Diabetes Mellitus
According to recent recommendations by the American Diabetes Association and the World Health Organization, diabetes mellitus is classified by the underlying disease etiology (i.e., type 1 vs. type 2) rather than by age-of-onset (i.e., juvenile-onset vs. adult-onset diabetes) or treatment modality (i.e., insulin-dependent vs. non–insulin-dependent diabetes).1 The insulin deficiency in type 1 diabetes is the result of autoimmune-mediated destruction of pancreatic β cells. Patients depend on exogenous insulin to regulate metabolism. Onset of type 1 diabetes is at a younger age than onset of type 2 diabetes, and sensitivity to insulin is normal. Lack of insulin may precipitate diabetic ketoacidosis, a complex and potentially life-threatening metabolic derangement. In contrast, the peripheral insulin resistance of type 2 diabetes is often coupled with a failure to secrete insulin because of pancreatic β cell dysfunction. Oral hypoglycemic drugs are alternatives to exogenous administration of insulin to patients with type 2 diabetes. The vast majority of cases of diabetes are either type 1 or type 2 in an approximate ratio of 1:9. Gestation, exocrine pancreas disease, medications, endocrinopathies, genetic defects in insulin action and β cell function, infections, and uncommon immune-mediated disorders also cause diabetes2 (Table 38-1).
Without sufficient insulin, transport of glucose across certain cell membranes slows markedly to cause hyperglycemia. The formation of glucose from protein accounts for the discovery that glucose in urine may exceed oral intake. Much of the protein used for glucose formation comes from skeletal muscles; glucose loss may manifest in extreme cases as skeletal muscle wasting. Elevations in blood glucose levels and hypoinsulinemia cause diabetic myopathy via muscle proteolysis. Increased free fatty acid concentrations in the plasma of diabetic patients show inhibition of the lipase enzyme system so that mobilization of fatty acids proceeds unopposed. The insulin-deficient liver is likely to use fatty acids to produce ketones, which can serve as an energy source for skeletal muscles and cardiac muscle. Production of ketones can lead to ketoacidosis; urinary excretion of ketones contributes to the depletion of electrolytes, especially potassium. Hypokalemia, however, may not be apparent, because intracellular potassium ions are exchanged for extracellular ions to compensate for the acidosis.
Low plasma concentrations of insulin, although inadequate to prevent hyperglycemia, may block lipolysis. This differential effect of insulin explains why hyperglycemia can exist without the presence of ketone bodies. Ketosis can be reliably prevented by continuously providing all diabetic patients with glucose and insulin.3 Prevention is uniquely important in the perioperative period when nutritional intake is altered.
Hyperglycemia impairs vasodilation and induces a chronic proinflammatory, prothrombotic, and proatherogenic state leading to vascular complications.4 Although all tissues are affected, of greatest relevance for anesthesia are atherosclerotic vascular, renal, and nervous system effects with peripheral vascular disease, renal insufficiency, and cerebrovascular disease.
The goals of therapy for patients with diabetes mellitus include preventing the adverse consequences of hypoglycemia and hyperglycemia, avoiding weight gain, and reducing microvascular and macrovascular complications. Symptoms often resolve when blood glucose levels are less than 200 mg/dL. Long-term metabolic control of diabetes is best monitored by measurement of glycosylated hemoglobin (HbA1c), which reflects glucose control over the previous 2 to 3 months. In general, HbA1c values less than 6.0% to 7.0% are associated with fewer microvascular complications. Therapy choices consider compliance, age, comorbidities, and impact on organ function (heart, kidney, liver).5
Insulin
Because patients with type 1 diabetes mellitus do not produce insulin, they require insulin therapy to survive. Insulin is prescribed for patients with type 2 diabetes mellitus if treatment with oral glucose regulators fails. In these patients, pancreatic β cells have been destroyed or autoantibodies have developed (see Chapter 37 for insulin’s mechanism of action). Insulin therapy mirrors the normal pattern of insulin secretion (pulsatile secretion that occurs under basal conditions and in response to meals) with basal supplementation and by short-acting insulin taken before food absorption. Insulin receptors become fully saturated with low concentrations of insulin. For example, continuous infusion of insulin, 1 to 2 units per hour, has the same or even greater pharmacologic effect than a single larger intravenous (IV) dose that is cleared rapidly from the circulation. Large doses of insulin, however, will last longer and exert a greater net effect than small doses. The number of insulin receptors seems to be inversely related to the plasma concentration of insulin, which reflect the ability of insulin to regulate the population of its receptors. Obesity and type 1 diabetes mellitus appear to be associated with fewer insulin receptors.
