Chapter 41: Pancreatic Hormones & Antidiabetic Drugs

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least five hormone-producing cells are present (Table 41–1). Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified; and ghrelin, a peptide known to increase pituitary growth hormone release.

TABLE 41–1¹Pancreatic islet cells and their secretory products.

TABLE 41–1 Pancreatic islet cells and their secretory products.

Cell Types¹

Approximate Percent of Islet Mass

Secretory Products

Alpha (A) cell

Glucagon, proglucagon

Beta (B) cell

Insulin, C-peptide, proinsulin, amylin

Delta (D) cell

3–5

Somatostatin

Epsilon cell

Ghrelin

Within pancreatic polypeptide-rich lobules of adult islets, located only in the posterior portion of the head of the human pancreas, glucagon cells are scarce (<0.5%) and F cells make up as much as 80% of the cells.

INSULIN

Chemistry

Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids (Figure 41–1).

FIGURE 41–1

Structure of human proinsulin (C-peptide plus A and B chains) and insulin. Insulin is shown as the shaded (orange color) peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro, and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)

Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram.

Insulin Secretion

Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), amino acids (especially gluconeogenic amino acids, eg, leucine, arginine), hormones such as glucagon-like polypeptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity are recognized. Stimulatory drugs include sulfonylureas, meglitinide and nateglinide, isoproterenol, and acetylcholine. Inhibitory signals are hormones including insulin itself, islet amyloid polypeptide, somatostatin, and leptin; α-adrenergic sympathetic activity; chronically elevated glucose; and low concentrations of fatty acids. Inhibitory drugs include diazoxide, phenytoin, vinblastine, and colchicine.

One mechanism of stimulated insulin release is diagrammed in Figure 41–2. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the beta cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and D-phenylalanine) exploits parts of this mechanism.

FIGURE 41–2

One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism.

Insulin Degradation

The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35–40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%. The half-life of circulating insulin is 3–5 minutes.

Circulating Insulin

Basal serum insulin values of 5–15 μU/mL (30–90 pmol/L) are found in normal humans, with a peak rise to 60–90 μU/mL (360–540 pmol/L) during meals.

The Insulin Receptor

After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues regulating energy metabolism, ie, liver, muscle, and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an α subunit, which is entirely extracellular and constitutes the recognition site, and a β subunit that spans the membrane (Figure 41–3). The β subunit contains a tyrosine kinase. The binding of an insulin molecule to the α subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic β subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the β subunits and tyrosine kinase activity directed at cytoplasmic proteins.

FIGURE 41–3

Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; MAP, mitogen-activated protein; P, phosphate; Tyr, tyrosine.

The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins: insulin receptor substrates (IRS). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases subserving energy metabolism—most significantly phosphatidylinositol-3-kinase—which produce further phosphorylations. Alternatively, they may stimulate a mitogenic pathway and bind to an adaptor protein such as growth factor receptor–binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein, Ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4–5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin’s second message and results in multiple effects, including translocation of glucose transporters (especially GLUT 4, Table 41–2) to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division.

TABLE 41–2Glucose transporters.

TABLE 41–2 Glucose transporters.

Transporter

Tissues

Glucose K_m (mmol/L)

Function

GLUT 1

All tissues, especially red cells, brain

1–2

Basal uptake of glucose; transport across the blood-brain barrier

GLUT 2

Beta cells of pancreas; liver, kidney; gut

15–20

Regulation of insulin release, other aspects of glucose homeostasis

GLUT 3

Brain, placenta

Uptake into neurons, other tissues

GLUT 4

Muscle, adipose

Insulin-mediated uptake of glucose

GLUT 5

Gut, kidney

1–2

Absorption of fructose

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor β subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.

Effects of Insulin on Its Targets

Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells (Figure 41–4) and influences cell growth and the metabolic functions of a wide variety of tissues (Table 41–3).

FIGURE 41–4

Insulin promotes synthesis (from circulating nutrients) and storage of glycogen, triglycerides, and protein in its major target tissues: liver, fat, and muscle. The release of insulin from the pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, and other factors (see text).

TABLE 41–3Endocrine effects of insulin.

TABLE 41–3 Endocrine effects of insulin.

Effect on liver:

Reversal of catabolic features of insulin deficiency

Inhibits glycogenolysis

Inhibits conversion of fatty acids and amino acids to keto acids

Inhibits conversion of amino acids to glucose

Anabolic action

Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)

Increases triglyceride synthesis and very-low-density lipoprotein formation

Effect on muscle:

Increased protein synthesis

Increases amino acid transport

Increases ribosomal protein synthesis

Increased glycogen synthesis

Increases glucose transport

Induces glycogen synthase and inhibits phosphorylase

Effect on adipose tissue:

Increased triglyceride storage

Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins

Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport

Intracellular lipase is inhibited by insulin

GLUCAGON

Chemistry & Metabolism

Glucagon is synthesized in the alpha cells of the pancreatic islets of Langerhans (Table 41–1). Glucagon is a peptide—identical in all mammals—consisting of a single chain of 29 amino acids, with a molecular weight of 3485. Selective proteolytic cleavage converts a large precursor molecule of approximately 18,000 MW to glucagon. One of the precursor intermediates consists of a 69-amino-acid peptide called glicentin, which contains the glucagon sequence interposed between peptide extensions.

Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin.

Pharmacologic Effects of Glucagon

A. Metabolic Effects

The first six amino acids at the amino terminal of the glucagon molecule bind to specific G_s protein–coupled receptors on liver cells. This leads to an increase in cAMP, which facilitates catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate pharmacological result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. There is no effect on skeletal muscle glycogen, presumably because of the lack of glucagon receptors on skeletal muscle. Pharmacological amounts of glucagon cause release of insulin from normal pancreatic beta cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells.

B. Cardiac Effects

Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism described above. Thus, it produces an effect very similar to that of β-adrenoceptor agonists without requiring functioning β receptors.

C. Effects on Smooth Muscle

Large doses of glucagon produce profound relaxation of the intestine. In contrast to the above effects of the peptide, this action on the intestine may be due to mechanisms other than adenylyl cyclase activation.

Clinical Uses

A. Severe Hypoglycemia

The major clinical use of glucagon is for emergency treatment of severe hypoglycemic reactions in patients with type 1 diabetes when unconsciousness precludes oral feedings and intravenous glucose treatment is not possible. Recombinant glucagon is currently available in 1-mg vials for parenteral (IV, IM, or SC) use (Glucagon Emergency Kit).

B. Endocrine Diagnosis

Several tests use glucagon to diagnose endocrine disorders. In patients with type 1 diabetes mellitus, a classic research test of pancreatic beta-cell secretory reserve uses 1 mg of glucagon administered as an intravenous bolus. Because insulin-treated patients develop circulating anti-insulin antibodies that interfere with radioimmunoassays of insulin, measurements of C-peptide are used to indicate beta-cell secretion.

C. Beta-Adrenoceptor Blocker Overdose

Glucagon is sometimes useful for reversing the cardiac effects of an overdose of β-blocking agents because of its ability to increase cAMP production in the heart independent of β-receptor function. However, it is not clinically useful in the treatment of heart failure.

D. Radiology of the Bowel

Glucagon has been used extensively in radiology as an aid to x-ray visualization of the bowel because of its ability to relax the intestine.

Adverse Reactions

Transient nausea and occasional vomiting can result from glucagon administration. These are generally mild, and glucagon is relatively free of severe adverse reactions. It should not be used in a patient with pheochromocytoma.

DIABETES MELLITUS

Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories: type 1, type 2, other, and gestational diabetes mellitus.

Type 1 Diabetes Mellitus

The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. Type 1 diabetes is further subdivided into immune-mediated (type 1a) and idiopathic causes (type 1b). The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage, but only 10–15% of patients have a positive family history. Most patients with type 1 diabetes have one or more circulating antibodies to glutamic acid decarboxylase 65 (GAD 65), insulin autoantibody, tyrosine phosphatase IA2 (ICA 512), and zinc transporter 8 (ZnT8) at the time of diagnosis. These antibodies facilitate the diagnosis of type 1a diabetes and can also be used to screen family members at risk for developing the disease. Most type 1 patients with acute symptomatic presentation have significant beta cell loss and insulin therapy is essential to control glucose levels and to prevent ketosis.

Some patients have a more indolent autoimmune process and initially retain enough beta cell function to avoid ketosis. They can be treated at first with oral hypoglycemic agents but then need insulin as their beta cell function declines. Antibody studies in northern Europeans indicate that up to 10–15% of “type 2” patients may actually have this milder form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA).

Type 2 Diabetes Mellitus

Type 2 diabetes is a heterogenous group of conditions characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more beta-cell deficiency, and the abnormalities may be mild or severe. Although the circulating endogenous insulin is sufficient to prevent ketoacidosis, it is inadequate to prevent hyperglycemia. Patients with type 2 diabetes can initially be controlled with diet, exercise and oral glucose lowering agents or non-insulin injectables. Some patients have progressive beta cell failure and eventually may also need insulin therapy.

Other Specific Types of Diabetes Mellitus

The “other” designation refers to multiple other specific causes of an elevated blood glucose: pancreatectomy, pancreatitis, non-pancreatic diseases, drug therapy, etc. For a detailed list the reader is referred to the reference Expert Committee, 2003.

Gestational Diabetes Mellitus

Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Gestational diabetes is diagnosed in approximately 7% of all pregnancies in the United States. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. Risk assessment for diabetes is suggested starting at the first prenatal visit. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until the 24th to 28th week of gestation.

Laboratory Findings

A. Plasma or Serum Glucose

A plasma glucose level of 126 mg/dL (7 mmol/L) or higher on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes mellitus (Table 41–4). Fasting plasma glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associated with increased risk of diabetes (impaired fasting glucose tolerance).

Table 41–4¹²Diagnostic criteria for diabetes.

Table 41–4 Diagnostic criteria for diabetes.

Normal Glucose Tolerance, mg/dL (mMol/L)

Prediabetes

Diabetes Mellitus²

Fasting plasma glucose mg/dL (mmol/L)

<100 (5.6)

100–125 (5.6–6.9)

(impaired fasting glucose)

≥126 (7.0)

Two hours after glucose load¹ mg/dL (mmol/L)

<140 (7.8)

≥140–199 (7.8–11.0)

(impaired glucose tolerance)

≥200 (11.1)

HbA_1c (%) (ADA criteria)

<5.7

5.7–6.4

≥6.5

Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in persons who have been receiving at least 150–200 g of carbohydrate daily for 3 days before the test.

