopathy or nephropathy, suggesting a genetic susceptibility for developing particular complications.

■ MECHANISMS OF COMPLICATIONS

Chronic hyperglycemia is the important etiologic factor leading to

complications of DM, but the mechanism(s) by which it leads to such

diverse cellular and organ dysfunction is unknown. The complications

are likely multifactorial with an emerging hypothesis that hyperglycemia leads to epigenetic changes (Chap. 466) that influence gene

expression in affected cells. Chronic hyperglycemia leads to formation

of advanced glycosylation end products (AGEs; e.g., pentosidine,

glucosepane, and carboxymethyllysine), which bind to specific cell

surface receptor and/or the nonenzymatic glycosylation of intra- and

extracellular proteins, leading to cross-linking of proteins, glomerular

dysfunction, endothelial dysfunction, altered extracellular matrix

composition, and accelerated atherosclerosis. The reduction of cellular glucose entry afforded in certain tissues such as myocardium and

renal tubular epithelium through inhibition of the sodium glucose

co-transporter-2 (SGLT-2) may contribute to the reduction in CHD

events and renoprotective effects.

Growth factors may play an important role in some diabetes-related

microvascular complications, and their production is increased by

most of these proposed pathways. For example, vascular endothelial

growth factor A (VEGF-A) is increased locally in diabetic proliferative

retinopathy, decreases after laser photocoagulation, and is the target

inhibited by intravitreous injection therapy. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive

oxygen species or superoxide in the mitochondria and this may activate several pathways. Although hyperglycemia serves as the initial

trigger for complications of diabetes, it is still unknown whether the

same pathophysiologic processes are operative in all complications or

whether some pathways predominate in certain organs.

The mechanisms of diabetes-related macrovascular complications

including MI and stroke are glucose-related mechanisms but also

include traditional cardiovascular risk factors (dyslipidemia, hypertension) and insulin resistance. In type 2 diabetes, insulin resistance is

present years prior to diagnosis and is associated with obesity and ectopic accumulation of lipids in muscle and liver. Additionally, insulin fails

to appropriately suppress lipolysis from adipose tissue, which results in

increased delivery of fatty acids to liver, muscle, endothelial cells, and

postprandial plasma glucose levels as well the hemoglobin A1c (HbA1c),

and can be reduced by intensive diabetes management as demonstrated

in patients with type 1 DM.

The Diabetes Control and Complications Trial (DCCT) provided

definitive proof that reduction in chronic hyperglycemia can prevent

many complications of type 1 DM (Fig. 405-1). This large multicenter

clinical trial randomized >1400 individuals with type 1 DM to either

intensive or conventional diabetes management and prospectively

evaluated the development of diabetes-related complications during a

mean follow-up of 6.5 years. Individuals in the intensive diabetes management group received insulin by multiple daily injections or pump

delivery along with extensive educational, psychological, and medical

support, and achieved a substantially lower HbA1c (7.3%) than individuals in the conventional diabetes management group (9.1%). After the

DCCT results were reported in 1993, study participants were all offered

intensive therapy and continue to be followed in the Epidemiology of

Diabetes Intervention and Complications (EDIC) trial, which has completed >30 years of follow-up (DCCT + EDIC). During the subsequent

follow-up of >18 years, the initial separation in glycemic control disappeared with both arms maintaining a mean HbA1c of 8.0%, allowing

assessment of a legacy effect of 6.5 years of near-normoglycemia on the

development of long-term complications.

The DCCT phase demonstrated that improvement of glycemic

control reduced nonproliferative and proliferative retinopathy (47%

reduction), albuminuria (39% reduction), clinical nephropathy (54%

reduction), and neuropathy (60% reduction). Improved glycemic

control also slowed the progression of early diabetic complications.

During the DCCT phase, weight gain (4.6 kg) and severe hypoglycemia

(requiring assistance of another person to treat) were more common

in the intensive therapy group. The benefits of an improvement in glycemic control occurred over the entire range of elevated HbA1c values

(Fig. 405-1). The results of the DCCT predicted that individuals in

the intensive diabetes management group would gain 7.7 additional

years of vision, 5.8 additional years free from end-stage renal disease

(ESRD), and 5.6 years free from lower extremity amputations. If all

complications of DM were combined, individuals in the intensive

diabetes management group would experience >15.3 more years of life

without significant microvascular complications of DM, compared to

individuals who received standard therapy. This translates into an additional 5.1 years of life expectancy for individuals in the intensive diabetes management group. The 30-year follow-up data in the intensively

treated group show a continued reduction in retinopathy, nephropathy,

and cardiovascular disease. For example, individuals in the intensive

therapy group had a 42–57% reduction in cardiovascular events (nonfatal myocardial infarction [MI], stroke, or death from a cardiovascular

event) at a mean follow-up of 18 years, even though their subsequent

glycemic control was the same as those in the conventional diabetes

management group from years 6.5 to 17. During the EDIC phase, <1%

of the cohort had become blind, lost a limb to amputation, or required

dialysis. Other complications of diabetes, including autonomic neuropathy, bladder and sexual dysfunction, and cardiac autonomic neuropathy, were reduced in the intensive therapy group.

The United Kingdom Prospective Diabetes Study (UKPDS) studied the course of >5000 individuals with type 2 DM for >10 years.

This study used multiple treatment regimens and monitored the

effect of intensive glycemic control and risk factor treatment on the

development of diabetic complications. Newly diagnosed individuals

with type 2 DM were randomized to (1) intensive management using

various combinations of insulin, a sulfonylurea, or metformin or (2)

conventional therapy using dietary modification and pharmacotherapy

with the goal of symptom prevention. In addition, individuals were

randomly assigned to different antihypertensive regimens. Individuals

in the intensive treatment arm achieved an HbA1c of 7% compared to

7.9% in the standard treatment group. The UKPDS demonstrated that

each percentage point reduction in HbA1c was associated with a 35%

reduction in microvascular complications. As in the DCCT, there was

a continuous relationship between glycemic control and development

of complications. Improved glycemic control also reduced the cardiovascular event rate in the follow-up period of >10 years.

3122 PART 12 Endocrinology and Metabolism

cardiac tissues, leading to tissue accumulation of triglycerides, diacylglycerol, and ceramides.

■ OPHTHALMOLOGIC COMPLICATIONS

OF DIABETES MELLITUS

DM is the leading cause of blindness between the ages of 20 and

74 in the United States. Severe vision loss is primarily the result of

progressive diabetic retinopathy, which leads to significant macular

edema and new blood vessel formation. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or

early in the second decade of hyperglycemia and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton-wool

spots (Fig. 405-2). Mild nonproliferative retinopathy may progress

to more extensive disease, characterized by changes in venous vessel

caliber, intraretinal microvascular abnormalities, and more numerous

microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal

pericytes, increased retinal vascular permeability, alterations in retinal

blood flow, and abnormal retinal microvasculature, all of which can

lead to retinal ischemia.