Pharmacokinetics
The elimination half-time of IV insulin is 5 to 10 minutes in both healthy and diabetic patients. Insulin is metabolized in the kidneys and liver by a proteolytic enzyme. Approximately 50% of the insulin that reaches the liver through its portal vein is metabolized in a single passage. Nevertheless, renal dysfunction alters the disappearance rate of circulating insulin to a greater extent than does hepatic disease. Indeed, unexpected prolonged effects of insulin are found in patients with renal disease, reflecting impairment of both its metabolism and excretion by the kidneys. Peripheral tissues such as skeletal muscles and fat can bind and inactivate insulin, but this effect is of minor quantitative significance. Despite rapid clearance from plasma after IV injection of insulin, the pharmacologic effect lasts for 30 to 60 minutes because insulin is tightly bound to tissue receptors. Insulin administered subcutaneously releases slowly into the circulation to produce a sustained biologic effect.
Insulin is secreted into the portal venous system in the basal state at a rate of approximately 1 unit per hour. After food intake, the rate of insulin secretion increases to 5- to 10-fold. The total daily secretion of insulin is approximately 40 units. The sympathetic and parasympathetic nervous systems innervate the insulin-producing islet cells to influence the basal rate of hormone secretion as well as the response to stress. For example, α-adrenergic stimulation decreases and β-adrenergic or parasympathetic nervous system stimulation increases the basal secretion of insulin. The insulin response to glucose is greater after oral ingestion than after IV infusion because glucose-dependent insulinotropic polypeptide is released after oral ingestion of glucose and the pancreatic β cell response is augmented. To gain adequate glycemic control in type 1 diabetes, at least two daily subcutaneous injections of intermediate- or long-acting insulin combined with rapid-acting insulin are nearly always required.
Insulin Preparations and Delivery
Human insulin manufactured using recombinant DNA technology has replaced insulin extracted from beef and pork pancreas. Allergy or immunoresistance to animal insulins is no longer a serious problem. In rare instances of local allergy to human insulin, pure porcine insulin or lispro insulin is substituted. The basic principle of replacement is to provide a slow, long-acting, continuous supply of insulin (neutral protamine Hagedorn [NPH] insulin, insulin glargine, insulin detemir, or insulin degludec) that mimics the nocturnal and interprandial basal secretion of normal pancreatic β cells.6 A rapid and relatively short-acting form of insulin (insulin aspart, lispro, or glulisine) delivered before meals mimics the normal meal-stimulated (prandial) release of insulin.
A number of insulin preparations for subcutaneous administration are available (Table 38-2).7 The pharmacokinetics of these insulins vary from individual to individual and even within the same individual from day to day. Rates of insulin absorption from subcutaneous sites differ with the injection site (absorption from abdominal sites is least variable), depth and angle of injection, ambient temperature, and exercise of an injected extremity.
Commercially prepared insulin is bioassayed, and its physiologic activity (potency), based on the ability to decrease blood glucose concentration, is expressed in units. The potency of insulin is 22 to 26 U/mg. Insulin U-100 (100 U/mL) is the most commonly used commercial preparation. The total daily exogenous dose of insulin for treatment of type 1 diabetes mellitus is usually in the range of 0.5 to 1 U/kg/day. This insulin requirement, however, may be increased dramatically by stress associated with sepsis or trauma.
Continuous subcutaneous insulin infusion (CSII) through an external pump delivers basal insulin (0.01 to 0.015 U/kg/hour) and bolus doses before meals. With this system, nocturnal versus daytime basal requirements can be accommodated, infusions can be altered during exercise, and doses can be calculated via algorithms of previous glucose values and insulin delivery. Short-acting insulin (regular) and ultra rapid–acting insulins (lispro, aspart, and glulisine) are the only preparations used for CSII delivery pumps.