A fasting plasma glucose ≥126 mg/dL (7.0 mmol) or HbA_1c ≥ 6.5% is diagnostic of diabetes if confirmed by repeat testing.

Symptoms and random glucose level >200 mg/dL (11.1 mmol/L) are diagnostic, and there is no need to do additional testing.

If the fasting plasma glucose level is less than 126 mg/dL (7 mMol/L) but diabetes is nonetheless suspected, then a standardized oral glucose tolerance test may be done (Table 41–4). The patient should eat nothing after midnight prior to the test day. On the morning of the test, adults are then given 75 g of glucose in 300 mL of water; children are given 1.75 g of glucose per kilogram of ideal body weight. The glucose load is consumed within 5 minutes. Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose. An oral glucose tolerance test is normal if the fasting venous plasma glucose value is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value falls below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus. Patients with 2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have impaired glucose tolerance.

B. Hemoglobin A1c Measurements

When plasma glucose levels are in the normal range, about 4–6% of hemoglobin A has one or both of the N terminal valines of their beta chains irreversibly glycated by glucose—referred to as hemoglobin A1c (HbA1_c). The HbA1_c fraction is abnormally elevated in people with diabetes with chronic hyperglycemia. Since red cells have a lifespan of up to 120 days, the HbA1_c value reflects plasma glucose levels over the preceding 8–12 weeks. In patients who monitor their glucose levels, the HbA1_c value provides a valuable check on the accuracy of their monitoring. In patients who do not monitor their glucose levels, HbA1c measurements are essential for adjusting treatment. HbA1_c can be used to diagnose diabetes. An HbA1_c of 6.5% or greater if confirmed by repeat testing is diagnostic of diabetes. Less than 5.7% is normal, and patients with levels of 5.7–6.4% are considered at high risk for developing diabetes (Table 41–4).

C. Urine or Blood Ketones

Qualitative detection of ketone bodies can be accomplished by nitroprusside tests (Acetest or Ketostix). Although these tests do not detect beta-hydroxybutyric acid, which lacks a ketone group, the semiquantitative estimation of ketonuria thus obtained is nonetheless usually adequate for clinical purposes. Many laboratories now measure beta-hydroxybutyric acid, and meters are available (Precision Xtra; Nova Max Plus) for patient use that measure beta-hydroxybutyric acid levels in capillary glucose samples. Beta-hydroxybutyrate levels >0.6 mmol/L require evaluation. A level >3.0 mmol/L, which is equivalent to very large urinary ketones, will require hospitalization.

D. Self-Monitoring of Blood Glucose

Capillary blood glucose measurements performed by patients themselves, as outpatients, are extremely useful. In type 1 patients in whom “tight” metabolic control is attempted, they are indispensable. Several paper strip methods and a large number of blood glucose meters are now available for measuring glucose on capillary blood samples. All are accurate, but they vary with regard to speed, convenience, size of blood samples required, reporting capability, and cost. Some meters are designed to communicate with an insulin pump. A number of continuous glucose monitoring (CGM) systems are also available for clinical use. The systems utilize a subcutaneous sensor that measures glucose concentrations in the interstitial fluid for 3–7 days. Studies show that adult type 1 patients who use continuous systems have improved glucose control without an increased incidence of hypoglycemia. There is great interest in using continuous glucose monitoring systems to automatically deliver insulin by continuous subcutaneous insulin infusion pump. The first artificial pancreas system has been approved by the U.S. Food and Drug Administration (FDA) and will become available in 2017. With this system, the continuous glucose monitor readings are used to automatically adjust the basal insulin dosing by the insulin pump.

MEDICATIONS FOR HYPERGLYCEMIA

Insulin Preparations

Human insulin is dispensed as regular (R) and neutral protamine hagedorn (NPH) formulations. There are also six analogs of human insulin. Three of the analogs are rapidly acting: insulin lispro, insulin aspart, and insulin glulisine; and three are long acting: insulin glargine, insulin detemir, and insulin degludec. Animal insulins are not available in the United States. Pork and beef preparations (isophane, neutral, 30/70, and lente) are still available in other parts of the world. All the insulins in the United States are available in a concentration of 100 units/ML (U100) and dispensed as 10-mL vials or 0.3-mL cartridges or prefilled disposable pens. Several insulins are also available at higher concentrations in the prefilled disposable pen form: insulin glargine 300 units/mL (U300); insulin degludec (U200); insulin lispro 200 units/mL (U200); and regular insulin 500 units/mL (U500) (Tables 41–5, 41–6).

TABLE 41–5Summary of bioavailability characteristics of the insulins.

TABLE 41–5 Summary of bioavailability characteristics of the insulins.

Insulin Preparations

Onset of Action

Peak Action

Effective Duration

Insulins lispro, aspart, glulisine

5–15 min

1–1.5 h

3–4 h

Human regular

30–60 min

2 h

6–8 h

Technosphere inhaled insulin

5–15 min

1 h

3 h

Human NPH

2–4 h

6–7 h

10–20 h

Insulin glargine

0.5–1 h

Flat

~24 h

Insulin detemir

0.5–1 h

Flat

17 h

Insulin degludec

0.5–1.5 h

Flat

>42 h

TABLE 41–6Some insulin preparations available in the United States.¹

TABLE 41–6 Some insulin preparations available in the United States.¹

Preparation

Species Source

Concentration

Short-acting insulins

Insulin lispro (Humalog, Lilly)

Human analog

U100, U200

Insulin aspart (Novolog, Novo Nordisk)

Human analog

U100

Insulin glulisine (Apidra, Sanofi Aventis)

Human analog

U100

Regular insulin (Humulin R, Lilly; Novolin R, Novo Nordisk)

Human

U100, U500

Regular insulin inhaled (MannKind)

Human

—

Long-acting insulins

NPH insulin (Humulin N, Lilly, Novolin N, Novo Nordisk)

Human

U100

Insulin glargine (Lantus, Toujeo, Sanofi Aventis, Basaglar, Lilly)

Human analog

U100, U300

Insulin detemir (Levemir, Novo Nordisk)

Human analog

U100

Insulin degludec (Tresiba, Novo Nordisk)

Human analog

U100, U200

Premixed insulins

70 NPH/30 regular (Novolin, Novo Nordisk; Humulin, Lilly)

Human

U100

75/25 NPL, Lispro (Humalog mix 75/25, Lilly)

Human analog

U100

50/50 NPL, Lispro (Humalog mix 50/50, Lilly)

Human analog

U100

70/30 NPA, Aspart (Novolog mix 70/30, Novo Nordisk)

Human analog

U100

70/30 Degludec/Aspart (Ryzodeg, Novo Nordisk)

Human analog

U100

All insulins are now made by recombinant technology; they should be refrigerated and brought to room temperature just before injection.

NPA, neutral protamine aspart; NPL, neutral protamine lispro.

A. Short-Acting Insulin Preparations

The short-acting preparations include regular human insulin and the three rapidly acting insulin analogs (Tables 41–5, 41–6). All are clear solutions at neutral pH. The insulin molecules exist as dimers that assemble into hexamers in the presence of two zinc ions. The hexamers are further stabilized by phenolic compounds such as phenol and meta-Cresol. The mutations engineered into the rapidly acting insulin analogs are designed to disrupt the stabilizing intermolecular interactions of the dimers and hexamers, leading to more rapid absorption into the circulation after subcutaneous injection.

1. Regular insulin—Regular insulin is a short-acting, soluble crystalline zinc insulin whose hypoglycemic effect appears within 30 minutes after subcutaneous injection, peaks at about 2 hours, and lasts for 5–7 hours when usual quantities (ie, 5–15 U) are administered. For very insulin-resistant subjects who would otherwise require large volumes of insulin solution, a U500 preparation of human regular insulin is available both in a vial form and a disposable pen. If the vial form is used, it is necessary to use a U100-insulin syringe or tuberculin syringe to measure doses. The physician should then carefully note dosages in both units and volume to avoid overdosage. The disposable pen avoids this conversion issue and dispenses the regular U500 insulin in 5-unit increments.

Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics.

2. Rapidly acting insulin analogs—Insulin lispro (Humalog) is an insulin analog in which the proline at position B28 is reversed with the lysine at B29. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. When injected subcutaneously, these three analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as little as 1 hour. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical to those of human regular insulin.

Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapid-acting insulin analogs and of regular human insulin are 15 minutes and 45 minutes before the meal, respectively. Although the more rapid onset of action has been welcomed as a great convenience by patients with diabetes who object to waiting as long as 45 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. The analogs also have lowest variability of absorption: approximately 5%. This compares with 25% for regular insulin. Another desirable feature of rapidly acting insulin analogs is that their duration of action remains at about 4 hours for most commonly used dosages. This contrasts with regular insulin, whose duration of action is significantly prolonged when larger doses are used.

The rapidly acting analogs are commonly used in insulin pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA_1c values and improved postprandial glucose control with the same frequency of hypoglycemia. However, the concern remains that in the event of pump failure, users of the rapidly acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.

While insulin aspart has been approved for intravenous use (eg, in hyperglycemic emergencies), there is no advantage in using insulin aspart over regular insulin by this route. A U200 concentration of insulin lispro is available in a disposable prefilled pen. The only advantage of the U200 over the U100 insulin lispro preparation is that it delivers the same dose in half the volume.

B. Long-Acting Insulin Preparations

1. NPH (neutral protamine Hagedorn, or isophane) insulin—NPH insulin is an intermediate-acting insulin whose absorption and onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form (“isophane”) (Tables 41–5, 41–6). After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2–5 hours and duration of 4–12 hours (Figure 41–5); it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement. The dose regulates the action profile; specifically, small doses have lower, earlier peaks and a short duration of action with the converse true for large doses.

FIGURE 41–5

Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase considerably when dosage is increased.

2. Insulin glargine—Insulin glargine is a soluble, “peakless” (ie, having a broad plasma concentration plateau), long-acting insulin analog. The attachment of two arginine molecules to the B-chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position created an analog that is soluble in an acidic solution but precipitates in the more neutral body pH after subcutaneous injection. Individual insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin. Insulin glargine has a slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours. This maximum activity is maintained for 11–24 hours or longer. Glargine is usually given once daily, although some very insulin-sensitive or insulin-resistant individuals benefit from split (twice a day) dosing. To maintain solubility, the formulation is unusually acidic (pH 4.0), and insulin glargine should not be mixed with other insulins. Separate syringes must be used to minimize the risk of contamination and subsequent loss of efficacy. The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection, and this drug is associated with less immunogenicity than human insulin in animal studies. Glargine’s interaction with the insulin receptor is similar to that of native insulin and shows no increase in mitogenic activity in vitro. It has sixfold to sevenfold greater binding than native insulin to the insulin-like growth factor 1 (IGF-1) receptor, but the clinical significance of this is unclear.