The appearance of neovascularization in response to retinal hypoxemia is the hallmark of proliferative diabetic retinopathy (Fig. 405-2).

These newly formed vessels appear near the optic nerve and/or macula

and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Not all individuals with nonproliferative

retinopathy go on to develop proliferative retinopathy, but the more

severe the nonproliferative disease, the greater the chance of evolution

to proliferative retinopathy within 5 years. This creates an important

opportunity for early detection and treatment of diabetic retinopathy.

Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Fluorescein angiography and

optical coherence tomography are useful to detect macular edema,

which is associated with a 25% chance of moderate visual loss over

the next 3 years. Duration of DM and degree of glycemic control are

the best predictors of the development of retinopathy; hypertension,

nephropathy, and dyslipidemia are also risk factors. Nonproliferative retinopathy is found in many individuals who have had DM for

>20 years. Although there is genetic susceptibility for retinopathy, it

confers less influence than either the duration of DM or the degree of

glycemic control.

TREATMENT

Diabetic Retinopathy

The most effective therapy for diabetic retinopathy is prevention.

Intensive glycemic and blood pressure control will delay the development and slow the progression of retinopathy in individuals

with either type 1 or type 2 DM. Paradoxically, during the first

6–12 months of improved glycemic control, established diabetic

retinopathy may transiently worsen. Fortunately, this progression

is temporary, and in the long term, improved glycemic control is

associated with less diabetic retinopathy. Individuals with known

retinopathy may be candidates for prophylactic laser photocoagulation when initiating intensive therapy, and especially prior to

pancreas or islet transplantation that can rapidly normalize glycemia. Women with type 1 or type 2 DM who are planning pregnancy

should be screened prior to and during pregnancy. Once advanced

retinopathy is present, improved glycemic control imparts less

benefit, although adequate ophthalmologic care can prevent most

blindness. Lowering elevated levels of triglycerides with fenofibrate

may reduce the progression of retinopathy.

Regular, comprehensive eye examinations are essential for all

individuals with DM (see Table 404-1). Most diabetic eye disease

can be successfully treated if detected early. Routine, nondilated eye

examinations by the primary care provider or diabetes specialist are

inadequate to detect diabetic eye disease, which requires a dilated

eye exam performed by an optometrist or ophthalmologist, and

subsequent management by a retinal specialist. Treatment of severe

nonproliferative or proliferative retinopathy or macular edema with

laser photocoagulation and/or anti-VEGF therapy (intravitreous

injection) usually is successful in preserving vision. Aspirin therapy

(up to 650 mg/d) does not appear to influence the natural history

of diabetic retinopathy, and antiplatelet agents and anticoagulation

may be continued in patients receiving intravitreal injections of

anti-VEGF agents. Patients with severe proliferative retinopathy

with vitreous hemorrhage and/or traction involving the macula

often require surgical vitrectomy.

■ RENAL COMPLICATIONS OF DIABETES MELLITUS

Diabetic nephropathy is the leading cause of chronic kidney disease

(CKD) and ESRD requiring renal replacement therapy. CKD in individuals with DM is associated with an increased risk of cardiovascular

disease, and the prognosis of individuals with diabetes on dialysis is

poor. Individuals with diabetic nephropathy commonly have diabetic

retinopathy. The presence of CKD in individuals with DM and no

retinopathy should prompt investigation for alternative causes of kidney disease.

Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia. The mechanisms by which chronic hyperglycemia leads to diabetic nephropathy,

although incompletely defined, involve the effects of soluble factors

(growth factors, angiotensin II, endothelin, AGEs), hemodynamic

alterations in the renal microcirculation (glomerular hyperfiltration

or hyperperfusion, increased glomerular capillary pressure), and

structural changes in the glomerulus (increased extracellular matrix,

basement membrane thickening, mesangial expansion, fibrosis). Some

of these effects may be mediated through angiotensin II and mineralocorticoid receptors. Smoking accelerates the decline in renal function. Because only 20–40% of patients with diabetes develop diabetic

nephropathy, additional genetic or environmental susceptibility factors

likely contribute. Known risk factors include a family history of diabetic nephropathy. Diabetic nephropathy and ESRD secondary to DM

develop more commonly in blacks, Native Americans, and Hispanic

individuals with diabetes.

The natural history of diabetic nephropathy is characterized by a

sequence of events that was initially defined for individuals with type

1 DM but appears similar in type 2 DM (Fig. 405-3). Glomerular

hyperperfusion and renal hypertrophy occur in the first years after

the onset of DM and are associated with an increase of the estimated

glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy,

and mesangial volume expansion occur as the GFR returns to normal.

After 5–10 years of type 1 DM, many individuals begin to excrete small

amounts of albumin in the urine. The ADA defines albuminuria as a

persistently increased urinary albumin-to-creatinine ratio >30 mg/g

FIGURE 405-2 Diabetic retinopathy results in scattered hemorrhages, yellow

exudates, and neovascularization. This patient has neovascular vessels

proliferating from the optic disc, requiring urgent panretinal laser photocoagulation.

3123 Diabetes Mellitus: Complications CHAPTER 405

on a spot specimen. In some individuals with DM and albuminuria

of short duration, the albuminuria can regress with improvement in

glycemic control (Fig. 405-4) or with improvement in blood pressure

control using angiotensin-aldosterone system blockade and/or SGLT-2

inhibitor therapy. Diabetic kidney disease refers to albuminuria and

reduced GFR (<60 mL/min per 1.73 m2

); CKD related to diabetes,

which may not be accompanied by albuminuria, is also discussed in

Chap. 311. Once there is marked albuminuria and a reduction in GFR,

the pathologic changes are likely irreversible.

The nephropathy that develops in type 2 DM differs from that of

type 1 DM in that albuminuria may be present when type 2 DM is

diagnosed, reflecting its long asymptomatic period, and hypertension

more often contributes to albuminuria and reduced GFR. Finally, it

should be noted that albuminuria in type 2 DM may be secondary to

factors unrelated to DM, such as hypertension, congestive heart failure

(CHF), prostate disease, or infection.

As part of comprehensive diabetes care (Chap. 404), albuminuria

should be detected at an early stage when effective therapies can be

instituted. Because some individuals with type 1 or type 2 DM have

a decline in GFR in the absence of albuminuria, assessment should

include a spot urinary albumin-to-creatinine ratio and an estimated

GFR. The urine protein measurement by routine urinalysis does not

detect low levels of albumin excretion. Screening for albuminuria

should commence 5 years after the onset of type 1 DM and at the time

of diagnosis of type 2 DM.

Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism)

may occur in type 1 or 2 DM. These individuals develop a propensity to

hyperkalemia and acidemia, which may be exacerbated by medications

(especially angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and mineralocorticoid receptor antagonists). Patients with DM are predisposed to radiocontrast-induced

nephrotoxicity. Risk factors for radiocontrast-induced nephrotoxicity

are preexisting nephropathy and volume depletion. Individuals with

DM undergoing radiographic procedures with contrast dye should be

well hydrated before and after dye exposure, and the serum creatinine

should be monitored for 24–48 h following the procedure. Metformin

should be held until postintervention confirmation of preserved kidney function.

TREATMENT

Diabetic Nephropathy

The optimal therapy for diabetic nephropathy is prevention by

control of glycemia (Chap. 404 outlines glycemic goals and

approaches). Interventions effective in slowing progression of

Time from onset

 of diabetes, years

120 150 150 120 60 <10

0 3 5 1 10 5 20

Albuminuria

25

GFR, mL/min

FIGURE 405-3 Time course of development of diabetic nephropathy. The relationship of time from onset of diabetes, albuminuria, and the glomerular filtration rate (GFR) are

shown. This figure is typical for type 1 diabetes; individuals with type 2 diabetes may present with a lower GFR at the time of diagnosis.

FIGURE 405-4 Diabetic glomerular changes in a patient with type 1 diabetes are reversed by 10 years of normoglycemia as a result of pancreas transplantation. Left panel

shows diabetic glomerulosclerosis (arrow) and arteriolar hyalinosis (arrowhead) on kidney biopsy. Right panel shows a near-normal glomerulus in the same patient after

10 years of normoglycemia from pancreas transplantation. (Reproduced with permission from P Fioretto et al: Reversal of lesions of diabetic nephropathy after pancreas

transplantation. N Engl J Med 339:69, 1998.)

3124 PART 12 Endocrinology and Metabolism

albuminuria and declining kidney function include (1) improved

glycemic control, (2) strict blood pressure control, (3) administration of an ACE inhibitor or ARB, and (4) in individuals with type

2 DM, administration of a SGLT-2 inhibitor. Dyslipidemia should

also be treated.

Improved glycemic control reduces the rate at which albuminuria

appears and progresses in type 1 and type 2 DM. However, once

there is a large amount of albuminuria, it becomes more difficult

for improved glycemic control to slow progression of renal disease,

although 10-years of normoglycemia resulting from pancreas transplantation may lead to regression of mesangial glomerular lesions

(Fig. 405-4). During the later phase of declining renal function,

insulin requirements may fall as the kidney is a site of insulin degradation. As the GFR decreases with progressive nephropathy, the use

and dose of glucose-lowering agents should be reevaluated (see Table

404-5). Some glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency, while

others may require dose adjustment (glinides and DPP-4 inhibitors).

Many individuals with type 1 or type 2 DM develop hypertension. Numerous studies in both type 1 and type 2 DM demonstrate

the effectiveness of strict blood pressure control in reducing albumin excretion and slowing the decline in renal function. Blood

pressure should be maintained at <140/90 mmHg in individuals with diabetes and possibly <130/80 mmHg in individuals at

increased risk for CVD and CKD progression.

Either ACE inhibitors or ARBs should be used to reduce the

albuminuria and the associated decline in GFR in individuals with

type 1 or type 2 DM (see “Hypertension,” below). Most experts

believe that the two classes of drugs are equivalent in patient with

diabetes. ARBs can be used as an alternative in patients who develop

ACE inhibitor–associated cough or angioedema. After initiation of

therapy, some increase the dose and monitor the urinary albumin.

There is no benefit of intervention prior to onset of albuminuria

or using a combination of an ACE inhibitor and an ARB. If use of

either ACE inhibitors or ARBs is not possible or the blood pressure

is not controlled, then diuretics, calcium channel blockers (nondihydropyridine class), or beta blockers (with caution in individuals

at increased risk for experiencing hypoglycemia) may be used. Mineralocorticoid receptor antagonists can help reduce blood pressure

and albuminuria in refractory cases but require close monitoring of

the serum potassium. SGLT-2 inhibitors can reduce albuminuria

and, after an initial decline (~3 mL/min per 1.73 m2

) in GFR,

may slow further decline in kidney function in individuals with

and without T2DM and CKD. The mechanism of action of SGLT-2

inhibitors is multifactorial and includes inducing natriuresis, reducing intraglomerular pressure through restored tubuloglomerular

feedback, and potentially altering signaling pathways related to

nutrient sensing (e.g., AMPK). Because of the elevated risk of

euglycemic diabetic ketoacidosis with SGLT-2 inhibitors, use in

individuals with type 1 DM and insulin-deficient type 2 DM is not

recommended. Some glucagon-like peptide-1 (GLP-1) receptor

agonists may also both improve glycemic control and reduce the

progression of diabetic kidney disease in individuals with type 2

DM and established CVD (Chap. 404). The ADA suggests a protein

intake of 0.8 mg/kg of body weight/day in individuals with diabetic

kidney disease.

Nephrology consultation should be considered when the estimated GFR is <30 mL/min per 1.743 m2

 or with atypical features

such as hematuria, rapidly declining renal function, or proteinuria

> 3 g/day. Complications of atherosclerosis are the leading cause of

death in diabetic individuals with nephropathy and hyperlipidemia

should be treated aggressively. Referral for transplant evaluation

should be made when the GFR approaches 20 mL/min per 1.73 m2

.

Preemptive (before dialysis) kidney transplantation from a living

donor or simultaneous pancreas-kidney transplantation from a

deceased donor both offer improved patient and kidney survival

over waiting for a deceased donor kidney alone. A combined

pancreas-kidney transplant offers the promise of normoglycemia

and freedom from both insulin and dialysis. As compared with

nondiabetic individuals, hemodialysis in patients with DM is associated with more frequent complications, such as hypotension

(due to autonomic neuropathy or loss of reflex tachycardia), more

difficult vascular access, and accelerated progression of retinopathy.

■ NEUROPATHY AND DIABETES MELLITUS

Diabetic neuropathy, which occurs in ~50% of individuals with longstanding type 1 and type 2 DM, manifests as a diffuse neuropathy

(distal symmetrical polyneuropathy and/or autonomic neuropathy), a

mononeuropathy, and/or a radiculopathy/polyradiculopathy. As with

other complications of DM, the development of neuropathy correlates

with the duration of diabetes and glycemic control. Additional risk

factors are body mass index (BMI) (the greater the BMI, the greater the

risk of neuropathy) and smoking. The presence of CVD, elevated triglycerides, and hypertension is also associated with diabetic peripheral

neuropathy. Both myelinated and unmyelinated nerve fibers are lost.