Lispro
Lispro is a short-acting insulin analogue that more closely parallels physiologic insulin secretion and needs. A feature of natural or synthetic human insulin is that six molecules associate with a zinc molecule to form hexamers. Insulin hexamers must dissociate to monomers before absorption from subcutaneous injection sites. This feature is the reason that crystalline zinc insulin (regular insulin) has a peak action 2 to 4 hours after its subcutaneous injection. It must be administered 30 to 60 minutes before eating to effectively limit postprandial hyperglycemia. By exchanging lysine and proline at positions 28 and 29 of the insulin B chain, hexamer formation is prevented and the monomer is rapidly absorbed from the injection site. Therefore, lispro insulin injected subcutaneously begins to act within 15 minutes, the peak effect is reached in 45 to 75 minutes, and the duration of action is only 2 to 4 hours. Lispro injected just before eating provides a postprandial plasma insulin concentration profile similar to that of normal insulin secretion. An important benefit of lispro is a decrease in postprandial hyperglycemia and less risk of hypoglycemia, which may follow injection of regular insulin. Loss of the late action of regular insulin, however, may result in recurrent hyperglycemia before the next meal. In patients treated with lispro, HbA1c may not decrease unless the doses of basal insulin (NPH, detemir, or glargine) are increased.
Insulin Aspart and Glulisine
Insulin aspart and glulisine are synthetic rapid-acting analogues with a profile of action and therapeutic benefits similar to those of lispro.
Regular Insulin (Crystalline Zinc Insulin)
Regular insulin is a fast-acting preparation and is the only form of insulin that can be administered IV as well as subcutaneously. This form can be mixed in the same syringe with other insulin preparations if the pH of the solutions is similar.
Administration of regular insulin is preferred for treating the abrupt onset of hyperglycemia or the appearance of ketoacidosis. In the perioperative period, regular insulin is administered as a single IV injection (1 to 5 units) or as a continuous infusion (0.5 to 2.0 units per hour) to treat metabolic derangements associated with diabetes mellitus.
Neutral Protamine Hagedorn
NPH is an intermediate-acting preparation whose absorption from its subcutaneous injection site is delayed because the insulin is conjugated with protamine. The acronym NPH designates a neutral solution (N), protamine (P), and origin in Hagedorn’s (H) laboratory.8 This insulin preparation contains 0.005 mg protamine/U of insulin.
Glargine, Detemir, Degludec
Glargine, detemir, and degludec are long-acting insulin analogues for basal insulin replacement. Compared to NPH insulin, these long-acting insulins have a later onset of action and less pronounced peaks. Glargine or detemir can be administered as a single bedtime injection to provide basal insulin for 24 hours with less nocturnal hypoglycemia.9 Unlike glargine and detemir, degludec can be mixed with rapid-acting insulins. Degludec is not approved for use in the United States.
Side Effects
Side effects of treatment with insulin may manifest as (a) hypoglycemia, (b) allergic reactions, (c) lipodystrophy, (d) insulin resistance, or (e) drug interactions.
Hypoglycemia
The most serious side effect of insulin therapy is hypoglycemia. Patients are vulnerable to hypoglycemia if they receive exogenous insulin in the absence of carbohydrate intake, as during a perioperative period, especially before surgery. The first symptoms of hypoglycemia are the compensatory effects of increased epinephrine secretion: diaphoresis, tachycardia, and hypertension. Rebound hyperglycemia caused by sympathetic nervous system activity in response to hypoglycemia (Somogyi effect) may mask the correct diagnosis. Symptoms of hypoglycemia involving the central nervous system (CNS) include mental confusion progressing to seizures and coma. The CNS effects are intense because the brain depends on glucose as a selective substrate for oxidative metabolism. A prolonged period of hypoglycemia may result in irreversible brain damage.
The diagnosis of hypoglycemia during general anesthesia is difficult because anesthetic drugs mask the classic signs of sympathetic nervous system stimulation. The signs of sympathetic nervous system stimulation are likely to be confused with responses evoked by painful surgical stimulation in an anesthetized patient. The anesthesiologist may then decide to increase the dose of anesthetic drugs. Changes in heart rate and systemic blood pressure may be caused by hypoglycemia.10 Nonselective β-adrenergic antagonists also may mask the symptoms of hypoglycemia.
Severe hypoglycemia is treated with 50 to 100 mL of 50% glucose solution administered IV. Alternatively, glucagon, 0.5 to 1.0 mg IV or administered subcutaneously, is given. Nausea and vomiting are frequent side effects of glucagon treatment. In the absence of CNS depression, carbohydrates may be administered orally.
