The pancreas produces the peptide hormones insulin, glucagon, and somatostatin. The peptide hormones are secreted from cells in the islets of Langerhans (β cells produce insulin, α cells produce glucagon, and δ cells produce somatostatin). These hormones play an important role in regulating metabolic activities of the body, particularly glucose homeostasis. A relative or absolute lack of insulin, as seen in diabetes mellitus, can cause serious hyperglycemia. Left untreated, retinopathy, nephropathy, neuropathy, and cardiovascular complications may result. Administration of insulin preparations or other glucose-lowering agents can reduce morbidity and mortality associated with diabetes.
Drugs for Diabetes: DIABETES MELLITUS
Focus topic: Drugs for Diabetes
The incidence of diabetes is growing rapidly in the United States and worldwide. An estimated 25.8 million people in the United States and 347 million people worldwide are afflicted with diabetes. Diabetes is not a single disease. Rather, it is a heterogeneous group of syndromes characterized by elevated blood glucose attributed to a relative or absolute deficiency of insulin. The American Diabetes Association (ADA) recognizes four clinical classifications of diabetes: type 1 diabetes (formerly insulin-dependent diabetes mellitus), type 2 diabetes (formerly non–insulin-dependent diabetes mellitus), gestational diabetes, and diabetes due to other causes such as genetic defects or medications.Gestational diabetes is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Uncontrolled gestational diabetes can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia. Diet, exercise, and/or insulin administration are effective in this condition. Glyburide and metformin may be reasonable alternatives to insulin therapy for gestational diabetes.
A. Type 1 diabetes
Type 1 diabetes most commonly afflicts children, adolescents, or young adults, but some latent forms occur later in life. The disease is characterized by an absolute deficiency of insulin due to destruction of β cells. Loss of β-cell function results from autoimmune-mediated processes that may be triggered by viruses or other environmental toxins. Without functional β cells, the pancreas fails to respond to glucose, and a person with type 1 diabetes shows classic symptoms of insulin deficiency (polydipsia, polyphagia, polyuria, and weight loss). Type 1 diabetics require exogenous insulin to avoid severe hyperglycemia and the life-threatening catabolic state of ketoacidosis.
- Cause of type 1 diabetes: In a normal post-absorptive period, constant β-cell secretion maintains low basal levels of circulating insulin. This suppresses lipolysis, proteolysis, and glycogenolysis. A burst of insulin secretion occurs within 2 minutes after ingesting a meal, in response to transient increases in circulating glucose and amino acids. This lasts for up to 15 minutes, followed by the postprandial secretion of insulin. However, without functional β cells, those with type 1 diabetes can neither maintain basal secretion of insulin nor respond to variations in circulating glucose.
- Treatment: A person with type 1 diabetes must rely on exogenous insulin to control hyperglycemia, avoid ketoacidosis, and maintain acceptable levels of glycosylated hemoglobin (HbA1c). [Note: The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous 3 months. A higher average glucose results in a higher HbA1c.] The goal of insulin therapy in type 1 diabetes is to maintain blood glucose as close to normal as possible and to avoid wide swings in glucose. The use of home blood glucose monitors facilitates frequent self-monitoring and treatment with insulin.
B. Type 2 diabetes
Type 2 diabetes accounts for greater than 90% of cases. Type 2 diabetes is influenced by genetic factors, aging, obesity, and peripheral insulin resistance, rather than autoimmune processes. The metabolic alterations are generally milder than those observed with type 1 (for example, patients with type 2 diabetes typically are not ketotic), but the long-term clinical consequences are similar.
- Cause: Type 2 diabetes is characterized by a lack of sensitivity of target organs to insulin. In type 2 diabetes, the pancreas retains some β-cell function, but insulin secretion is insufficient to maintain glucose homeostasis in the face of increasing peripheral insulin resistance. The β-cell mass may gradually decline over time in type 2 diabetes. In contrast to patients with type 1, those with type 2 diabetes are often obese. Obesity contributes to insulin resistance, which is considered the major underlying defect of type 2 diabetes.