Because the clinical features of diabetic neuropathy are similar to those

of other neuropathies, the diagnosis of diabetic neuropathy should be

made only after other possible etiologies are excluded (Chap. 446).

Distal Symmetric Polyneuropathy (DSPN) DSPN, the most

common form of diabetic neuropathy, most frequently presents with

distal sensory loss and pain, but up to 50% of patients do not have

symptoms of neuropathy. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads

proximally. Hyperesthesia, paresthesia, and dysesthesia also may occur.

Pain typically involves the lower extremities, is usually present at rest,

and worsens at night. Both an acute (lasting <12 months) and a chronic

form of painful diabetic neuropathy may occur. The acute form is

sometimes treatment-related, occurring in the context of improved

glycemic control. As diabetic neuropathy progresses, the pain subsides

and eventually disappears, but a sensory deficit persists, and motor

defects may develop. Physical examination (Chap. 403) often reveals

sensory loss (to 10-g monofilament and/or vibration), loss of ankle

deep-tendon reflexes, abnormal position sense, and muscular atrophy

or foot drop. Annual screening for DSPN should begin 5 years after

diagnosis of type 1 DM and at the time of diagnosis of type 2 DM and

is aimed at detecting loss of protective sensation (LOPS). LOPS and

DSPN are major risk factors for foot ulceration and falls due to small

and large nerve fiber dysfunction and predispose to lower extremity

amputation.

Autonomic Neuropathy Individuals with long-standing type 1

or 2 DM may develop signs of autonomic dysfunction involving the

parasympathetic (cholinergic) and sympathetic (adrenergic) systems.

DM-related autonomic neuropathy can affect multiple organ systems,

including the cardiovascular, gastrointestinal (GI), genitourinary,

sudomotor, and metabolic systems. Cardiovascular autonomic neuropathy, reflected by decreased heart rate variability, resting tachycardia, and orthostatic hypotension, is associated with an increase

in CVD. Orthostatic hypotension, a late and unusual complication

of diabetes, is sometimes seen in patients with associated DPN and

severe parasympathetic dysfunction. Reports of sudden death in

DM have also been attributed to autonomic neuropathy affecting the

cardiovascular system and predisposing to severe hypoglycemia, both

of which may prolong the QTc interval. Autonomic neuropathy may

reduce counterregulatory hormone release (especially epinephrine),

leading to an inability to sense hypoglycemia appropriately (hypoglycemia unawareness) (Chap. 406) and subjecting the patient to

the risk of severe hypoglycemia. Gastroparesis and bladder-emptying

abnormalities are often caused by the autonomic neuropathy seen in

DM (discussed below). Hyperhidrosis of the upper extremities and

anhidrosis of the lower extremities result from sympathetic nervous

system dysfunction. Anhidrosis of the feet can promote dry skin with

cracking, which increases the risk of foot ulcers.

Mononeuropathy and/or Radiculopathy/Polyradiculopathy

Mononeuropathy (dysfunction of isolated cranial or peripheral nerves)

is less common than polyneuropathy in DM and presents with pain

3125 Diabetes Mellitus: Complications CHAPTER 405

and motor weakness in the distribution of a single nerve. Mononeuropathies can occur at entrapment sites such as carpal tunnel or

be noncompressive. Involvement of the third cranial nerve is most

common and is heralded by diplopia. Physical examination reveals

ptosis and ophthalmoplegia with normal pupillary constriction to light.

Sometimes other cranial nerves, such as IV, VI, or VII (Bell’s palsy), are

affected. Peripheral mononeuropathies or simultaneous involvement

of more than one nerve (mononeuropathy multiplex) may also occur.

Diabetic radiculopathy or polyradiculopathy is a syndrome characterized by severe disabling pain in the distribution of one or more nerve

roots. It may be accompanied by motor weakness. Intercostal or truncal

radiculopathy causes pain over the thorax or abdomen. Involvement of

the lumbar plexus or femoral nerve may cause severe pain in the thigh

or hip and may be associated with muscle weakness in the hip flexors

or extensors (diabetic amyotrophy). Fortunately, diabetic polyradiculopathies are usually self-limited and resolve over 6–12 months.

TREATMENT

Diabetic Neuropathy

Prevention of diabetic neuropathy is critical through improved

glycemic control. Treatment of diabetic neuropathy is less than

satisfactory. Lifestyle modifications (exercise, diet) have some efficacy in DSPN in type 2 DM and hypertension, and hypertriglyceridemia should be treated. Efforts to improve glycemic control

in long-standing diabetes may be confounded by hypoglycemia

unawareness. Patients should avoid neurotoxins (including alcohol)

and smoking, and consider supplementation with vitamins for possible deficiencies (B12, folate; Chap. 333). Metformin may reduce

intestinal absorption of vitamin B12 in type 2 DM, and pernicious

anemia is more common in type 1 DM where it is associated with

anti–parietal cell autoantibodies and may require sublingual or

parenteral B12 replacement. Patients should be educated that loss of

sensation in the foot increases the risk for ulceration and its sequelae and that prevention of such problems is paramount. Patients

with symptoms or signs of neuropathy or LOPS should check their

feet daily and take precautions (footwear) aimed at preventing

calluses or ulcerations. If foot deformities are present, a podiatrist

should be involved.

Chronic, painful diabetic neuropathy is difficult to treat with

only symptomatic treatment being available; evidence of the effectiveness of improved glycemic control in painful diabetic neuropathy is lacking. Two oral agents approved by the U.S. Food and Drug

Administration (FDA), duloxetine and pregabalin, or gabapentin is

usually initially used for pain associated with diabetic neuropathy.

Diabetic neuropathy may respond to tricyclic antidepressants, venlafaxine, carbamazepine, tramadol, or topical capsaicin products.

An 8% capsaicin patch requires application by a health care provider. Tapentadol, a centrally acting opioid, is also approved by the

FDA, but has only modest efficacy and poses addiction risk, making

it and other opioids less desirable and not a first-line therapy. No

direct comparisons of agents are available, and it is reasonable to

switch agents if there is no response or if side effects develop. Referral to a pain management center may be necessary.