3. Insulin detemir—In this insulin the terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the B29 lysine. These modifications prolong the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. The affinity of insulin detemir is four- to fivefold lower than that of human soluble insulin and, therefore, the U100 formulation of insulin detemir has a concentration of 2400 nmol/mL compared with 600 nmol/mL for NPH. The duration of action for insulin detemir is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. This insulin has been reported to have lower within-subject pharmacodynamic variability compared with NPH insulin and insulin glargine.

4. Insulin Degludec—In this insulin analog, the threonine at position B30 has been removed and the lysine at position B29 is conjugated to hexadecanoic acid via a gamma-L-glutamyl spacer. In the vial, in the presence of phenol and zinc, the insulin is in the form of dihexamers but, when injected subcutaneously, it self-associates into large multihexameric chains consisting of thousands of dihexamers. The chains slowly dissolve in the subcutaneous tissue, and insulin monomers are steadily released into the systemic circulation. The half-life of the insulin is 25 hours. Its onset of action is in 30–90 minutes, and its duration of action is more than 42 hours. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. Insulin degludec is available in two concentrations, U100 and U200, and dispensed in pre-filled disposable pens.

5. Mixtures of insulins—Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in patients with diabetes usually requires supplements of rapid- or short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. The regular insulin or rapidly acting insulin analog is withdrawn first, then the NPH insulin and then injected immediately.

Stable premixed insulins (70% NPH and 30% regular) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or insufficient manual dexterity. Premixed preparations of rapidly acting insulin analogs (lispro, aspart) and NPH are not stable because of exchange of the rapidly acting insulin analog for the human regular insulin in the protamine complex. Consequently, over time, the soluble component becomes a mixture of regular and rapidly acting insulin analog at varying ratios. To remedy this problem, intermediate insulins composed of isophane complexes of protamine with the rapidly acting insulin analogs were developed (neutral protamine lispro [NPL]; aspart protamine). Premixed combinations of NPL and insulin lispro are now available for clinical use (Humalog Mix 75/25 and Humalog Mix 50/50). These mixtures have a more rapid onset of glucose-lowering activity compared with 70% NPH/30% regular human insulin mixture and can be given within 15 minutes before or after starting a meal. A similar 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is now available. The main advantages of these new mixtures are that (1) they can be given within 15 minutes of starting a meal and (2) they are superior in controlling the postprandial glucose rise after a carbohydrate-rich meal.

Insulin glargine or insulin detemir cannot be acutely mixed with either regular insulin or the rapid-acting insulin analogs. Insulin degludec, however, can be mixed and is available as 70% insulin degludec/30% insulin aspart and is injected once or twice a day.

Insulin Delivery Systems

A. Insulin Syringes and Needles

Disposable plastic syringes with needles attached are available in 1-mL (100 units), 0.5-mL (50 units), and 0.3-mL (30 units) sizes. The “low-dose” 0.3-mL syringes are popular because many patients with diabetes do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. They are also available in half-unit marking. Three lengths of needles are available; longer needles are preferable in obese patients to reduce variability of insulin absorption. If the skin is clean it is not necessary to use alcohol. Rotation of sites is recommended to avoid problems with absorption due to lipohypertrophy from overuse of injection sites.

B. Insulin Pens

The pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro, insulin aspart, and insulin glargine are available for reusable pens (Lilly, Novo Nordisk, and Owen Mumford). Disposable prefilled pens are also available for regular insulin (U100, U500), insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine, insulin degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50% insulin lispro, 70% insulin aspart protamine/30% insulin aspart, and 70% insulin degludec/30% insulin aspart (Table 41–6).

C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)

Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results.

Normally, the 24-hour background basal rates are preprogrammed and relatively constant from day to day, although temporarily altered rates can be superimposed to adjust for a short-term change in requirement. For example, the basal delivery rate might need to be decreased for several hours because of the increased insulin sensitivity associated with strenuous activity.

Boluses are used to correct high blood glucose levels and to cover mealtime insulin requirements based on the carbohydrate content of the food and concurrent activity. Bolus amounts are either dynamically programmed or use pre-programmed algorithms. When the boluses are dynamically programmed, the user calculates the dose based on the amount of carbohydrate consumed and the current blood glucose level. Alternatively, the meal or snack dose algorithm (grams of carbohydrate covered by a unit of insulin) and insulin sensitivity or blood glucose correction factor (fall in blood glucose level in response to a unit of insulin) can be preprogrammed into the pump. If the user enters the carbohydrate content of the food and current blood glucose value, the insulin pump will calculate the most appropriate dose of insulin. Advanced insulin pumps also have an “insulin on board” feature that adjusts a high blood glucose correction dose to correct for residual activity of previous bolus doses.

The traditional pump (by MiniMed, Animas, Roche, Sooil)—which contains an insulin reservoir, the program chip, the keypad, and the display screen—is about the size of a pager. It is usually placed on a belt or in a pocket, and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion set, although flanks and thighs are also used. The insulin reservoir, tubing, and infusion set need to be changed using sterile techniques every 2 or 3 days. Currently, only one pump does not require tubing (OmniPod, Insulet). In this model, the pump is attached directly to the infusion set (electronic patch pump). Programming is done through a hand-held unit that communicates wirelessly with the pump.

Optimal use of these devices requires responsible involvement and commitment by the patient. Insulin aspart, lispro, and glulisine all are specifically approved for pump use and are preferred pump insulins because their favorable pharmacokinetic attributes allow glycemic control without increasing the risk of hypoglycemia.

A mechanical patch pump (V-Go, Valeritas) designed specifically for patients with type 2 diabetes is available on a basal-plus-bolus insulin regimen. The device is preset to deliver one of three fixed and flat basal rates (20, 30, or 40 units) for 24 hours (at which point it must be replaced), and there is a button that delivers two units per press to help cover meals.

D. Inhaled Insulin

A dry powder formulation of recombinant regular insulin (technosphere insulin, Afrezza) is now approved for use in adults with diabetes. It consists of 2- to 2.5-μm crystals of the excipient, fumaryl diketopiperazine, that provide a large surface area for adsorption of proteins like insulin. After inhalation from the small, single-use device, pharmacokinetic studies show that peak levels are reached in 12–15 minutes and decline to baseline in 3 hours, significantly faster in onset and shorter in duration than subcutaneous insulin. Pharmacodynamic studies show that median time to maximum effect with inhaled insulin is approximately 1 hour and declines to baseline by about 3 hours. In contrast, the median time to maximum effect with subcutaneous insulin lispro is about 2 hours and declines to baseline by 4 hours. In trials, inhaled insulin combined with injected basal insulin was as effective in lowering glucose as injected rapid-acting insulin combined with basal insulin. It is formulated as a single-use color coded cartridge delivering 4, 8 or 12 units immediately before the meal. The manufacturer provides a dose conversion table; patients injecting up to 4 units of rapid-acting insulin analog should use the 4-unit cartridge. Those injecting 5–8 units should use the 8-unit cartridge. If the dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit cartridge and one 8-unit cartridge or one 12-unit cartridge should be used. The inhaler is about the size of a referee’s whistle. The most common adverse effect of inhaled insulin was cough, affecting 27% of trial patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV₁]) was seen in the first 3 months of use, which persisted over 2 years of follow-up. Inhaled insulin is contraindicated in smokers and patients with chronic lung disease, such as asthma and chronic obstructive pulmonary disease. Spirometry should be performed to identify potential lung disease prior to initiating therapy. During the clinical trials, there were two cases of lung cancer in patients who were taking inhaled insulin and none in the comparator-treated patients.

Immunopathology of Insulin Therapy

At least five molecular classes of insulin antibodies may be produced in diabetics during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. There are two major types of immune disorders in these patients:

1. Insulin allergy—Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to non-insulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.

2. Immune insulin resistance—A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus.

Lipodystrophy at Injection Sites

Injection of animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. Since the development of human and analog insulin preparations of neutral pH, this type of immune complication is almost never seen. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours.

Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoiding the specific injection site.

MEDICATIONS FOR TREATMENT OF TYPE 2 DIABETES

Several categories of glucose-lowering agents are available for patients with type 2 diabetes: (1) agents that bind to the sulfonylurea receptor and stimulate insulin secretion (sulfonylureas, meglitinides, D-phenylalanine derivatives); (2) agents that lower glucose levels by their actions on liver, muscle, and adipose tissue (biguanides, thiazolidinediones); (3) agents that principally slow the intestinal absorption of glucose (α-glucosidase inhibitors); (4) agents that mimic incretin effect or prolong incretin action (GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors), (5) agents that inhibit the reabsorption of glucose in the kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and (6) agents that act by other or ill-defined mechanisms (pramlintide, bromocriptine, colesevelam).

DRUGS THAT PRIMARILY STIMULATE INSULIN RELEASE BY BINDING TO THE SULFONYLUREA RECEPTOR

SULFONYLUREAS

Mechanism of Action

The major action of sulfonylureas is to increase insulin release from the pancreas (Table 41–7). They bind to a 140-kDa high-affinity sulfonylurea receptor that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel (Figure 41–2). Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin.

TABLE 41–7Regulation of insulin release in humans.

TABLE 41–7 Regulation of insulin release in humans.

Stimulants of insulin release

Humoral: Glucose, mannose, leucine, arginine, other amino acids, fatty acids (high concentrations)

Hormonal: Glucagon, glucagon-like peptide 1 (7–37), glucose-dependent insulinotropic polypeptide, cholecystokinin, gastrin

Neural: β-Adrenergic stimulation, vagal stimulation

Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol, acetylcholine

Inhibitors of insulin release

Hormonal: Somatostatin, insulin, leptin

Neural: α-Sympathomimetic effect of catecholamines

Drugs: Diazoxide, phenytoin, vinblastine, colchicine

Efficacy & Safety of the Sulfonylureas

Sulfonylureas are metabolized by the liver and, with the exception of acetohexamide, the metabolites are either weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of cases. The second-generation sulfonylureas have greater affinity for their receptor compared with the first-generation agents. The correspondingly lower effective doses and plasma levels of the second-generation drugs therefore lower the risk of drug-drug interactions based on competition for plasma binding sites or hepatic enzyme action.