- Treatment: The goal in treating type 2 diabetes is to maintain blood glucose within normal limits and to prevent the development of long-term complications. Weight reduction, exercise, and dietary modification decrease insulin resistance and correct hyperglycemia in some patients with type 2 diabetes. However, most patients require pharmacologic intervention with oral glucose-lowering agents. As the disease progresses, β-cell function declines and insulin therapy is often needed to achieve satisfactory glucose levels.
Drugs for Diabetes: INSULIN AND INSULIN ANALOGS
Focus topic: Drugs for Diabetes
Insulin [IN-su-lin] is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds. It is synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin and C-peptide, both of which are secreted by the β cells of the pancreas. [Note: Because insulin undergoes significant hepatic and renal extraction, plasma insulin levels may not accurately reflect insulin production. Thus, measurement of C-peptide provides a better index of insulin levels.] Insulin secretion is regulated by blood glucose levels, certain amino acids, other hormones, and autonomic mediators. Secretion is most often triggered by increased blood glucose, which is taken up by the glucose transporter into the β cells of the pancreas. There, it is phosphorylated by glucokinase, which acts as a glucose sensor. The products of glucose metabolism enter the mitochondrial respiratory chain and generate adenosine triphosphate (ATP). The rise in ATP levels causes a blockade of K+ channels, leading to membrane depolarization and an influx of Ca2+. The increase in intracellular Ca2+ causes pulsatile insulin exocytosis.
A. Mechanism of action
Exogenous insulin is administered to replace absent insulin secretion in type 1 diabetes or to supplement insufficient insulin secretion in type 2 diabetes.
B. Pharmacokinetics and fate
Human insulin is produced by recombinant DNA technology using strains of Escherichia coli or yeast that are genetically altered to contain the gene for human insulin. Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties. Insulin preparations vary primarily in their onset and duration of activity. For example, insulin lispro, aspart, and glulisine have a faster onset and shorter duration of action than regular insulin, because they do not aggregate or form complexes. Dose, injection site, blood supply, temperature, and physical activity can also affect the onset and duration of various insulin preparations. Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. Therefore, it is generally administered by subcutaneous injection. [Note: In a hyperglycemic emergency, regular insulin is administered intravenously (IV).] Continuous subcutaneous insulin infusion (also called the insulin pump) is another method of insulin delivery. This method of administration may be more convenient for some patients, eliminating multiple daily injections of insulin. The pump is programmed to deliver a basal rate of insulin. In addition, it allows the patient to deliver a bolus of insulin to cover mealtime carbohydrate intake and compensate for high blood glucose.
C. Adverse reactions to insulin
Hypoglycemia is the most serious and common adverse reaction to insulin. Other adverse reactions include weight gain, local injection site reactions, and lipodystrophy. Lipodystrophy can be minimized by rotation of injection sites. Diabetics with renal insufficiency may require a decrease in insulin dose.
Drugs for Diabetes: INSULIN PREPARATIONS AND TREATMENT
Focus topic: Drugs for Diabetes
Insulin preparations are classified as rapid-, short-, intermediate-, or long-acting. It is important that clinicians exercise caution when adjusting insulin treatment, paying strict attention to the dose and type of insulin.
A. Rapid-acting and short-acting insulin preparations
Four preparations fall into this category: regular insulin, insulin lispro [LIS-proe], insulin aspart [AS-part], and insulin glulisine [gloo-LYSEeen]. Regular insulin is a short-acting, soluble, crystalline zinc insulin. Insulin lispro, aspart, and glulisine are classified as rapid-acting insulins. Modification of the amino acid sequence of regular insulin produces analogs that are rapid-acting insulins. For example, insulin lispro differs from regular insulin in that the lysine and proline at positions 28 and 29 in the B chain are reversed. This modification results in more rapid absorption, a quicker onset, and a shorter duration of action after subcutaneous injection. Peak levels of insulin lispro are seen at 30 to 90 minutes, as compared with 50 to 120 minutes for regular insulin. Insulin aspart and insulin glulisine have pharmacokinetic and pharmacodynamic properties similar to those of insulin lispro. Rapid- or short-acting insulins are administered to mimic the prandial (mealtime) release of insulin and to control postprandial glucose. They may also be used in cases where swift correction of elevated glucose is needed. Rapid- and short-acting insulins are usually used in conjunction with a longer-acting basal insulin that provides control of fasting glucose. Regular insulin should be injected subcutaneously 30 minutes before a meal, whereas rapid-acting insulins are administered in the 15 minutes proceeding a meal or within 15 to 20 minutes after starting a meal. Rapid-acting insulins are commonly used in external insulin pumps, and they are suitable for IV administration, although regular insulin is most commonly used when the IV route is needed.