Allergic Reactions
Use of human insulin preparations has eliminated the problem of systemic allergic reactions that could result from administration of animal-derived insulins. Local allergic reactions to insulin are approximately 10 times more frequent than systemic allergic reactions. Local allergic reactions are characterized by an erythematous indurated area that develops at the site of insulin injection. The cause of local allergic reactions is likely to be noninsulin materials in the insulin preparation. Chronic exposure to low doses of protamine in NPH insulin may stimulate the production of antibodies against protamine. Patients remain asymptomatic until a large dose of protamine is administered IV to antagonize the anticoagulant effects of heparin. Indeed, patients with diabetes who are treated with NPH insulin have had allergic reactions to protamine.11 Yet allergic reactions to protamine are not found more in patients treated with NPH insulin than in nondiabetics.12
Lipodystrophy
Lipodystrophy results when fat atrophies at the site of subcutaneous injection of insulin. This side effect is minimized by frequently changing the site used for injection of insulin.
Insulin Resistance
Patients requiring greater than 100 units of exogenous insulin daily are in a state of insulin resistance. Even this value is high, because insulin requirements for pancreatectomized adults are often as low as 30 units. The use of human insulins has eliminated the problem of immunoresistance that could accompany administration of animal insulins. Acute insulin resistance is associated with trauma from infection or surgery.
Drug Interactions
There are hormones administered as drugs that counter the hypoglycemic effect of insulin: adrenocorticotrophic hormone, estrogens, and glucagon. Epinephrine inhibits the secretion of insulin and stimulates glycogenolysis. Certain antibiotics (tetracycline or chloramphenicol), salicylates, and phenylbutazone increase the duration of action of insulin and may have a direct hypoglycemic effect. The hypoglycemic effect of insulin may be potentiated by monoamine oxidase inhibitors.
Oral Glucose Regulators
Oral drugs with different mechanisms of action are available for controlling plasma glucose concentrations in patients with type 2 diabetes mellitus (Table 38-3). None of these drugs will adequately control hyperglycemia indefinitely. Therefore, use of combinations of oral drugs from the onset of treatment may be indicated.13 Insulin itself may be administered with sulfonylureas and meglitinides. The effect on HbA1c is similar for these drugs.
Metformin
Metformin is an oral biguanide that is often prescribed as the initial agent to prevent hyperglycemia in patients with type 2 diabetes (Fig. 38-1). Metformin decreases blood glucose concentrations in both the fasting and postprandial state and rarely causes hypoglycemia. It can be used in combination with other medications such as insulin and sulfonylureas. Metformin should not be prescribed for patients with lactic acidosis, acute kidney injury, gastrointestinal intolerance, or acute hepatic disease. Metformin has pleiotropic effects. It improves lipid profiles and fibrinolysis and promotes mild to moderate weight loss.14 Metformin also has been used in patients with polycystic ovarian disease, nonalcoholic fatty liver disease, and premature puberty.
Pharmacokinetics
In contrast to sulfonylureas, metformin is not bound to plasma proteins and does not undergo metabolism. It is eliminated by the kidneys, with 90% of an oral dose excreted in approximately 12 hours. Peak plasma concentrations of metformin occur approximately 2 hours after oral administration. The drug has an elimination half-time of 2 to 4 hours, which means that it is taken up to three times a day (500 to 1,000 mg with meals). In view of its dependence on renal clearance, metformin is prescribed with caution, if at all, to patients with renal dysfunction.
Mechanism of Action
The blood glucose–lowering effect of metformin is not mediated through stimulation of endogenous insulin secretion.15 Metformin activates adenosine monophosphate–activated protein kinase to suppress hepatic glucose production by decreasing gluconeogenesis and glycogenolysis and to enhance postprandial insulin suppression of hepatic glucose production. Metformin also regulates glucose levels by decreasing gastrointestinal glucose absorption, increasing insulin sensitivity in peripheral tissues, and enhancing synthesis of glucagon-like peptide-1 (GLP-1) in the ileum.14
Side Effects
The most common side effects of metformin are anorexia, nausea, and diarrhea, which are dose related. Up to 15% of patients experience side effects sufficient to warrant withdrawal of the drug.5 In contrast to sulfonylureas, metformin does not cause hypoglycemia. Metformin is associated with vitamin B12 deficiency.5 The most serious, although rare, side effect of metformin therapy is lactic acidosis.