In 1970, the University Group Diabetes Program (UGDP) in the United States reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide was excessive compared with either insulin-treated patients or those receiving placebos. Owing to design flaws, this study and its conclusions were not generally accepted. In the United Kingdom, the UKPDS did not find an untoward cardiovascular effect of sulfonylurea usage in their large, long-term study. The sulfonylureas continue to be widely prescribed, and six are available in the United States.

FIRST-GENERATION SULFONYLUREAS

Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short (6–10 hours), with an elimination half-life of 4–5 hours, and it is best administered in divided doses (eg, 500 mg before each meal). Some patients only need one or two tablets daily. The maximum dosage is 3000 mg daily. Because of its short half-life and inactivation by the liver, it is relatively safe in the elderly and in patients with renal impairment. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These drugs inhibit the metabolism of tolbutamide in the liver and increase its circulating levels.

Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; approximately 20–30% is excreted unchanged in the urine. The average maintenance dosage is 250 mg daily, given as a single dose in the morning. Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group. Other adverse effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and hyponatremia due to its effect on vasopressin secretion and action.

Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dosage should be divided and given twice daily.

Acetohexamide is no longer available in the United States. Its half-life is only about 1 hour but its more active metabolite, hydroxyhexamide, has a half-life of 4–6 hours; thus the drug duration of action is 8–24 hours. Where available, its dosage is 0.25–1.5 g/d as single dose or in two divided doses.

Chlorpropamide, tolazamide, and acetohexamide are now rarely used in clinical practice.

SECOND-GENERATION SULFONYLUREAS

Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. They should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.

Glyburide is metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended. A formulation of “micronized” glyburide (Glynase PresTab) is available in a variety of tablet sizes. However, there is some question as to its bioequivalence with non-micronized formulations, and the FDA recommends careful monitoring to re-titrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs.

Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion, and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.

Glipizide has the shortest half-life (2–4 hours) of the more potent agents. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast because absorption is delayed when the drug is taken with food. The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. When higher daily dosages are required, they should be divided and given before meals. The maximum total daily dosage recommended by the manufacturer is 40 mg/d, although some studies indicate that the maximum therapeutic effect is achieved by 15–20 mg of the drug. An extended-release preparation (Glucotrol XL) provides 24-hour action after a once-daily morning dose (maximum of 20 mg/d). However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over the latter (which can be obtained as a generic drug). At least 90% of glipizide is metabolized in the liver to inactive products, and the remainder is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with significant hepatic impairment. Because of its lower potency and shorter duration for action, it is preferable to glyburide in the elderly and for those patients with renal impairment.

Glimepiride is approved for once-daily use as monotherapy or in combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dosage of any sulfonylurea compound. A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dosage is 8 mg. Glimepiride’s half-life under multidose conditions is 5–9 hours. It is completely metabolized by the liver to metabolites with weak or no activity.

Gliclazide (not available in the United States) has a half-life of 10 hours. The recommended starting dosage is 40–80 mg daily with a maximum dosage of 320 mg daily. Higher dosages are usually divided and given twice a day. It is completely metabolized by the liver to inactive metabolites.

MEGLITINIDE ANALOGS

Repaglinide is the first member of the meglitinide group of insulin secretagogues. These drugs modulate beta-cell insulin release by regulating potassium efflux through the potassium channels previously discussed. There is overlap with the sulfonylureas in their molecular sites of action because the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site.

Repaglinide has a fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion, but the duration of action is 4–7 hours. It is cleared by hepatic CYP3A4 with a plasma half-life of 1 hour. Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions. The drug should be taken just before each meal in doses of 0.25–4 mg (maximum 16 mg/d); hypoglycemia is a risk if the meal is delayed or skipped or contains inadequate carbohydrate. It can be used in patients with renal impairment and in the elderly. Repaglinide is approved as monotherapy or in combination with biguanides. There is no sulfur in its structure, so repaglinide may be used in type 2 diabetics with sulfur or sulfonylurea allergy.

Mitiglinide (not available in the United States) is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It has been approved for use in Japan.

D-PHENYLALANINE DERIVATIVE

Nateglinide, a D-phenylalanine derivative, stimulates rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K⁺ channel. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. The overall duration of action is about 4 hours. It is taken before the meal and reduces the postprandial rise in blood glucose levels. It is available as 60- and 120-mg tablets. The lower dose is used in patients with mild elevations in HbA_1c. Nateglinide is efficacious when given alone or in combination with non-secretagogue oral agents (such as metformin). Hypoglycemia is the main adverse effect. It can be used in patients with renal impairment and in the elderly.

DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE

BIGUANIDES

The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the United States because of its association with lactic acidosis. Metformin is the only biguanide currently available in the United States.

Mechanisms of Action

A full explanation of the mechanism of action of the biguanides remains elusive, but their primary effect is to activate the enzyme AMP-activated protein kinase (AMPK) and reduce hepatic glucose production. Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after administration of biguanides; however, hypoglycemia during biguanide therapy is rare. These agents are therefore more appropriately termed “euglycemic” agents.

Metabolism & Excretion

Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin’s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, the biguanide accumulates and thereby increases the risk of lactic acidosis, which appears to be a dose-related complication. Metformin can be safely used in patients with estimated glomerular filtration rates (eGFR) between 60 and 45 mL/min per 1.73 m². It can be used cautiously in patients with eGFR between 45 and 30 mL/min per 1.73 m². It is contraindicated if the eGFR is less than 30 mL/min per 1.73 m².

Clinical Use

Biguanides are recommended as first-line therapy for type 2 diabetes. Because metformin is an insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such persons. The UKPDS reported that metformin therapy decreases the risk of macrovascular as well as microvascular disease; this is in contrast to the other therapies, which only modified microvascular morbidity. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. Metformin is useful in the prevention of type 2 diabetes; the landmark Diabetes Prevention Program concluded that metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner prediabetics.

Although the recommended maximal dosage is 2.55 g daily, little benefit is seen above a total dosage of 2000 mg daily. Treatment is initiated at 500 mg with a meal and increased gradually in divided doses. Common schedules would be 500 mg once or twice daily increased to 1000 mg twice daily. The maximal dosage is 850 mg three times a day. Epidemiologic studies suggest that metformin use may reduce the risk of some cancers. These data are still preliminary, and the speculative mechanism of action is a decrease in insulin (which also functions as a growth factor) levels as well as direct cellular effects mediated by AMPK. Other studies suggest a reduction in cardiovascular deaths in humans and an increase in longevity in mice (see Chapter 60).

Toxicities

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), occurring in up to 20% of patients. They are dose related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3–5% of patients because of persistent diarrhea.

Metformin interferes with the calcium-dependent absorption of vitamin B₁₂–intrinsic factor complex in the terminal ileum, and vitamin B₁₂ deficiency can occur after many years of metformin use. Periodic screening for vitamin B₁₂ deficiency should be considered, especially in patients with peripheral neuropathy or macrocytic anemia. Increased intake of calcium may prevent the metformin-induced B₁₂ malabsorption.

Lactic acidosis can sometimes occur with metformin therapy. It is more likely to occur in conditions of tissue hypoxia when there is increased production of lactic acid and in renal failure when there is decreased clearance of metformin. Almost all reported cases have involved patients with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency; alcoholism). Acute kidney failure can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that renal function has not deteriorated. Renal function should be checked at least annually in patients on metformin therapy, and lower doses should be used in the elderly who may have limited renal reserve and in those with eGFR between 30 and 45 mL/min per 1.73 m².

THIAZOLIDINEDIONES

Thiazolidinediones act to decrease insulin resistance. They are ligands of peroxisome proliferator-activated receptor gamma (PPAR-γ), part of the steroid and thyroid superfamily of nuclear receptors. These PPAR receptors are found in muscle, fat, and liver. PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. Observed effects of the thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, increased adiponectin and decreased release of resistin from adipocytes, and increased differentiation of preadipocytes to adipocytes. Thiazolidinediones have also been shown to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Two thiazolidinediones are currently available: pioglitazone and rosiglitazone. Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. An earlier compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain.

Pioglitazone has some PPAR-α as well as PPAR-γ activity. It is absorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected. Absorption is decreased with concomitant use of bile acid sequestrants. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites. The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estrogen-containing oral contraceptives; additional methods of contraception are advised. Pioglitazone may be taken once daily; the usual starting dosage is 15–30 mg/d, and the maximum is 45 mg/d. Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.

Rosiglitazone is rapidly absorbed and highly protein bound. It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 2–8 mg is the usual total dosage. Rosiglitazone is approved for use in type 2 diabetes as monotherapy, in double combination therapy with a biguanide or sulfonylurea, or in quadruple combination with a biguanide, sulfonylurea, and insulin.

The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia.

These drugs also have some additional effects apart from glucose lowering. Pioglitazone lowers triglycerides and increases high-density lipoprotein (HDL) cholesterol without affecting total cholesterol and low-density lipoprotein (LDL) cholesterol. Rosiglitazone increases total cholesterol, HDL cholesterol, and LDL cholesterol but does not have significant effect on triglycerides. These drugs have been shown to improve the biochemical and histologic features of nonalcoholic fatty liver disease. They seem to have a positive effect on endothelial function: pioglitazone reduces neointimal proliferation after coronary stent placement, and rosiglitazone has been shown to reduce microalbuminuria.

Safety concerns and troublesome side effects have significantly reduced the use of this class of drugs. A meta-analysis of 42 randomized clinical trials with rosiglitazone suggested that this drug increased the risk of angina pectoris or myocardial infarction. As a result, its use was suspended in Europe and severely restricted in the United States. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and so the United States restrictions have been lifted. The drug remains unavailable in Europe.

Fluid retention occurs in about 3–4 % patients on thiazolidinedione monotherapy and occurs more frequently (10–15%) in patients on concomitant insulin therapy. Heart failure can occur, and the drugs are contraindicated in patients with New York Heart Association class III and IV cardiac status (see Chapter 13). Macular edema is a rare adverse effect that improves when the drug is discontinued. Loss of bone mineral density and increased atypical extremity bone fractures in women are described for both compounds; this is postulated to be due to decreased osteoblast formation. Other adverse effects include anemia, which might be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when used in combination with a sulfonylurea or insulin. Some of the weight gain is fluid retention but there is also an increase in total fat mass. In preclinical trials, bladder tumors were observed in male rats on pioglitazone. Initial clinical reports indicated that this might also be true in humans. A 10-year observational cohort study of patients taking pioglitazone, however, failed to find an association with bladder cancer. A large multi-population pooled analysis (1.01 million persons over 5.9 million person-years) also failed to find an association between cumulative exposure of pioglitazone or rosiglitazone and incidence of bladder cancer. Another population based study generating 689,616 person-years of follow-up did find that pioglitazone but not rosiglitazone was associated with an increased risk of bladder cancer.