B. Intermediate-acting insulin
Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting insulin formed by the addition of zinc and protamine to regular insulin. [Note: Another name for this preparation is insulin isophane.] The combination with protamine forms a complex that is less soluble, resulting in delayed absorption and a longer duration of action. NPH insulin is used for basal (fasting) control in type 1 or 2 diabetes and is usually given along with rapid- or short-acting insulin for mealtime control. NPH insulin should be given only subcutaneously (never IV), and it should not be used when rapid glucose lowering is needed (for example, diabetic ketoacidosis).
C. Long-acting insulin preparations
The isoelectric point of insulin glargine [GLAR-geen] is lower than that of human insulin, leading to formation of a precipitate at the injection site that releases insulin over an extended period. It has a slower onset than NPH insulin and a flat, prolonged hypoglycemic effect with no peak. Insulin detemir [deh-TEE-meer] has a fatty acid side chain that enhances association to albumin. Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine. As with NPH insulin, insulin glargine and insulin detemir are used for basal control and should only be administered subcutaneously. Neither long-acting insulin should be mixed in the same syringe with other insulins, because doing so may alter the pharmacodynamic profile.
D. Insulin combinations
Various premixed combinations of human insulins, such as 70% NPH insulin plus 30% regular insulin, or 50% of each of these are also available. Use of premixed combinations decreases the number of daily injections but makes it more difficult to adjust individual components of the insulin regimen.
E. Standard treatment versus intensive treatment
Standard insulin therapy involves twice-daily injections. In contrast, intensive treatment utilizes three or more injections daily with frequent monitoring of blood glucose levels. The ADA recommends a target mean blood glucose level of 154 mg/dL or less (HbA1c ≤ 7%), and intensive treatment is more likely to achieve this goal. [Note: Normal mean blood glucose is approximately 115 mg/dL or less (HbA1c < 5.7%).] The frequency of hypoglycemic episodes, coma, and seizures is higher with intensive insulin regimens. However, patients on intensive therapy show a significant reduction in microvascular complications of diabetes such as retinopathy, nephropathy, and neuropathy compared to patients receiving standard care. Intensive therapy should not be recommended for patients with long-standing diabetes, significant microvascular complications, advanced age, and those with hypoglycemic unawareness. Intensive therapy has not been shown to significantly reduce macrovascular complications of diabetes.
Drugs for Diabetes: SYNTHETIC AMYLIN ANALOG
Focus topic: Drugs for Diabetes
Amylin is a hormone that is cosecreted with insulin from β cells following food intake. It delays gastric emptying, decreases postprandial glucagon secretion, and improves satiety. Pramlintide [PRAM-lin-tide] is a synthetic amylin analog that is indicated as an adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes. Pramlintide is administered by subcutaneous injection immediately prior to meals. When pramlintide is initiated, the dose of mealtime insulin should be decreased by 50% to avoid a risk of severe hypoglycemia. Other adverse effects include nausea, anorexia, and vomiting. Pramlintide may not be mixed in the same syringe with insulin, and it should be avoided in patients with diabetic gastroparesis (delayed stomach emptying), cresol hypersensitivity, or hypoglycemic unawareness.
Drugs for Diabetes: INCRETIN MIMETICS
Focus topic: Drugs for Diabetes
Oral glucose results in a higher secretion of insulin than occurs when an equal load of glucose is given IV. This effect is referred to as the “incretin effect” and is markedly reduced in type 2 diabetes. The incretin effect occurs because the gut releases incretin hormones, notably glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, in response to a meal. Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion. Exenatide [EX-e-nah-tide] and liraglutide [LIR-a-GLOO-tide] are injectable incretin mimetics used for the treatment of type 2 diabetes.