Lactic Acidosis
Lactic acidosis is a possible side effect associated with metformin that has been described during the intraoperative period.15–17 For this reason, some have recommended discontinuing metformin 48 hours or longer before elective operations.16 If metformin cannot be discontinued before surgery, the patient is monitored for the development of lactic acidosis (arterial blood gases and pH, serum lactate concentrations, renal function) in the perioperative period.
Metformin binds to mitochondrial membranes to decrease intracellular adenosine triphosphate and increase adenosine monophosphate concentrations. Glucose is metabolized anaerobically. The resulting pyruvate is reduced to lactate, which is usually metabolized quickly in the liver. For this reason, metformin should be administered with caution, if at all, to patients with a history of hepatic dysfunction, renal insufficiency (creatinine level >1.5 mg/dL), IV administration of radiographic iodinated contrast media, acute myocardial infarction, congestive heart failure, arterial hypoxemia, or sepsis. Hemodialysis along with bicarbonate administration can be effective therapy for metformin-induced lactic acidosis. Management of biguanide-induced lactic acidosis is supportive because the underlying pathologic change (blockade of the mitochondrial respiratory chain) cannot be treated.
Sulfonylureas
Sulfonylurea compounds are drugs capable of lowering blood glucose concentrations even to hypoglycemic levels (Fig. 38-2).15,18 The drug-induced improvement in blood glucose control is associated with decreased hepatic production of very-low-density lipoproteins as well as amelioration of hypertriglyceridemia. Yet as many as 20% of patients with type 2 diabetes mellitus who begin sulfonylurea therapy do not have an adequate hypoglycemic response to maximal doses (primary failures), and each year, an additional 10% to 15% of patients who responded initially fail to respond to sulfonylurea therapy (secondary failure). Successful management of glucose control with sulfonylureas requires some β cell function. The sulfonylureas have no effect on and no role in the treatment of patients with type 1 diabetes mellitus. Although sulfonylureas are derivatives of sulfonamides, they have no antibacterial actions. These drugs should not be administered to patients with known allergy to sulfa drugs.
Mechanism of Action
Sulfonylurea receptors are found on pancreatic and cardiac cells. These drugs inhibit adenosine triphosphate–sensitive potassium ion channels (now known as the sulfonylurea receptor-1) on pancreatic β cells.5 As a result, there is an influx of calcium and stimulation of exocytosis (release) of insulin storage granules. Although sulfonylureas decrease insulin resistance, this effect is minor, if at all, in decreasing blood glucose concentrations.
Pharmacokinetics
Oral hypoglycemics are readily absorbed from the gastrointestinal tract, with the most important distinguishing features being differences in duration of action and elimination half-time (Table 38-4).18 The biological effects of sulfonylureas such as glyburide may be longer than plasma half-lives because of the formation of active metabolites.19 Weakly acidic, sulfonylureas circulate bound to protein (90% to 98%), principally to albumin. Metabolism in the liver is extensive, and the active and inactive metabolites are eliminated by renal tubular secretion. Approximately 50% of glyburide is excreted in feces.
Side Effects
Sulfonylureas are generally well tolerated; the most common severe complication of these drugs is hypoglycemia. The greatest risk of hypoglycemia occurs with drugs with the longest elimination half-times, glyburide and chlorpropamide; sulfonylureas may act for up to 7 days. Although hypoglycemia from sulfonylureas may be infrequent, it is often more prolonged and more dangerous than hypoglycemia from insulin (Table 38-5).
Hypoglycemia caused by sulfonylureas is treated with prolonged infusion of glucose-containing solutions. Risk factors for sulfonylurea-induced hypoglycemia include (a) impaired nutrition, as in the perioperative period; (b) age older than 60 years; (c) impaired renal function; and (d) concomitant drug therapy that potentiates sulfonylureas (phenylbutazone, sulfonamide antibiotics, warfarin) or itself produces hypoglycemia (alcohol or salicylates). Renal disease decreases elimination of sulfonylureas and their active metabolites, thus increasing the likelihood of hypoglycemia. In this regard, only small amounts of tolbutamide and glipizide are excreted unchanged in urine, making these drugs preferable for patients with renal disease. Sulfonylureas cross the placenta and may produce fetal hypoglycemia.