Troglitazone, the first medication in this class, was withdrawn because of cases of fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the drugs are not recommended for use in patients with active liver disease or pretreatment elevation of alanine aminotransferase (ALT) 2.5 times greater than normal. Liver function tests should be performed prior to initiation of treatment and periodically thereafter.

DRUGS THAT AFFECT ABSORPTION OF GLUCOSE

The α-glucosidase inhibitors competitively inhibit the intestinal α-glucosidase enzymes and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides. Acarbose and miglitol are available in the United States. Voglibose is available in Japan, Korea, and India. Acarbose and miglitol are potent inhibitors of glucoamylase, α-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose has the molecular mass and structural features of a tetrasaccharide and very little is absorbed. In contrast, miglitol has structural similarity to glucose and is absorbed.

Acarbose treatment is initiated at a dosage of 50 mg twice daily with gradual increase to 100 mg three times a day. It lowers postprandial glucose levels by 30–50%. Miglitol therapy is initiated at a dosage of 25 mg three times a day. The usual maintenance dosage is 50 mg three times a day, but some patients may need 100 mg three times a day. The drug is not metabolized and is cleared by the kidney. It should not be used in renal failure.

Prominent adverse effects of α-glucosidase inhibitors include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. These adverse effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of α-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. An increase in hepatic aminotransferases has been noted in clinical trials with acarbose, especially with dosages greater than 300 mg/d. The abnormalities resolve on stopping the drug.

These drugs are infrequently prescribed in the United States because of their prominent gastrointestinal adverse effects and relatively modest glucose-lowering benefit.

DRUGS THAT MIMIC INCRETIN EFFECT OR PROLONG INCRETIN ACTION

An oral glucose load provokes a higher insulin response compared with an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones (“incretins”), principally GLP-1 and glucose-dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion. When GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin release and lowers glucose levels. The GLP-1 effect is glucose dependent in that the insulin release is more pronounced when glucose levels are elevated but less so when glucose levels are normal. For this reason, GLP-1 has a lower risk for hypoglycemia than the sulfonylureas. In addition to its insulin stimulatory effect, GLP-1 has a number of other biologic effects. It suppresses glucagon secretion, delays gastric emptying, and reduces apoptosis of human islets in culture. In animals, GLP-1 inhibits feeding by a central nervous system mechanism. Type 2 diabetes patients on GLP-1 therapy are less hungry. It is unclear whether this is mainly related to the deceleration of gastric emptying or whether there is a central nervous system effect as well.

GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and by other enzymes such as endopeptidase 24.11 and is also cleared by the kidney. The native peptide therefore cannot be used therapeutically. One approach to this problem has been to develop metabolically stable analogs or derivatives of GLP-1 that are not subject to the same enzymatic degradation or renal clearance. Four such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide, and dulaglutide are available for clinical use. The other approach has been to develop inhibitors of DPP-4 and prolong the action of endogenously released GLP-1 and GIP. Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States. An additional inhibitor, vildagliptin, is available in Europe.

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

Exenatide, a derivative of the exendin-4 peptide in Gila monster venom, has a 53% homology with native GLP-1 and a glycine substitution to reduce degradation by DPP-4. Exenatide is approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control.

Exenatide is dispensed as fixed-dose pens (5 mcg and 10 mcg). It is injected subcutaneously within 60 minutes before breakfast and dinner. It reaches a peak concentration in approximately 2 hours with a duration of action of up to 10 hours. Therapy is initiated at 5 mcg twice daily for the first month and if tolerated can be increased to 10 mcg twice daily. Exenatide LAR is a once-weekly preparation that is dispensed as a powder (2 mg). It is suspended in the provided diluent just prior to injection. When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. The major adverse effect is nausea (about 44% of users), which is dose dependent and declines with time. Exenatide monotherapy and combination therapy results in HbA1c reductions of 0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contributes to the improvement of glucose control. In comparative trials the long-acting (LAR) preparation lowers the HbA_1c level a little more than the twice-daily preparation. Exenatide undergoes glomerular filtration, and the drug is not approved for use in patients with estimated GFR of less than 30 mL/min.

High-titer antibodies against exenatide develop in about 6% of patients, and in half of these patients an attenuation of glycemic response has been seen.

Liraglutide is a soluble fatty acid-acylated GLP-1 analog. The half-life is approximately 12 hours, permitting once-daily dosing. It is approved in patients with type 2 diabetes who achieve inadequate control with diet and exercise and are receiving concurrent treatment with metformin, sulfonylureas, or thiazolidinediones. Treatment is initiated at 0.6 mg and increased after 1 week to 1.2 mg daily. If needed the dosage can be increased to 1.8 mg daily. In clinical trials liraglutide results in a reduction of HbA_1c of 0.8–1.5%; weight loss ranges from none to 3.2 kg. The most frequent adverse effects are nausea (28%) and vomiting (10%). Liraglutide at a dose of 3 mg daily has been approved for weight loss.

Albiglutide is a human GLP-1 dimer fused to human albumin. The half-life of albiglutide is about 5 days and a steady state is reached after 4–5 weeks of once weekly administration. The usual dose is 30 mg weekly by subcutaneous injection. The drug is supplied in a self-injection pen containing a powder that is reconstituted just prior to administration. Weight loss is much less common than with exenatide and liraglutide. The most frequent adverse effects were nausea and injection-site erythema.

Dulaglutide consists of two GLP-1 analog molecules covalently linked to an Fc fragment of human IgG4. The GLP-1 molecule has amino acid substitutions that resist DPP-4 action. The half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg weekly by subcutaneous injection. The maximum recommended dose is 1.5 mg weekly. The most frequent adverse reactions were nausea, diarrhea, and vomiting.

All of the GLP-1 receptor agonists may increase the risk of pancreatitis. Patients on these drugs should be counseled to seek immediate medical care if they experience unexplained persistent severe abdominal pain. Cases of renal impairment and acute renal injury have been reported in patients taking exenatide. Some of these patients had preexisting kidney disease or other risk factors for renal injury. A number of them reported having nausea, vomiting, and diarrhea and it is possible that volume depletion contributed to the development of renal injury. Both exenatide and liraglutide stimulate thyroidal C-cell (parafollicular) tumors in rodents. Human thyroidal C cells express very few GLP-1 receptors, and the relevance to human therapy is unclear. The drugs, however, should not be used in persons with a past medical or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2.

DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS

Sitagliptin is given orally as 100 mg once daily, has an oral bioavailability of over 85%, achieves peak concentrations within 1–4 hours, and has a half-life of approximately 12 hours. It is primarily excreted in the urine, in part by active tubular secretion of the drug. Hepatic metabolism is limited and mediated largely by the cytochrome CYP3A4 isoform and, to a lesser degree, by CYP2C8. The metabolites have insignificant activity. Dosage should be reduced in patients with impaired renal function (50 mg if estimated GFR is 30–50 mL/min and 25 mg if <30 mL/min. Sitagliptin has been studied as monotherapy and in combination with metformin, sulfonylureas, and thiazolidinediones. Therapy with sitagliptin has resulted in HbA_1c reductions of 0.5–1.0%.

Common adverse effects include nasopharyngitis, upper respiratory infections, and headaches. Hypoglycemia can occur when the drug is combined with insulin secretagogues or insulin. There have been postmarketing reports of acute pancreatitis (fatal and nonfatal) and severe allergic and hypersensitivity reactions. Sitagliptin should be immediately discontinued if pancreatitis or allergic and hypersensitivity reactions occur.

Saxagliptin is given orally as 2.5–5 mg daily. The drug reaches maximal concentrations within 2 hours (4 hours for its active metabolite). It is minimally protein bound and undergoes hepatic metabolism by CYP3A4/5. The major metabolite is active, and excretion is by both renal and hepatic pathways. The terminal plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for its active metabolite. Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial agents. It is approved as monotherapy and in combination with biguanides, sulfonylureas, and thiazolidinediones. During clinical trials, mono- and combination therapy with saxagliptin resulted in an HbA1c reduction of 0.4–0.9%.

Adverse effects include an increased rate of infections (upper respiratory tract and urinary tract), headaches, and hypersensitivity reactions (urticaria, facial edema). The dosage of a concurrently administered insulin secretagogue or insulin may need to be lowered to prevent hypoglycemia. Saxagliptin may increase the risk of heart failure. In a postmarketing study of 16,492 type 2 diabetes patients, there were 289 cases of heart failure in the saxagliptin group (3.5%) and 228 cases in the placebo group (2.8%)—a hazard ratio of 1.27. Patients at the highest risk for failure were those who had a history of heart failure or had elevated levels of N-terminal of the prohormone brain natriuretic peptide (NT-pBNP) or had renal impairment.

Linagliptin lowers HbA_1c by 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dosage is 5 mg daily orally and, since it is primarily excreted via the bile, no dosage adjustment is needed in renal failure.

Adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity). The risk of pancreatitis may be increased.

Alogliptin lowers HbA_1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg orally daily. The 12.5-mg dose is used in patients with calculated creatinine clearance of 30 to 60 mL/min; the dose is 6.25 mg for clearance <30 mL/min. In clinical trials, pancreatitis occurred in 11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients receiving all comparators (<0.1%). There have been reports of hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome). Cases of hepatic failure have been reported, but it is unclear if alogliptin was the cause. The medication, however, should be discontinued in the event of liver failure.

Vildagliptin (not available in the United States) lowers HbA_1c levels by 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes. The dosage is 50 mg orally once or twice daily. Adverse reactions include upper respiratory infections, nasopharyngitis, dizziness, and headache. Rarely, it can cause hepatitis, and liver function tests should be performed quarterly in the first year of use and periodically thereafter.

In animal studies, high doses of DPP-4 inhibitors and GLP-1 agonists cause expansion of pancreatic ductal glands and generation of premalignant pancreatic intraepithelial (PanIN) lesions that have the potential to progress to pancreatic adenocarcinoma. The relevance to human therapy is unclear and currently there is no evidence that these drugs cause pancreatic cancer in humans.

SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by the action of sodium-glucose transporters (SGLTs). Sodium-glucose transporter 2 (SGLT2) accounts for 90% of glucose reabsorption, and its inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes. SGLT2 inhibitors lower glucose levels by changing the renal threshold and not by insulin action. The SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, all oral medications, are approved for clinical use.

Canagliflozin reduces the threshold for glycosuria from a plasma glucose threshold of approximately 180 mg/dL to 70–90 mg/dL. It has been shown to reduce HbA_1c by 0.6–1% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–5 kg. The usual dosage is 100 mg daily. Increasing the dosage to 300 mg daily in patients with normal renal function can lower the HbA_1c by an additional 0.5%.

Dapagliflozin reduces HbA_1c by 0.5–0.8% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of about 2–4 kg. The usual dosage is 10 mg daily, but 5 mg daily is recommended initially in patients with hepatic failure.

Empagliflozin reduces HbA_1c by 0.5–0.7% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–3 kg. The usual dosage is 10 mg daily, but 25 mg/d may be used. In a postmarketing multinational study of 7020 type 2 patients with known cardiovascular disease, the addition of empagliflozin was associated with a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio, 0.86; p = 0.04). The mechanisms regarding this benefit remain unclear. Weight loss, lower blood pressure, and diuresis may have played a role since there were fewer deaths from heart failure in the treated group whereas the rates of myocardial infarction were unaltered.

As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. Canagliflozin and empagliflozin are contraindicated in patients with estimated GFR less than 45 mL/min per 1.73 m². Dapagliflozin is not recommended for use in patients with estimated GFR less than 60 mL/min per 1.73 m². The main adverse effects are increased incidence of genital infections and urinary tract infections affecting about 8–9% of patients. The osmotic diuresis can also cause intravascular volume contraction and hypotension. Canagliflozin and empagliflozin caused a modest increase in LDL cholesterol levels (4–8%). In clinical trials patients taking dapagliflozin had higher rates of breast cancer (nine cases versus none in comparator arms) and bladder cancer (nine cases versus one in placebo arm). These cancer rates exceeded the expected rates in an age-matched reference diabetes population. Canagliflozin has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip. In a pooled analysis of 8 clinical trial (mean duration 68 weeks), an increase in fractures by about 30% was observed in patients on canagliflozin. It is likely that the effect on the bones is a class effect and not restricted to canagliflozin. A modest increase in upper limb fractures was observed with canagliflozin therapy. It is not known if this is due to an effect on bone strength or related to falls due to hypotension. Interim analysis of the Canagliflozin Cardiovascular Assessment Study clinical trial reported an approximately doubled risk of leg and foot amputations in the trial group assigned to Canagliflozin; in 2017 the FDA issued a drug safety communication regarding the association. Cases of diabetic ketoacidosis have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1 patients are taught to give less insulin if their glucose levels are not elevated. Because type 1 patients on an SGLT2 inhibitor may have normal glucose levels, they may either withhold or reduce their insulin doses to such a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labelled as having type 2 diabetes but who are very insulin deficient and prone to ketosis.

OTHER HYPOGLYCEMIC DRUGS

Pramlintide is an islet amyloid polypeptide (IAPP, amylin) analog. IAPP is a 37-amino-acid peptide present in insulin secretory granules and secreted with insulin. It has approximately 46% homology with the calcitonin gene-related peptide (CGRP; see Chapter 17) and physiologically acts as a negative feedback on insulin secretion. At pharmacologic doses, IAPP reduces glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally decreases appetite. Pramlintide is an IAPP analog with substitutions of proline at positions 25, 28, and 29. These modifications make pramlintide soluble, non-self-aggregating, and suitable for pharmacologic use. Pramlintide is approved for use in insulin-treated type 1 and type 2 patients who are unable to achieve their target postprandial blood glucose levels. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. It is metabolized and excreted by the kidney, but even at low creatinine clearance there is no significant change in bioavailability. It has not been evaluated in dialysis patients.

Pramlintide is injected immediately before eating; dosages range from 15 to 60 mcg subcutaneously for type 1 patients and from 60 to 120 mcg for type 2 patients. Therapy with this agent should be initiated at the lowest dosage and titrated upward. Because of the risk of hypoglycemia, concurrent rapid- or short-acting mealtime insulin dosages should be decreased by 50% or more. Pramlintide should always be injected by itself using a separate syringe; it cannot be mixed with insulin. The major adverse effects of pramlintide are hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia. Since the drug slows gastric emptying, recovery from hypoglycemia can be problematic because of the delay in absorption of fast-acting carbohydrates.

Selected patients with type 1 diabetes who have problems with postprandial hyperglycemia can use pramlintide effectively to control the glucose rise especially in the setting of a high-carbohydrate meal. The drug is not very useful in type 2 patients who can instead use the GLP-1 receptor agonists.

Colesevelam hydrochloride, the bile acid sequestrant and cholesterol-lowering drug, is approved as an antihyperglycemic therapy for persons with type 2 diabetes who are taking other medications or have not achieved adequate control with diet and exercise. The exact mechanism of action is unknown but presumed to involve an interruption of the enterohepatic circulation and a decrease in farnesoid X receptor (FXR) activation. FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism. Bile acids are natural ligands of the FXR. Additionally, the drug may impair glucose absorption. In clinical trials, it lowered the HbA_1c concentration 0.3–0.5%. Adverse effects include gastrointestinal complaints (constipation, indigestion, flatulence). It can also exacerbate the hypertriglyceridemia that commonly occurs in people with type 2 diabetes.

Bromocriptine, the dopamine agonist, in randomized placebo-controlled studies lowered HbA_1c by 0–0.2% compared with baseline and by 0.4–0.5% compared with placebo. The mechanism by which it lowers glucose levels is not known. The main adverse events are nausea, fatigue, dizziness, vomiting, and headache.

Colesevelam and bromocriptine have very modest efficacy in lowering glucose levels, and their use for this purpose is questionable.

MANAGEMENT OF THE PATIENT WITH DIABETES

Diet

A well-balanced, nutritious diet remains a fundamental element of therapy for diabetes. It is recommended that the macronutrient proportions (carbohydrate, protein, and fat) be individualized based on the patient’s eating patterns, preferences, and goals. Generally most patients with diabetes consume about 45% of their calories as carbohydrates; 25–35% fats; and 10–35% proteins. Limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. A Mediterranean-style eating pattern (a diet supplemented with walnuts, almonds, hazelnuts, and olive oil) has been shown to improve glycemic control and lower combined endpoints for cardiovascular events and stroke. Caloric restriction and weight loss is an important goal for the obese patient with type 2 diabetes.

Education

Education of the patient and family is a critical component of care. The patient should be informed about the kind of diabetes he or she has and the rationale for controlling the glucose levels (see Box: Benefits of Tight Glycemic Control in Diabetes). Self-monitoring of glucose levels should be emphasized, especially if the patient is on insulin or oral secretagogues that can cause hypoglycemia. The patient on insulin therapy should understand the action profile of the insulins. He or she should know how to determine if the basal insulin dose is correct and how to adjust the rapidly acting insulin dose for carbohydrate content of meals. Insulin adjustments for exercise and infections should be discussed. The patient and family members also should be informed about the signs and symptoms of hypoglycemia.

Glycemic Targets

The American Diabetes Association criteria for acceptable control include an HbA_1c of less than 7% (53 mmol/mol) and pre-meal glucose levels of 90–130 mg/dL (5–7.2 mmol/L) and less than 180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3 mmol/L) two hours after meals. While the HbA_1c target is appropriate for individuals treated with lifestyle interventions and euglycemic therapy, it may need to be modified for individuals treated with insulin or insulin secretagogues due to their increased risk of hypoglycemia. Less stringent blood glucose control also is appropriate for children as well as patients with a history of severe hypoglycemia, limited life expectancy, and significant microvascular and macrovascular disease. For the elderly frail patient an HbA_1c greater than 8% may be appropriate.

Benefits of Tight Glycemic Control in Diabetes

A long-term randomized prospective study involving 1441 type 1 patients in 29 medical centers reported in 1993 that “near normalization” of blood glucose resulted in a delay in onset and a major slowing of progression of microvascular and neuropathic complications of diabetes during follow-up periods of up to 10 years (Diabetes Control and Complications Trial [DCCT] Research Group, 1993). In the intensively treated group, mean glycated hemoglobin (HbA_1c) of 7.2% (normal <6%) and mean blood glucose of 155 mg/dL were achieved, whereas in the conventionally treated group, HbA_1c averaged 8.9% with mean blood glucose of 225 mg/dL. Over the study period, which averaged 7 years, a reduction of approximately 60% in risk of diabetic retinopathy, nephropathy, and neuropathy was noted in the tight control group compared with the standard control group.

The DCCT study, in addition, introduced the concept of glycemic memory, which comprises the long-term benefits of any significant period of glycemic control. During a 6-year follow-up period, both the intensively and conventionally treated groups had similar levels of glycemic control, and both had progression of carotid intimal-medial thickness. However, the intensively treated cohort had significantly less progression of intimal thickness.

The United Kingdom Prospective Diabetes Study (UKPDS) was a very large randomized prospective study carried out to study the effects of intensive glycemic control with several types of therapies and the effects of blood pressure control in type 2 diabetic patients. A total of 3867 newly diagnosed type 2 diabetic patients were studied over 10 years. A significant fraction of these were overweight and hypertensive. Patients were given dietary treatment alone or intensive therapy with insulin, chlorpropamide, glyburide, or glipizide. Metformin was an option for patients with inadequate response to other therapies. Tight control of blood pressure was added as a variable, with an angiotensin-converting enzyme inhibitor, a β blocker, or in some cases, a calcium channel blocker available for this purpose.

Tight control of diabetes, with reduction of HbA_1c from 9.1% to 7%, was shown to reduce the risk of microvascular complications overall compared with that achieved with conventional therapy (mostly diet alone, which decreased HbA_1c to 7.9%). Cardiovascular complications were not noted for any particular therapy; metformin treatment alone reduced the risk of macrovascular disease (myocardial infarction, stroke). Epidemiologic analysis of the study suggested that every 1% decrease in the HbA_1c achieved an estimated risk reduction of 37% for microvascular complications, 21% for any diabetes-related end point and death related to diabetes, and 14% for myocardial infarction.