Therapy of orthostatic hypotension secondary to autonomic

neuropathy is also difficult. Nonpharmacologic maneuvers (adequate salt intake, avoidance of dehydration and diuretics, lower

extremity support hose, and physical activity) may offer some

benefit. A variety of agents have limited success (midodrine and

droxidopa are approved by the FDA for orthostatic hypotension of

any etiology). Patients with resting tachycardia may be considered

for beta blocker therapy with caution exercised if there is hypoglycemia unawareness. Patients with type 1 DM and orthostatic

hypotension should be evaluated for primary adrenal insufficiency

(Addison’s disease) that may be associated with anti-21-hydroxylase

autoantibodies as part of an autoimmune polyendocrine syndrome

(Chap. 389).

■ GASTROINTESTINAL/GENITOURINARY

DYSFUNCTION

Long-standing type 1 and 2 DM may affect the motility and function of

the GI and genitourinary systems. The most prominent GI symptoms

are delayed gastric emptying (gastroparesis) and altered small- and

large-bowel motility (constipation or diarrhea). Gastroparesis may

present with symptoms of anorexia, nausea, vomiting, early satiety,

and abdominal bloating. Microvascular complications (retinopathy

and neuropathy) are usually present. Nuclear medicine scintigraphy

after ingestion of a radiolabeled meal may document delayed gastric

emptying but may not correlate well with the patient’s symptoms. Noninvasive “breath tests” following ingestion of a radiolabeled meal are

emerging as a diagnostic tool. Although parasympathetic dysfunction

secondary to chronic hyperglycemia is important in the development

of gastroparesis, hyperglycemia itself also impairs gastric emptying.

Nocturnal diarrhea, alternating with constipation, is a feature of

DM-related GI autonomic neuropathy. In type 1 DM, these symptoms

should also prompt evaluation for celiac disease that is associated with

anti-tissue transglutaminase autoantibodies because of its increased

frequency.

Diabetic autonomic neuropathy may lead to genitourinary dysfunction including cystopathy and female sexual dysfunction (reduced

sexual desire, dyspareunia, reduced vaginal lubrication). Symptoms of

diabetic cystopathy begin with an inability to sense a full bladder and

a failure to void completely. As bladder contractility worsens, bladder

capacity and the postvoid residual increase, leading to symptoms of

urinary hesitancy, decreased voiding frequency, incontinence, and

recurrent urinary tract infections.

Erectile dysfunction and retrograde ejaculation are very common

in DM and may be one of the earliest signs of diabetic neuropathy

(Chap. 397). Erectile dysfunction, which increases in frequency with

the age of the patient and the duration of diabetes, may occur in the

absence of other signs of diabetic autonomic neuropathy.

TREATMENT

Gastrointestinal/Genitourinary Dysfunction

Current treatments for these complications of DM are inadequate

and nonspecific. Improved glycemic control should be a goal but

has not clearly shown benefit. Smaller, more frequent meals that

are easier to digest (liquid) and low in fat and fiber may minimize

symptoms of gastroparesis. Medications that slow gastric emptying

(opioids, GLP-1 receptor agonists) should be avoided. Metoclopramide may be used with severe symptoms but is restricted to shortterm treatment in both the United States and Europe. Symptoms of

gastroesophageal reflux disease may require acid blocking therapy

with a histamine-2 receptor antagonist or proton pump inhibitor.

Gastric electrical stimulatory devices are available but not approved.

Diabetic diarrhea in the absence of bacterial overgrowth is treated

symptomatically (Chap. 325).

Diabetic cystopathy should be treated with scheduled voiding

or self-catheterization. Drugs that inhibit type 5 phosphodiesterase

are effective for erectile dysfunction, but their efficacy in individuals with DM is slightly lower than in the nondiabetic population

(Chap. 397).

■ CARDIOVASCULAR MORBIDITY AND MORTALITY

CVD is increased in individuals with type 1 or type 2 DM. The

Framingham Heart Study revealed a marked increase in PAD, coronary

artery disease, MI, and CHF (risk increase from one- to fivefold) in

DM. In addition, the prognosis for individuals with diabetes who have

coronary artery disease or MI is worse than for nondiabetics. CHD

is more likely to involve multiple vessels in individuals with DM. In

addition to CHD, cerebrovascular disease is increased in individuals

with DM (threefold increase in stroke). Thus, after controlling for all

known cardiovascular risk factors, both type 1 and type 2 DM increases

the cardiovascular death rate twofold in men and fourfold in women.

CHF is common in long-standing DM.

3126 PART 12 Endocrinology and Metabolism

The American Heart Association considers DM as a controllable

risk factor for cardiovascular disease; in some studies, type 2 DM

patients without a prior MI have a similar risk for coronary arteryrelated events as nondiabetic individuals who have had a prior MI.

Cardiovascular risk assessment in type 2 DM should encompass a more

nuanced approach. Cardiovascular risk is lower and not equivalent in

a younger individual with a brief duration of type 2 DM compared

to an older individual with long-standing type 2 DM. In individuals

without a known diagnosis of diabetes, elevated HbA1c is predictive

not just of diabetes risk but also risk of CHD, stroke, and all-cause

mortality. Because of the extremely high prevalence of underlying

CVD in individuals with diabetes (especially in type 2 DM), evidence

of atherosclerotic vascular disease (e.g., cardiac stress test) should

be sought in an individual with diabetes who has symptoms, even if

atypical, suggestive of cardiac ischemia or peripheral or carotid arterial

disease. The screening of asymptomatic individuals with diabetes for

CHD is not recommended or cost-effective. The absence of chest pain

(“silent ischemia”) is common in individuals with diabetes, and a thorough cardiac evaluation should be considered prior to major surgical

procedures.

The increase in cardiovascular morbidity and mortality rates in

diabetes appears to relate to the synergism of hyperglycemia with

other cardiovascular risk factors such as dyslipidemia (elevated triglycerides, low high-density lipoprotein [HDL] cholesterol and small

dense low-density lipoprotein [LDL]), hypertension, obesity, reduced

physical activity, and cigarette smoking. Additional risk factors that

are prevalent include CKD (albuminuria, reduced GFR), abnormal

platelet function, increased markers of inflammation, and endothelial

dysfunction. The results of the ACCORD trial and VADT trial, which

demonstrated that tight glucose control had limited benefit on cardiovascular outcomes in individuals with established cardiovascular disease, suggesting the importance of insulin resistance and dyslipidemia.

TREATMENT

Cardiovascular Disease

Treatment of coronary disease in individuals with DM has substantial overlap with treatment in individuals without DM (Chap. 273).

Revascularization procedures for CHD, including percutaneous

coronary interventions (PCIs) and coronary artery bypass grafting

(CABG), may be less efficacious in individuals with DM. Initial

success rates of PCI in individuals with DM are similar to those in

the nondiabetic population, but higher rates of restenosis and lower

long-term patency and survival rates have been reported. CABG

plus optimal medical management likely has better outcomes than

PCI for individuals with diabetes.