A. Mechanism of action
The incretin mimetics are analogs of GLP-1 that exert their activity by acting as GLP-1 receptor agonists. These agents improve glucose-dependent insulin secretion, slow gastric emptying time, reduce food intake by enhancing satiety (a feeling of fullness), decrease postprandial glucagon secretion, and promote β-cell proliferation. Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline.
B. Pharmacokinetics and fate
Being polypeptides, exenatide and liraglutide must be administered subcutaneously. Liraglutide is highly protein bound and has a long half-life, allowing for once-daily dosing without regard to meals. Exenatide is eliminated mainly via glomerular filtration and has a much shorter half-life. Because of the short duration of action, exenatide should be injected twice daily within 60 minutes prior to morning and evening meals. A once-weekly extended-release preparation is also available. Exenatide should be avoided in patients with severe renal impairment.
C. Adverse effects
The main adverse effects of the incretin mimetics consist of nausea, vomiting, diarrhea, and constipation. Exenatide and liraglutide have been associated with pancreatitis. Patients should be advised to discontinue these agents and contact their health care provider immediately if they experience severe abdominal pain. Liraglutide causes thyroid C-cell tumors in rodents. However, it is unknown if it causes these tumors or thyroid carcinoma in humans.
Drugs for Diabetes: ORAL AGENTS
Focus topic: Drugs for Diabetes
Oral agents are useful in the treatment of patients who have type 2 diabetes that is not controlled with diet. Patients who developed diabetes after age 40 and have had diabetes less than 5 years are most likely to respond well to oral glucose-lowering agents. Patients with long-standing disease may require a combination of oral agents with or without insulin to control hyperglycemia.
These agents are classified as insulin secretagogues, because they promote insulin release from the β cells of the pancreas. The sulfonylureas in current use are the second-generation drugs glyburide [GLYE-byoor-ide], glipizide [GLIP-ih-zide], and glimepiride [GLYE-me-pih-ride].
- Mechanism of action: The main mechanism of action includes stimulation of insulin release from the β cells of the pancreas. Sulfonylureas block ATP-sensitive K+ channels, resulting in depolarization, Ca2+ influx, and insulin exocytosis. In addition, sulfonylureas may reduce hepatic glucose production and increase peripheral insulin sensitivity.
- Pharmacokinetics and fate: Given orally, these drugs bind to serum proteins, are metabolized by the liver, and are excreted in the urine and feces. The duration of action ranges from 12 to 24 hours.
- Adverse effects: Major adverse effects of the sulfonylureas are weight gain, hyperinsulinemia, and hypoglycemia. They should be used with caution in hepatic or renal insufficiency, since accumulation of sulfonylureas may cause hypoglycemia. Renal impairment is a particular problem for glyburide, as it may increase the duration of action and increase the risk of hypoglycemia significantly. Glipizide or glimepiride are safer options in renal dysfunction and in elderly patients. Glyburide has minimal transfer across the placenta and may be an alternative to insulin for diabetes in pregnancy.
This class of agents includes repaglinide [re-PAG-lin-ide] and nateglinide [nuh-TAY-gli-nide]. Glinides are also considered insulin secretagogues.
- Mechanism of action: Like the sulfonylureas, the glinides stimulate insulin secretion. They bind to a distinct site on the β cell, closing ATP-sensitive K+ channels, and initiating a series of reactions that results in the release of insulin. In contrast to the sulfonylureas, the glinides have a rapid onset and a short duration of action. They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators. Glinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action. This would increase the risk of serious hypoglycemia.