Tight control of hypertension also had a surprisingly significant effect on microvascular disease (as well as more conventional hypertension-related sequelae) in these diabetic patients. Epidemiologic analysis of the results suggested that every 10-mmHg decrease in the systolic pressure achieved an estimated risk reduction of 13% for diabetic microvascular complications, 12% for any diabetes-related complication, 15% for death related to diabetes, and 11% for myocardial infarction.

Post-study monitoring showed that 5 years after the closure of the UKPDS, the benefits of intensive management on diabetic end points were maintained and the risk reduction for a myocardial infarction became significant. The benefits of metformin therapy were maintained.

These studies show that tight glycemic control benefits both type 1 and type 2 patients.

Treatment

Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient.

A. Type 1 Diabetes

For most type 1 patients, at least 3 or 4 insulin injections a day are necessary for safe and effective control of glucose levels. A combination of rapidly acting insulin analogs and long-acting insulin analogs allow for more physiologic insulin replacement. Generally, for an adult with type 1 diabetes, the total daily insulin requirement in units is equal to the weight in pounds divided by four, or 0.55 times the person’s weight in kilograms. Approximately 40% of the total daily insulin dosage covers the background or basal insulin requirements, and the remainder covers meal and snack requirement and high blood sugar corrections. This is an approximate calculation and should be individualized. Examples of reduced insulin requirement include newly diagnosed persons and those with ongoing endogenous insulin production, long-standing diabetes with insulin sensitivity, significant renal insufficiency, or other endocrine deficiencies. Increased insulin requirements typically occur with obesity, during adolescence, and during the latter trimesters of pregnancy. Table 41–8 illustrates regimens of rapidly acting insulin analogs and basal analogs that might be appropriate for a 70-kg person with type 1 diabetes. If the patient is on an insulin pump, he or she may require about a basal infusion rate of 0.6 units per hour throughout the 24 hours with the exception of 4:00 AM to 8:00 AM, when 0.7 units per hour might be appropriate (dawn phenomenon). The ratios might be one unit for 12 grams carbohydrate plus one unit for 50 mg/dL (2.8 mmol/L) of blood glucose above a target value of 120 mg/dL (6.7 mmol/L).

TABLE 41–8¹²³Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and NPH, or insulin detemir, glargine, or degludec in a 70-kg man with type 1 diabetes.^1–3

TABLE 41–8 Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and NPH, or insulin detemir, glargine, or degludec in a 70-kg man with type 1 diabetes.^1–3

Prebreakfast

Prelunch

Predinner

Bedtime

Rapid-acting insulin analog

5 U

4 U

6 U

—

NPH insulin

3 U

2 U

8–9 U

Rapid-acting insulin analog

5 U

4 U

6 U

—

Insulin glargine or degludec

—

15–16 U

Insulin detemir

6–7 U

—

8–9 U

Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner.

The dose of rapid-acting insulin analogs can be raised by 1 or 2 U if extra carbohydrate (15–30 g) is ingested or if premeal blood glucose is >170 mg/dL. The rapid-acting insulin analogs can be mixed in the same syringe with NPH insulin.

Insulin glargine or insulin detemir must be given as a separate injection.

B. Type 2 Diabetes

Normalization of glucose levels can occur with weight loss and improved insulin sensitivity in the obese patient with type 2 diabetes. A combination of caloric restriction and increased exercise is necessary if a weight reduction program is to be successful. Understanding the long-term consequences of poorly controlled diabetes may motivate some patients to lose weight. For selected patients, medical or surgical options should be considered. Orlistat, phentermine/topiramate, lorcaserin, naltrexone plus extended release bupropion, and high-dose liraglutide are approved weight loss medications for use in combination with diet and exercise. Bariatric surgery (Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically result in significant weight loss and can result in remission of the diabetes.

Nonobese patients with type 2 diabetes frequently have increased visceral adiposity—the so-called metabolically obese normal weight patient. There is less emphasis on weight loss in such patients, but exercise is important.

Multiple medications may be required to achieve glycemic control (Figure 41–6) in patients with type 2 diabetes. Unless there is a contraindication, medical therapy should be initiated with intensive lifestyle interventions (diet and exercise), diabetes self-management education, and metformin. If clinical failure occurs with metformin monotherapy, a second agent is added. Options include sulfonylureas, repaglinide or nateglinide, pioglitazone, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, and insulin. In the choice of the second agent, consideration should be given to efficacy of the agent, hypoglycemic risk, effect on weight, adverse effects, and cost. In patients who experience hyperglycemia after a carbohydrate-rich meal (such as dinner), a short-acting secretagogue before that meal may suffice to control the glucose levels. Patients with severe insulin resistance may be candidates for pioglitazone. Patients who are very concerned about weight gain may benefit from a trial of a GLP-1 receptor agonist, a DPP-4 inhibitor, or an SGLT2 inhibitor, although the average weight loss with these medication is not great. If two agents are inadequate a third agent is added, although data regarding efficacy of such combined therapy are limited.

FIGURE 41–6

Suggested algorithm for the treatment of type 2 diabetes. The seven main classes of agents are metformin, sulfonylureas (includes nateglinide, repaglinide), pioglitazone, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, insulins. (α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocriptine not included because of limited efficacy and significant adverse reactions). (Data from the consensus panel of the American Diabetes Association/ European Association for the Study of Diabetes, as described in Inzucchi SE et al: Diabetes Care 2012;35:1364.)

When the combination of oral agents and injectable GLP-1 receptor agonists fails to adequately control glucose levels, insulin therapy should be instituted. Various insulin regimens may be effective. Simply adding nighttime intermediate- or long-acting insulin to the oral regimen may lead to improved fasting glucose levels and adequate control during the day. If daytime glucose levels are problematic, premixed insulins before breakfast and dinner may help. If such a regimen does not achieve adequate control or leads to unacceptable rates of hypoglycemia, a more intensive basal bolus insulin regimen (long-acting basal insulin) combined with rapid-acting analog before meals can be instituted. Metformin has been shown to be effective when combined with insulin therapy and should be continued. Pioglitazone can be used with insulin, but this combination is associated with more weight gain and peripheral and macular edema. Continuing with sulfonylureas, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors can be of benefit in selected patients. Cost, complexity, and risk for adverse events should be considered when deciding which drugs to continue once the patient starts on insulin therapy.

Acute Complications of Diabetes

A. Hypoglycemia

Hypoglycemic reactions are the most common complication of insulin therapy. It can also occur in any patient taking oral agents that stimulate insulin secretion (eg, sulfonylureas, meglitinide, D-phenylalanine analogs), particularly if the patient is elderly, has renal or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, warfarin). It occurs more frequently with the use of long-acting sulfonylureas.

Rapid development of hypoglycemia in persons with intact hypoglycemic awareness causes signs of autonomic hyperactivity—both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)—and may progress to convulsions and coma if untreated.

In persons exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. This dangerous acquired condition is termed hypoglycemic unawareness. When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop—confusion, weakness, bizarre behavior, coma, seizures—at which point they may not be able to procure or safely swallow glucose-containing foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes. An identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every diabetic person who is receiving hypoglycemic drug therapy.

All the manifestations of hypoglycemia are relieved by glucose administration. To expedite absorption, simple sugar or glucose should be given, preferably in liquid form. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given. If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is 1 mg of glucagon injected either subcutaneously or intramuscularly. This may restore consciousness within 15 minutes to permit ingestion of sugar. Emergency medical services should be called in the event of loss of consciousness. The emergency personnel can restore consciousness by giving 20–50 mL of 50% glucose solution by intravenous bolus over a period of 2–3 minutes.

B. Diabetic Coma

1. Diabetic ketoacidosis—Diabetic ketoacidosis (DKA) is a life-threatening medical emergency caused by inadequate or absent insulin replacement, which occurs in people with type 1 diabetes and infrequently in those with type 2 diabetes. It typically occurs in newly diagnosed type 1 patients or in those who have experienced interrupted insulin replacement, and rarely in people with type 2 diabetes who have concurrent unusually stressful conditions such as sepsis or pancreatitis or are on high-dose steroid therapy. DKA occurs more frequently in patients on insulin pumps. Poor compliance—either for psychological reasons or because of inadequate education—is one of the most common causes of DKA, particularly when episodes are recurrent.

Signs and symptoms include nausea, vomiting, abdominal pain, deep slow (Kussmaul) breathing, change in mental status (including coma), elevated blood and urinary ketones and glucose, an arterial blood pH lower than 7.3, and low bicarbonate (15 mmol/L).

The fundamental treatment for DKA includes aggressive intravenous hydration and insulin therapy and maintenance of potassium and other electrolyte levels. Fluid and insulin therapy is based on the patient’s individual needs and requires frequent reevaluation and modification. Close attention must be given to hydration and renal status, sodium and potassium levels, and the rate of correction of plasma glucose and plasma osmolality. Fluid therapy generally begins with normal saline. Regular human insulin should be used for intravenous therapy with a usual starting dosage of about 0.1 U/kg/h.

2. Hyperosmolar hyperglycemic syndrome—Hyperosmolar hyperglycemic syndrome (HHS) is diagnosed in persons with type 2 diabetes and is characterized by profound hyperglycemia and dehydration. It is associated with inadequate oral hydration, especially in elderly patients; with other illnesses; with the use of medication that elevates the blood sugar or causes dehydration, such as phenytoin, steroids, diuretics, and calcium channel blockers; and with peritoneal dialysis and hemodialysis. The diagnostic hallmarks are declining mental status and even seizures, a plasma glucose >600 mg/dL, and a calculated serum osmolality >320 mmol/L. Persons with HHS are not acidotic unless DKA is also present.

The treatment of HHS centers around aggressive rehydration and restoration of glucose and electrolyte homeostasis; the rate of correction of these variables must be monitored closely. Low-dose insulin therapy may be required.

Chronic Complications of Diabetes

Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state subsequent to the onset of puberty and glycemic control. In type 1 diabetes, end-stage chronic kidney disease develops in up to 40% of patients, compared with less than 20% of patients with type 2 diabetes. Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years’ duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Cigarette use adds significantly to the risk of both microvascular and macrovascular complications in diabetic patients.