Aggressive cardiovascular risk modification in all individuals

with DM and glycemic control should be individualized, as discussed in Chap. 404. In patients with known CHD and type 2 DM,

an ACE inhibitor or ARB, a statin, and acetylsalicylic acid (ASA;

aspirin) should be considered. Beta blockers can be used in individuals with diabetes after MI. In patients with CHF, thiazolidinediones should not be used (Chap. 404). However, metformin can

be used in patients with stable CHF if the renal function is normal.

Some newer glucose-lowering therapies also have cardiovascular

benefit, including the GLP-1 analogues liraglutide (LEADER trial),

semaglutide (SUSTAIN-6 trial), and dulaglutide (REWIND trial)

and the SGLT-2 inhibitors empagliflozin (EMPA-REG trial) and

canagliflozin (CANVAS trial). All SGLT-2 inhibitors have been

shown to exhibit benefits on prevention of CHF exacerbations. A

possible increased risk of lower limb amputation and Fournier’s

gangrene has been reported with SGLT-2 inhibitor therapy.

Antiplatelet therapy reduces cardiovascular events in individuals with DM who have CHD and is recommended. The ADA

recommends considering the use of aspirin for primary prevention

of coronary events in individuals with diabetes with an increased

cardiovascular risk (>50 years old with at least one risk factor

such as hypertension, dyslipidemia, smoking, family history, or

albuminuria). ASA is not recommended for primary prevention

in those with a low cardiovascular risk (<50 years old with no

risk factors). The aspirin dose is the same as in nondiabetic

individuals.

Cardiovascular Risk Factors • DYSLIPIDEMIA Individuals

with DM may have several forms of dyslipidemia (Chap. 407).

Because of the additive cardiovascular risk of hyperglycemia and

hyperlipidemia, lipid abnormalities should be assessed aggressively

and treated as part of comprehensive diabetes care (Chap. 404). The

most common pattern of dyslipidemia is hypertriglyceridemia and

reduced HDL cholesterol levels. DM itself does not increase levels of

LDL, but the small dense LDL particles found in type 2 DM are more

atherogenic because they are more easily glycated and susceptible to

oxidation.

Almost all treatment studies of diabetic dyslipidemia have been

performed in individuals with type 2 DM because of the greater frequency of dyslipidemia in this form of diabetes. Interventional studies

have shown that the beneficial effects of LDL reduction with statins are

similar in the diabetic and nondiabetic populations. No prospective

studies have addressed similar questions in individuals with type 1

DM. Because the frequency of CVD is low in children and young adults

with diabetes, assessment of cardiovascular risk should be incorporated

into the guidelines discussed below.

Based on the guidelines provided by the ADA, all individuals with

diabetes should be advised about lifestyle modification, including

diet, weight loss, and increased physical activity (Chap. 404). If individuals with diabetes have elevated triglyceride levels (>1.7 mmol/L

[150 mg/dL]) or low HDL cholesterol (<1 mmol/L [40 mg/dL] in

men and <1.3 mmol/L [50 mg/dL] in women), lifestyle modification

and improved glycemic control should be further emphasized. If triglycerides remain >5.7 mmol/L (500 mg/dL), treatment with fish oil,

fibrate drugs, and icosapent may reduce the risk of pancreatitis. Icosapent additionally lowers CHD risk.

In terms of pharmacologic therapy, the ADA recommends the

following: (1) all patients with diabetes and atherosclerotic cardiovascular disease should receive high-intensity statin therapy; (2) in

patients aged 40–75 years without cardiovascular disease, consider

moderate-intensity statin therapy to target LDL cholesterol <100 mg/

dL (without additional risk factors) or high-intensity statin therapy

to target LDL cholesterol <70 mg/dL (with additional risk factors);

and (3) in patients aged 20–39 years with additional risk factors, consider moderate-intensity statin therapy. Screening for coronary artery

calcification by electron beam computed tomography (CT) scan that

noninvasively detects the presence of coronary artery atherosclerosis

may help guide treatment initiation or intensity in equivocal cases or

ambivalent patients. Atorvastatin and rosuvastatin are generally well

tolerated if started at lower doses and titrated up to meet lipid goals.

Atorvastatin is the statin of choice in patients with renal disease. If

statin intolerant or the LDL cholesterol goal is not met, consider the

addition of ezetimibe or a PCSK9 inhibitor (Chap. 407). Icosapent

results in cardiovascular risk reduction on top of statin treatment and

may have a larger benefit in diabetic individuals. Statin usage is associated with a mild increase in the risk of developing type 2 DM. This risk

is greatest in individuals with other risk factors for type 2 DM (Chap.

403). However, the cardiovascular benefits of statin use outweigh the

mildly increased risk of diabetes. Niacin use is associated with an even

greater increased risk for type 2 DM or worsening glycemic control

and is not recommended because of a lack of improvement in cardiovascular outcomes.

In individuals with type 2 DM and kidney disease or type 2 DM

and atherosclerotic cardiovascular disease or multiple atherosclerotic

risk factors, the ADA recommends an SGLT-2 inhibitor or GLP-1

receptor agonist as a second-line agent after metformin. In individuals

with type 2 DM and heart failure (reduced ejection fraction), the ADA

recommends an SGLT-2 inhibitor. Individuals with atherosclerotic

3127 Diabetes Mellitus: Complications CHAPTER 405

cardiovascular disease and type 1 or type 2 DM should be treated with

an ACE inhibitor or angiotensin receptor blocker and beta blockers

and antiplatelet therapy, as in the nondiabetic population (Chap. 273).

HYPERTENSION Hypertension can accelerate other complications of

DM, particularly CVD, nephropathy, and retinopathy. Blood pressure

should be measured at every clinic visit. In targeting a goal of blood

pressure of <140/90 mmHg, therapy should first emphasize lifestyle

modifications such as weight loss, exercise, stress management, and

sodium restriction. The blood pressure goal should be individualized.

In some younger individuals or those with increased cardiovascular

risk, the provider may target a blood pressure of <130/80 mmHg.

Realizing that more than one agent is usually required to reach the

blood pressure goal, the ADA recommends that all patients with diabetes and hypertension be treated with an ACE inhibitor or an ARB

initially. Subsequently, agents that reduce cardiovascular risk (beta

blockers, thiazide diuretics, and calcium channel blockers) should be

incorporated into the regimen. ACE inhibitors and ARBs are likely

equivalent in most patients with diabetes and renal disease but should

not be combined. The addition of a potassium-sparing diuretic or

mineralocorticoid receptor antagonist can help achieve blood pressure

targets in refractory cases. Serum potassium and renal function should

be monitored.