Sulfonylureas close KATP channels and inhibit ischemic preconditioning, a cardioprotective mechanism.20 Cardiovascular mortality has been associated with some sulfonylureas, especially in patients who have had a prior myocardial infarction.21,22 Gliclazide, a newer sulfonylurea selective for pancreatic β cells may not be associated with the same cardiac morbidity.23,24 For this reason, sulfonylureas may be discontinued 24 to 48 hours before elective surgery in high-risk patients. Approximately 1% to 3% of patients treated with oral hypoglycemics experience gastrointestinal disturbances including nausea, vomiting, abnormal liver function tests, and cholestasis. Sulfonylureas are not recommended for patients with hepatic dysfunction as liver disease prolongs their elimination half-time and enhances their hypoglycemic action, with the exception of acetohexamide. Disulfiram-like reactions and inappropriate secretion of arginine vasopressin hormone that results in hyponatremia are unique side effects of chlorpropamide.
Glyburide
Glyburide stimulates insulin secretion over a 24-hour period after a morning oral dose.25 Peak plasma levels occur approximately 3 hours after an oral dose. Glyburide increases sensitivity to insulin and inhibits the production of glucose by the liver. Metabolism is in the liver, with metabolites excreted equally in urine and feces. One of the hepatic metabolites of glyburide has approximately 15% of the activity of the parent compound. A mild diuretic effect accompanies use of this drug. When administration is discontinued, the drug is cleared from plasma in about 36 hours.
Glipizide
Glipizide stimulates insulin secretion over a 12-hour period after a morning oral dose. Peak plasma levels occur approximately 1 hour after oral administration. Glipizide increases glucose uptake and suppresses glucose output by the liver.26 These effects persist for prolonged periods (at least 3 years) without evidence of tolerance. Unlike glyburide, metabolism of glipizide in the liver produces inactive substances that are excreted in urine. A mild diuretic effect accompanies use of this drug. Relatively rapid clearance from the plasma minimizes the potential for long-lasting hypoglycemia.
Glimepiride
Glimepiride decreases blood glucose concentrations by stimulating release of insulin from the pancreas and may decrease hepatic glucose production. It is combined with insulin therapy when oral sulfonylureas are not effective.
Tolbutamide
Tolbutamide is the shortest acting and least potent sulfonylurea (see Table 38-4).18 It is extensively metabolized in the liver to much less potent compounds before excretion in urine. Of all the sulfonylureas, tolbutamide probably causes the fewest side effects, although it can produce hypoglycemia and hyponatremia.
Acetohexamide
Acetohexamide differs from other sulfonylureas in that most of its hypoglycemic action comes from its principal metabolite hydroxyhexamide, which is 2.5 times as potent as the parent compound. After oral ingestion, peak plasma concentrations of acetohexamide and its active metabolite occur after 1.5 hours and 3.5 hours, respectively. This drug is not recommended for patients with renal disease because the kidneys excrete the active metabolite. Acetohexamide is the only sulfonylurea with uricosuric properties (urocosuric drugs increase the excretion of uric acid in the urine), making it an appropriate drug for the diabetic patient with gout.
Chlorpropamide
Chlorpropamide is the longest acting sulfonylurea, with a duration of action that may approach 72 hours (see Table 38-4).18 The maximal effect of chlorpropamide may not be apparent for 7 to 14 days, and several weeks are needed for complete elimination of the drug. Because 20% of a dose is excreted unchanged, impaired renal function can lead to accumulation and an enhanced hypoglycemic effect. Chlorpropamide is associated with reactions similar to those produced by disulfiram (facial flushing after ingestion of alcohol) and can cause severe hyponatremia. Approximately 5% of patients treated with chlorpropamide have serum sodium concentrations of less than 129 mEq/L, but they are usually asymptomatic. Risk factors for the development of hyponatremia include age older than 60 years, female gender, and the concomitant administration of thiazide diuretics. If all these risk factors are present, the frequency of hyponatremia increases threefold.
Meglitinides
Repaglinide and the phenylalanine derivative, nateglinide, differ in structure and timing of action from sulfonylurea drugs. Although these drugs exert effects on β cells similar to those of sulfonylurea drugs, their peak effect is about 1 hour and duration of action is about 4 hours. β cell stimulants lower HbA1c about 1%. Repaglinide and nateglinide must be administered 15 to 30 minutes before a meal and should never be ingested while fasting. The short duration of action and activity only in the presence of glucose should decrease the risk of prolonged hypoglycemic episodes.27 Nateglinide is metabolized by the liver, and its metabolites are excreted by the kidney. The accumulation of active metabolites may cause hypoglycemia. Excretion of repaglinide by the kidneys is minimal so adjustment is not necessary for patients with renal insufficiency.