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SUMMARY Drugs Used for Diabetes

Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

INSULINS

• Rapid-acting: Lispro, aspart, glulisine, inhaled regular

• Short-acting: Regular

• Intermediate-acting: NPH

• Long-acting: Detemir, glargine, degludec

Activate insulin receptor

Reduce circulating glucose

Type 1 and type 2 diabetes

Parenteral (SC or IV) • duration varies (see text) • Toxicity: Hypoglycemia, weight gain, lipodystrophy (rare)

SULFONYLUREAS

• Glipizide

• Glyburide

• Glimepiride

• Gliclazide¹

Insulin secretagogues: Close K⁺ channels in beta cells • increase insulin release

Reduce circulating glucose in patients with functioning beta cells

Type 2 diabetes

Orally active • duration 10–24 h • Toxicity: Hypoglycemia, weight gain

• Tolazamide, tolbutamide, chlorpropamide, acetohexamide: Older sulfonylureas, lower potency, greater toxicity; rarely used

MEGLITINIDE ANALOGS; D-PHENYLANALINE DERIVATIVE

• Repaglinide, nateglinide

• Mitiglinide¹

Insulin secretagogue: Similar to sulfonylureas with some overlap in binding sites

In patients with functioning beta cells, reduce circulating glucose

Type 2 diabetes

Oral • very fast onset of action • duration 5–8 h, nateglinide • 4 h • Toxicity: Hypoglycemia

BIGUANIDES

• Metformin

Activates AMP kinase • reduces hepatic and renal gluconeogenesis

Decreases circulating glucose

Type 2 diabetes

Oral • maximal plasma concentration in 2–3 h • Toxicity: Gastrointestinal symptoms, lactic acidosis (rare) • cannot use if impaired renal/hepatic function • congestive heart failure (CHF), hypoxic/acidotic states, alcoholism

ALPHA-GLUCOSIDASE INHIBITORS

• Acarbose, miglitol

• Voglibose¹

Inhibit intestinal α-glucosidases

Reduce conversion of starch and disaccharides to monosaccharides • reduce postprandial hyperglycemia

Type 2 diabetes

Oral • rapid onset • Toxicity: Gastrointestinal symptoms • cannot use if impaired renal/hepatic function, intestinal disorders

THIAZOLIDINEDIONES

• Pioglitazone, rosiglitazone

Regulate gene expression by binding to PPAR-γ and PPAR-α

Reduce insulin resistance

Type 2 diabetes

Oral • long-acting (>24 h) • Toxicity: Fluid retention, edema, anemia, weight gain, macular edema, bone fractures in women • cannot use if CHF, hepatic disease

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

• Exenatide, liraglutide, albiglutide, dulaglutide

Analogs of GLP-1: Bind to GLP-1 receptors

Reduce post-meal glucose excursions: Increase glucose-mediated insulin release, lower glucagon levels, slow gastric emptying, decrease appetite

Type 2 diabetes, liraglutide only: obesity

Parenteral (SC) • Toxicity: Nausea, headache, vomiting, anorexia, mild weight loss, pancreatitis, C-cell tumors in rodents

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

• Sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin¹

Block degradation of GLP-1, raise circulating GLP-1 levels

Reduces post-meal glucose excursions: Increases glucose-mediated insulin release, lowers glucagon levels, slows gastric emptying, decreases appetite

Type 2 diabetes

Oral • half-life ~12 h • 24-h duration of action • Toxicity: Rhinitis, upper respiratory infections, headaches, pancreatitis, rare allergic reactions

SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

• Canagliflozin, dapagliflozin, empagliflozin

Block renal glucose resorption

Increase glucosuria, lower plasma glucose levels

Type 2 diabetes

Oral • half-life ~10–14 h • Toxicity: Genital and urinary tract infections, polyuria, pruritus, thirst, osmotic diuresis, constipation

ISLET AMYLOID POLYPEPETIDE ANALOG

• Pramlintide

Analog of amylin: Binds to amylin receptors

Reduces post-meal glucose excursions: Lowers glucagon levels, slows gastric emptying, decreases appetite

Type 1 and type 2 diabetes

Parenteral (SC) • rapid onset • half-life ~48 min • Toxicity: Nausea, anorexia, hypoglycemia, headache

BILE ACID SEQUESTRANT

• Colesevelam hydrochloride

Bile acid binder: Lowers glucose through unknown mechanisms

Reduces glucose levels

Type 2 diabetes

Oral • 24-h duration of action • Toxicity: Constipation, indigestion, flatulence

DOPAMINE AGONIST

• Bromocriptine

D₂ receptor agonist: Lowers glucose through unknown mechanism

Reduces glucose levels

Type 2 diabetes

Oral • 24-h action • Toxicity: Nausea, vomiting, dizziness, headache

Not available in United States.

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PREPARATIONS AVAILABLE^*

GENERIC NAME

AVAILABLE AS

SULFONYLUREAS

Acetohexamide^‡

Generic, Dymelor

Chlorpropamide

Generic, Diabinese

Gliclazide^‡

Generic, Diamicron

Glimepiride

Generic, Amaryl

Glipizide

Generic, Glucotrol, Glucotrol XL

Glyburide

Generic, Diaβeta, Micronase, Glynase PresTab

Tolazamide

Generic, Tolinase

Tolbutamide

Generic, Orinase

MEGLITINIDES

Repaglinide

Generic, Prandin

Mitiglinide^‡

D-PHENYLALANINE DERIVATIVE

Nateglinide

Generic, Starlix

BIGUANIDE

Metformin

Generic, Glucophage, Glucophage XR

METFORMIN COMBINATIONS^†

Glipizide plus metformin

Generic, Metaglip

Glyburide plus metformin

Generic, Glucovance

Pioglitazone plus metformin

ACTOplus Met

Repaglinide plus metformin

Prandi-Met

Rosiglitazone plus metformin

Avandamet

Saxagliptin plus metformin

Kombiglyze

Sitagliptin plus metformin

Janumet

Linagliptin plus metformin

Jentadueto

Alogliptin plus metformin

Kazano

Dapagliflozin plus metformin

Xigduo

Canagliflozin plus metformin

Invokamet

Empagliflozin plus metformin

Synjardy

THIAZOLIDINEDIONE DERIVATIVES

Pioglitazone

Generic, Actos

Rosiglitazone

Avandia

THIAZOLIDINEDIONE COMBINATION

Pioglitazone plus glimepiride

Duetact

Alogliptin plus pioglitazone

Oseni

Rosiglitazone plus glimepiride

Avandaryl

ALPHA-GLUCOSIDASE INHIBITORS

Acarbose

Generic, Precose

Miglitol

Glyset

Voglibose^‡

GLUCAGON-LIKE POLYPEPTIDE-1 RECEPTOR AGONISTS

Byetta

Victoza

Tanzeum, Eperzan

Trulicity

DIPEPTIDYL PEPTIDASE-4 INHIBITORS

Tradjenta

Onglyza

Januvia

Nesina

Vildagliptin^‡

SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS

Canagliflozin

Invokana

Dapagliflozin

Farxiga

Empagliflozin

Jardiance

SODIUM GLUCOSE CO-TRANSPORTER INHIBITORS COMBINATION

Empagliflozin plus linagliptin

Glyxambi

ISMISCELLANEOUS DRUGSLET AMYLOID POLYPEPTIDE ANALOG

Pramlintide

Symlin

BILE ACID SEQUESTRANT

Colesevelam hydrochloride

Welchol

DOPAMINE RECEPTOR AGONIST

Bromocriptine

Generic, Parlodel, Cycloset

GLUCAGON

Glucagon

Generic

See Table 41–5 for insulin preparations.

^†

Other combinations are available.

^‡

Not available in the United States.

REFERENCES

Action to Control Cardiovascular Risks in Diabetes Study Group: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545. [PubMed: 18539917]

Adler AI et al: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. Br Med J 2000;321:412.

ADVANCE Collaborative Group: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560. [PubMed: 18539916]

Ahmadian M et al: PPARγ signaling and metabolism: The good, the bad and the future. Nat Med 2013;19:557. [PubMed: 23652116]

American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36(Suppl 1):S67. [PubMed: 23264425]

Andrianesis V, Doupis J: The role of kidney in glucose homeostasis—SGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol 2013;6:519. [PubMed: 23978089]

Bennett WL et al: Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602. Erratum in: Ann Intern Med 2011;155:67. [PubMed: 21403054]

Butler PC et al: A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013;36:2118. [PubMed: 23645885]

Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393. [PubMed: 11832527]

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26(Suppl 1):S5. [PubMed: 12502614]

Gaede P et al: Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580. [PubMed: 18256393]

Guo S: Insulin signaling, resistance, and the metabolic syndrome: Insights from mouse models to disease mechanisms. J Endocrinol 2014;220:T1. [PubMed: 24281010]

Inzucchi SE et al: Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015;58:429. [PubMed: 25583541]

Karagiannis T et al: Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: Systematic review and meta-analysis. BMJ 2012;344:e1369. [PubMed: 22411919]

Kitabchi A et al: Thirty years of personal experience in hyperglycemic crises: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab 2008;93:1541. [PubMed: 18270259]

Lefebvre P et al: Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147. [PubMed: 19126757]

Levin D et al: Pioglitazone and bladder cancer risk: A multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493. [PubMed: 25481707]

Miyazaki Y, DeFronzo RA: Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab 2008;10:1204. [PubMed: 18476983]

Nauck M: Incretin therapies: Highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016;18:203. [PubMed: 26489970]

Nwose OM, Jones MR: Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. Clin Med Insights Endocrinol Diabetes 2013;6:75. [PubMed: 24348081]

Ratner RE et al: Amylin replacement with pramlintide as an adjunct to insulin therapy improves long term glycemic and weight control in type 1 diabetes mellitus: A 1-year randomized controlled trial. Diabetic Med 2004;21:1204. [PubMed: 15498087]

Reitman ML et al: Pharmacogenetics of metformin response: A step in the path toward personalized medicine. J Clin Invest 2007;117:1226. [PubMed: 17476355]

Rizzo M et al: Non-glycemic effects of pioglitazone and incretin-based therapies. Expert Opin Ther Targets 2013;17:739. [PubMed: 23691979]

Rosenstock J, Ferrannini E: Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638. [PubMed: 26294774]

Standl E, Schnell O: Alpha-glucosidase inhibitors 2012—cardiovascular considerations and trial evaluation. Diab Vasc Dis Res 2012;9:163. [PubMed: 22508699]

Switzer SM et al: Intensive insulin therapy in patients with type 1 diabetes mellitus. Endocrinol Metab Clin North Am 2012;41:89. [PubMed: 22575408]

Tuccori M et al: Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541. [PubMed: 27029385]

United Kingdom Prospective Diabetes Study (UKPDS) Group: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies: UKPDS 49. JAMA 1999;281:2005. [PubMed: 10359389]

United Kingdom Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703. [PubMed: 9732337]

CASE STUDY ANSWER