- Pharmacokinetics and fate: Glinides should be taken prior to a meal and are well absorbed after oral administration. Both glinides are metabolized to inactive products by cytochrome P450 3A4 (CYP3A4;
- Adverse effects: Although glinides can cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas. [Note: Drugs that inhibit CYP3A4, such as itraconazole, fluconazole, erythromycin, and clarithromycin, may enhance the glucose lowering effect of repaglinide. Drugs that induce CYP3A4, such as barbiturates, carbamazepine, and rifampin, may have the opposite effect.] By inhibiting hepatic metabolism, the lipid-lowering drug gemfibrozil may significantly increase the effects of repaglinide, and concurrent use is contraindicated. These agents should be used with caution in patients with hepatic impairment.
Metformin [met-FOR-min], the only biguanide, is classified as an insulin sensitizer. It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance. Unlike sulfonylureas, metformin does not promote insulin secretion. Therefore, hyperinsulinemia is not a problem, and the risk of hypoglycemia is far less than that with sulfonylureas.
- Mechanism of action: The main mechanism of action of metformin is reduction of hepatic gluconeogenesis. [Note: Excess glucose produced by the liver is a major source of high blood glucose in type 2 diabetes, accounting for high fasting blood glucose.] Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization. Weight loss may occur because metformin causes loss of appetite. The ADA recommends metformin as the initial drug of choice for type 2 diabetes. Metformin may be used alone or in combination with other oral agents or insulin. Hypoglycemia may occur when metformin is taken in combination with insulin or insulin secretagogues, so adjustment in dosage may be required.
- Pharmacokinetics and fate: Metformin is well absorbed orally, is not bound to serum proteins, and is not metabolized. Excretion is via the urine.
- Adverse effects: These are largely gastrointestinal. Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis. It should be discontinued in cases of acute myocardial infarction, exacerbation of heart failure, sepsis, or other disorders that can cause acute renal failure. Metformin should be used with caution in patients older than 80 years and in those with heart failure or alcohol abuse. It should be temporarily discontinued in patients undergoing procedures requiring IV radiographic contrast. Rarely, potentially fatal lactic acidosis has occurred. Long-term use may interfere with vitamin B12 absorption. 4. Other uses: In addition to type 2 diabetes, metformin is effective in the treatment of polycystic ovary syndrome. It lowers insulin resistance seen in this disorder and can result in ovulation and, therefore, possibly pregnancy.
The thiazolidinediones (TZDs) are also insulin sensitizers. The two members of this class are pioglitazone [pye-oh-GLI-ta-zone] and rosiglitazone [roe-si-GLIH-ta-zone]. Although insulin is required for their action, the TZDs do not promote its release from the β cells, so hyperinsulinemia is not a risk.
- Mechanism of action: The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ), a nuclear hormone receptor. Activation of PPARγ regulates the transcription of several insulin responsive genes, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. Effects of these drugs on cholesterol levels are of interest. Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases triglycerides. Both drugs increase HDL cholesterol. The TZDs can be used as monotherapy or in combination with other glucose-lowering agents or insulin. The dose of insulin may have to be lowered when used in combination with these agents. The ADA recommends pioglitazone as a second- or third-line agent for type 2 diabetes. Rosiglitazone is less utilized due to concerns regarding cardiac adverse effects.
- Pharmacokinetics and fate: Pioglitazone and rosiglitazone are well absorbed after oral administration and are extensively bound to serum albumin. Both undergo extensive metabolism by different CYP450 isozymes (see Chapter 1). Some metabolites of pioglitazone have activity. Renal elimination of pioglitazone is negligible, with the majority of active drug and metabolites excreted in the bile and eliminated in the feces. Metabolites of rosiglitazone are primarily excreted in the urine. No dosage adjustment is required in renal impairment. These agents should be avoided in nursing mothers.
- Adverse effects: A few cases of liver toxicity have been reported with these drugs, and periodic monitoring of liver function is recommended. Weight gain can occur because TZDs may increase subcutaneous fat and cause fluid retention. [Note: Fluid retention can worsen heart failure. These drugs should be avoided in patients with severe heart failure.] TZDs have been associated with osteopenia and increased fracture risk. Pioglitazone may also increase the risk of bladder cancer. Several meta-analyses identified a potential increased risk of myocardial infarction and death from cardiovascular causes with rosiglitazone. As a result, use of rosiglitazone was limited to patients enrolled in a special restricted access program. After a further review of safety data, the restrictions on rosiglitazone use were subsequently lifted.