Because of the high prevalence of atherosclerotic disease in individuals with type 2 DM, the possibility of renovascular hypertension

should be considered when the blood pressure is not readily controlled.

■ LOWER EXTREMITY COMPLICATIONS

DM is the leading cause of nontraumatic lower extremity amputation

in the United States. Foot ulcers and infections are also a major source

of morbidity in individuals with DM. The reasons for the increased

incidence of these disorders in DM involve the interaction of several

pathogenic factors: neuropathy, abnormal foot biomechanics, PAD,

and poor wound healing. The peripheral sensory neuropathy interferes

with normal protective mechanisms and allows the patient to sustain

major or repeated minor trauma to the foot, often without knowledge

of the injury. Disordered proprioception causes abnormal weight

bearing while walking and subsequent formation of callus or ulceration. Motor and sensory neuropathy lead to abnormal foot muscle

mechanics and to structural changes in the foot (hammer toe, claw

toe deformity, prominent metatarsal heads, Charcot joint). Autonomic

neuropathy results in anhidrosis and altered superficial blood flow in

the foot, which promote drying of the skin and fissure formation. PAD

and poor wound healing impede resolution of minor breaks in the skin,

allowing them to enlarge and to become infected.

Many individuals with DM develop a foot ulcer (great toe or metatarsophalangeal areas are most common), and a significant subset who

develop an ulceration will ultimately undergo amputation (14–24%

risk with that ulcer or subsequent ulceration). Risk factors for foot

ulcers or amputation include male sex, diabetes for >10 years, peripheral neuropathy, abnormal structure of foot (bony abnormalities,

callus, thickened nails), PAD, smoking, history of previous ulcer or

amputation, visual impairment, poor glycemic control, and diabetic

nephropathy, especially dialysis. Large calluses are often precursors to

or overlie ulcerations. Aggressive treatment of LDL cholesterol with

the PCSK9 inhibitor evolocumab has been shown to reduce the risk of

future major adverse limb events in patients with PAD.

TREATMENT

Lower Extremity Complications

The optimal therapy for foot ulcers and amputations is prevention through identification of high-risk patients, education of the

patient, and institution of measures to prevent ulceration. High-risk

patients should be identified during the routine, annual foot examination performed on all patients with DM (see “Ongoing Aspects of

Comprehensive Diabetes Care” in Chap. 404). If the monofilament

test or one of the other tests is abnormal, the patient is diagnosed

with LOPS (Chap. 403). Providers should consider screening for

asymptomatic PAD in individuals >50 years of age who have diabetes and other risk factors using ankle-brachial index testing

(Chap. 281). Patient education should emphasize (1) careful selection of footwear, (2) daily inspection of the feet to detect early signs

of poor-fitting footwear or minor trauma, (3) daily foot hygiene

to keep the skin clean and moist, (4) avoidance of self-treatment

of foot abnormalities and high-risk behavior (e.g., walking barefoot), and (5) prompt consultation with a health care provider if an

abnormality arises. Calluses and nail deformities should be treated

by a podiatrist. Interventions directed at risk factor modification

include orthotic shoes and devices, callus management, nail care,

and prophylactic measures to reduce increased skin pressure from

abnormal bony architecture. Attention to other risk factors for vascular disease (smoking, dyslipidemia, hypertension) and improved

glycemic control are also important.

Despite preventive measures, foot ulceration and infection are

common and represent a serious problem. Due to the multifactorial pathogenesis of lower extremity ulcers, management of these

lesions is multidisciplinary and often demands expertise in orthopedics, vascular surgery, endocrinology, podiatry, and infectious

diseases. The plantar surface of the foot is the most common site of

ulceration. Ulcers may be primarily neuropathic (no accompanying infection) or may have surrounding cellulitis or osteomyelitis.

Cellulitis without ulceration should be treated with antibiotics that

provide broad-spectrum coverage (see below).

An infected ulcer is a clinical diagnosis, because superficial

culture of any ulceration will likely find multiple bacterial species

of unknown significance. The infection surrounding the foot ulcer

may be due to multiple organisms, with aerobic gram-positive

cocci (staphylococci including methicillin-resistant Staphylococcus

aureus [MRSA], group A and B streptococci) being most common

and with aerobic gram-negative bacilli and/or obligate anaerobes as

co-pathogens.

Gas gangrene may develop in the absence of clostridial infection.

Cultures should be obtained from the debrided ulcer base or from

purulent drainage or aspiration of the wound. Wound depth should

be determined by inspection and probing with a blunt-tipped sterile

instrument. A wound that probes to the bone represents clinical

evidence of osteomyelitis. Plain radiographs of the foot should be

performed to assess the possibility of osteomyelitis in chronic ulcers

that have not responded to therapy. Magnetic resonance imaging

(MRI) is the most specific modality, with nuclear medicine scans

and labeled white cell studies as alternatives. Surgical debridement

is often necessary.

Osteomyelitis is best treated by a combination of prolonged

antibiotics and debridement of infected bone when possible. The

possible contribution of vascular insufficiency should be considered in all patients. Peripheral arterial bypass procedures are often

effective in promoting wound healing and in decreasing the need

for amputation of the ischemic limb (Chap. 281).

Interventions with demonstrated efficacy in diabetic foot ulcers

or wounds include the following: (1) off-loading, (2) debridement, (3) wound dressings, (4) appropriate use of antibiotics, (5)

revascularization, and (6) limited amputation. Off-loading is the

complete avoidance of weight bearing on the ulcer, which removes

the mechanical trauma that retards wound healing. Bed rest and a

variety of orthotic devices or contact casting limit weight bearing

on wounds or pressure points. Surgical debridement is important

and effective, but the efficacy of other modalities for wound healing

(enzymes, growth factors, cellular therapy, hyperbaric oxygen) is

unclear. Dressings such as hydrocolloid dressings promote wound

healing by creating a moist environment, controlling the exudate,

and protecting the wound. Antiseptic agents should be avoided.

Topical antibiotics are of limited value. Referral for physical therapy, orthotic evaluation, and rehabilitation should occur once the

infection is controlled.

3128 PART 12 Endocrinology and Metabolism

Mild or non-limb-threatening infections can be treated with

oral antibiotics directed predominantly at methicillin-susceptible

staphylococci and streptococci (e.g., dicloxacillin, cephalosporin,

amoxicillin/clavulanate). However, in patients with a prior history

of MRSA or in locations with a high prevalence of MRSA, treatment

with clindamycin, doxycycline, or trimethoprim-sulfamethoxazole

is preferred. Trimethoprim-sulfamethoxazole exhibits less reliable

coverage of streptococci than the β-lactams, and individuals with

diabetes may develop adverse effects including acute kidney injury

and hyperkalemia. Surgical debridement of necrotic tissue, local

wound care (avoidance of weight bearing over the ulcer), and

close surveillance for progression of infection are crucial. More

severe infections require IV antibiotics as well as offloading and

local wound care. Urgent surgical debridement may be required.