α-Glucosidase Inhibitors
Acarbose and miglitol are α-glucosidase inhibitors (AGI) that decrease carbohydrate digestion and absorption of disaccharides by interfering with intestinal glucosidase activity.18 As a result, both release of glucose from food and absorption from the gastrointestinal tract are slow. HbA1c generally decreases 0.5% to 0.8%. These drugs are useful only as monotherapy when postprandial hyperglycemia is the main problem. Flatulence, abdominal cramping, and diarrhea are side effects that frequently result from undigested carbohydrates that reach bacteria in the lower colon. With the exception of occasional increases in liver transaminases, these drugs are considered nontoxic.15 Although hypoglycemia does not occur with monotherapy, it can occur when AGI are added to sulfonylureas or insulin.
Thiazolidinediones
Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, act principally at skeletal muscle, liver, and adipose tissue via peroxisome proliferator activator receptor-γ (PPAR-γ) to decrease insulin resistance and hepatic glucose production and to increase use of glucose by the liver.5 Like metformin, TZDs act in the presence of insulin and are especially effective in obese patients. As monotherapy, these drugs decrease HbA1c 1% to 1.5%. The clinical effect takes 4 to 12 weeks. TZDs can cause weight gain, which is partly extracellular fluid. The accumulation of extracellular fluid as edema is undesirable in patients with congestive heart failure. These drugs also are contraindicated in patients with liver failure. The possibility of drug-induced liver dysfunction is the reason that plasma concentrations of hepatic transaminases must be measured periodically. TZDs tend to decrease plasma concentrations of triglycerides and increase high-density lipoprotein and low-density lipoprotein cholesterol levels. Although rosiglitazone has been associated with cardiovascular risk, particularly heart failure, this risk may be similar to the cardiovascular risks observed with other standard diabetes medications.28
Glucagon-Like Peptide-1 Receptor Agonists
GLP-1 receptor agonists such as exenatide and liraglutide are injectable agents that bind to receptors in the pancreas, gastrointestinal tract, and brain to increase insulin secretion from β cells (glucose dependent), decrease glucagon production from α cells, and reduce gastric emptying. Nausea and vomiting is associated with GLP-1 receptor agonists. The risk of hypoglycemia increases when GLP-1 receptor agonists are combined with sulfonylureas. Exenatide formulations include a short-acting formulation and a long-acting formulation that is injected once weekly. Liraglutide has a half-life of 8 to 14 hours and is injected once daily.5
Dipeptidyl-Peptidase-4 Inhibitors
Dipeptidyl-peptidase-4 (DDP-4) inhibitors (saxagliptin, sitagliptin, linagliptin, alogliptin, vildagliptin) enhance the incretin effect via inhibition of native GLP-1 degradation. Similar to GLP-1 receptor agonists, DPP-4 inhibitors increase insulin secretion from α cells (glucose dependent) and reduce pancreatic α cell secretion of glucagon.5 This class of drugs has a duration of action of 12 to 24 hours, and doses are reduced for patients with renal insufficiency.
Amylin Agonists
Pancreatic β cells secrete insulin and amylin. Although amylin agonists (pramlintide) do not alter insulin levels, they suppress gastric emptying, inhibit glucagon release, and reduce HbA1c levels. Side effects of pramlintide include nausea and vomiting.
Other Medications
Colesevelam (bile acid sequestrant) and bromocriptine mesylate (dopamine receptor agonist) lower glucose levels and decrease HbA1c values, but the mechanisms are unclear. Neither of these medications is associated with hypoglycemia and both may cause gastrointestinal intolerance.5
Combination Therapy
Combination therapies target two or more different causes of hyperglycemia simultaneously. For example, insulin resistance in the liver is decreased with metformin while insulin secretion is increased with sulfonylureas or meglitinide. AGI complement the different actions of these two classes of drugs. Exogenous insulin also may be part of combination therapy. The primary aim of combination therapy is to decrease HbA1c; reductions in the daily insulin dose are a secondary benefit.
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