- Other uses: As with metformin, the relief of insulin resistance with the TZDs can cause ovulation to resume in premenopausal women with polycystic ovary syndrome.
E. α-Glucosidase inhibitors
Acarbose [AY-car-bose] and miglitol [MIG-li-tol] are oral agents used for the treatment of type 2 diabetes.
- Mechanism of action: Located in the intestinal brush border, α-glucosidase enzymes break down carbohydrates into glucose and other simple sugars that can be absorbed. Acarbose and miglitol reversibly inhibit α-glucosidase enzymes. When taken at the start of a meal, these drugs delay the digestion of carbohydrates, resulting in lower postprandial glucose levels. Since they do not stimulate insulin release or increase insulin sensitivity, these agents do not cause hypoglycemia when used as monotherapy. However, when used with insulin secretagogues or insulin, hypoglycemia may develop. [Note: It is important that hypoglycemia in this context be treated with glucose rather than sucrose, because sucrase is also inhibited by these drugs.]
- Pharmacokinetics and fate: Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. Miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.
- Adverse effects: The major side effects are flatulence, diarrhea, and abdominal cramping. Adverse effects limit the use of these agents in clinical practice. Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.
F. Dipeptidyl peptidase-4 inhibitors
Alogliptin [al-oh-GLIP-tin], linagliptin [lin-a-GLIP-tin], saxagliptin [saxa-GLIP-tin], and sitagliptin [si-ta-GLIP-tin] are orally active dipeptidyl peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes.
- Mechanism of action: These drugs inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1. Prolonging the activity of incretin hormones increases insulin release in response to meals and reduces inappropriate secretion of glucagon. DPP-4 inhibitors may be used as monotherapy or in combination with sulfonylureas, metformin, TZDs, or insulin. Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are weight neutral.
- Pharmacokinetics and fate: The DPP-4 inhibitors are well absorbed after oral administration. Food does not affect the extent of absorption. Alogliptin and sitagliptin are mostly excreted unchanged in the urine. Saxagliptin is metabolized via CYP450 3A4/5 to an active metabolite. The primary route of elimination for saxagliptin and the metabolite is renal. Linagliptin is primarily eliminated via the enterohepatic system. All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction.
- Adverse effects: In general, DPP-4 inhibitors are well tolerated, with the most common adverse effects being nasopharyngitis and headache. Although infrequent, pancreatitis has occurred with use of all DPP-4 inhibitors. Strong inhibitors of CYP450 3A4/5, such as ritonavir, atazanavir, itraconazole, and clarithromycin, may increase levels of saxagliptin. Therefore, reduced doses of saxagliptin should be used.
G. Sodium–glucose cotransporter 2 inhibitors
Canagliflozin [kan-a-gli-FLOE-zin] and dapagliflozin [dap-a-gli-FLOEzin] are the agents in this category of drugs for type 2 diabetes.
- Mechanism of action: The sodium–glucose cotransporter 2 (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney. By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose. Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure. However, they are not indicated for the treatment of hypertension.
- Pharmacokinetics and fate: These agents are given once daily in the morning. Canagliflozin should be taken before the first meal of the day. Both drugs are mainly metabolized by glucuronidation
to inactive metabolites. While the primary route of excretion for canagliflozin is via the feces, about one-third of a dose is renally eliminated. These agents should be avoided in patients with renal dysfunction.
- Adverse effects: The most common adverse effects with SGLT2 inhibitors are female genital mycotic infections (for example, vulvovaginal candidiasis), urinary tract infections, and urinary frequency. Hypotension has also occurred, particularly in the elderly or patients on diuretics. Thus, volume status should be evaluated prior to starting these agents.
H. Other agents
Both the dopamine agonist bromocriptine and the bile acid sequestrant colesevelam produce modest reductions in HbA1c. The mechanism of action of glucose lowering is unknown for both of these drugs. Although bromocriptine and colesevelam are indicated for the treatment of type 2 diabetes, their modest efficacy, adverse effects, and pill burden limit their use in clinical practice.