Optimization of glycemic control should be a goal. IV antibiotics

should provide broad-spectrum coverage directed toward S. aureus,

including MRSA, streptococci, gram-negative aerobes, and anaerobic bacteria. Initial antimicrobial regimens include vancomycin

plus a β-lactam/β-lactamase inhibitor or carbapenem, or vancomycin plus a quinolone with metronidazole. In some cases, daptomycin, ceftaroline, or linezolid may be substituted for vancomycin in

consultation with an Infectious Diseases expert. If the infection

surrounding the ulcer is not improving with IV antibiotics, reassessment of antibiotic coverage and reconsideration of the need

for surgical debridement or revascularization are indicated. With

clinical improvement, oral antibiotics and local wound care can be

continued on an outpatient basis with close follow-up.

■ INFECTIONS

Individuals with DM have a greater frequency and severity of infection.

The reasons for this include incompletely defined abnormalities in cellmediated immunity and phagocyte function associated with hyperglycemia, as well as diminished vascularization. Hyperglycemia aids the

colonization and growth of a variety of organisms (Candida and other

fungal species). Many common infections are more frequent and

severe in the diabetic population, whereas several rare infections are

seen almost exclusively in the diabetic population. Examples of this

latter category include rhinocerebral mucormycosis, emphysematous

infections of the gallbladder and urinary tract, and “malignant” or

invasive otitis externa. Invasive otitis externa is usually secondary to

Pseudomonas aeruginosa infection in the soft tissue surrounding the

external auditory canal, usually begins with pain and discharge, and

may rapidly progress to osteomyelitis and meningitis. These infections

should be sought, in particular, in patients presenting with severe

hyperglycemia (Chap. 404).

Pneumonia, urinary tract infections, and skin and soft tissue infections are all more common in the diabetic population. In general, the

organisms that cause pulmonary infections are similar to those found

in the nondiabetic population; however, gram-negative organisms,

S. aureus, and Mycobacterium tuberculosis are more frequent pathogens. Adults with DM should receive vaccination against pneumococcus, annually against influenza, and now also against the coronavirus

SARS-CoV-2, which causes increased morbidity and mortality in

obese individuals and patients with DM (Chap. 199). In addition to

early antibiotic therapy for presumed bacterial infections, patients with

DM should be considered for early intervention with antiviral agents

(e.g., against influenza in flu or varicella-zoster virus in shingles) or

with monoclonal antibodies in COVID-19. Urinary tract infections

(either lower tract or pyelonephritis) are the result of common bacterial agents such as Escherichia coli, although several yeast species

(e.g., Candida albicans and Candida glabrata) are commonly observed.

Complications of urinary tract infections include emphysematous pyelonephritis and emphysematous cystitis. Bacteriuria occurs frequently

in individuals with diabetic cystopathy and does not require antibiotic therapy except in specific circumstances such as pregnancy or a

planned urologic procedure. Susceptibility to furunculosis, superficial

candidal infections, and vulvovaginitis are increased. Poor glycemic

control is a common denominator in individuals with these infections.

Individuals with diabetes have an increased rate of colonization of S.

aureus in the skinfolds and nares. Individuals with diabetes also have

a greater risk of postoperative wound infections that may be mitigated

by perioperative protocols for insulin administration to maintain glycemic control.

■ DERMATOLOGIC MANIFESTATIONS

The most common skin manifestations of DM are xerosis and pruritus

and are usually relieved by skin moisturizers. Protracted wound healing and skin ulcerations are also frequent complications. Diabetic dermopathy, sometimes termed pigmented pretibial papules, or “diabetic

skin spots,” begins as an erythematous macule or papule that evolves

into an area of circular hyperpigmentation. These lesions result from

minor mechanical trauma in the pretibial region and are more common in elderly men with DM. Bullous diseases, such as bullosa diabeticorum (shallow ulcerations or erosions in the pretibial region), are

also seen. Necrobiosis lipoidica diabeticorum is an uncommon disorder,

accompanying diabetes in predominantly young women. This usually

begins in the pretibial region as an erythematous plaque or papules that

gradually enlarge, darken, and develop irregular margins, with atrophic

centers and central ulceration. They are often painful. Vitiligo and

alopecia areata occur at increased frequency in individuals with type

1 DM. Acanthosis nigricans (hyperpigmented velvety plaques seen on

the neck, axilla, or extensor surfaces) is sometimes a feature of severe

insulin resistance and accompanying diabetes. Generalized or localized granuloma annulare (erythematous plaques on the extremities

or trunk), lichen planus (violaceous papules on the cutaneous surface

with or without erosions in the mouth and genitalia), and scleredema

(areas of skin thickening on the back or neck at the site of previous

superficial infections) are more common in the diabetic population.

Lipoatrophy and lipohypertrophy can occur at insulin injection sites but

are now unusual with the use of human insulin and avoided by rotating

injection sites.

■ FURTHER READING

American Diabetes Association: Cardiovascular disease and risk

management: Standards of Medical Care in Diabetes-2021. Diabetes

Care 44(suppl 1):S125, 2021.

American Diabetes Association: Microvascular complications and

foot care: Standards of Medical Care in Diabetes-2021. Diabetes Care

44(suppl 1):S151, 2021.

Drucker DJ: Diabetes, obesity, metabolism, and SARS-CoV-2

infection: The end of the beginning. Cell Metab 33:479, 2021.

Hingorani A et al: The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration

with the American Podiatric Medical Association and the Society for

Vascular Medicine. J Vasc Surg 63:3S, 2016.

Holman RR et al: 10-year follow-up of intensive glucose control in

type 2 diabetes. N Engl J Med 359:1577, 2008.

Nathan DM et al: Diabetes control and complications trial/

epidemiology of diabetes interventions and complications study at

30 years: Advances and contributions. Diabetes 62:3976, 2013.

Pop-Busui R et al: Diabetic neuropathy: A position statement by the

American Diabetes Association. Diabetes Care 40:136, 2017.

Solomon SD et al: Diabetic retinopathy: A position statement by the

American Diabetes Association. Diabetes Care 40:412, 2017.

Williams DM et al: Renal outcomes in type 2 diabetes: A review of

cardiovascular and renal outcome trials. Diabetes Ther 11:369, 2020.