Pharmacology Lecture 5: Drugs For Diabetes PDF

Pharmacology Drugs For Diabetes Lec 5 Pharmacology | Biologic DMARDs Contents : introduction 3 Diabetes mellitus 6 Insulin and Insulin analogs 18 Insulin preparations and treatment 26 Synthetic amylin analog 40 Glucagon-like peptide receptor agonists 42 Oral hypoglycemic drugs 49 Pharmacology | Drug...

Pharmacology Drugs For Diabetes Lec 5 Pharmacology | Biologic DMARDs Contents : introduction 3 Diabetes mellitus 6 Insulin and Insulin analogs 18 Insulin preparations and treatment 26 Synthetic amylin analog 40 Glucagon-like peptide receptor agonists 42 Oral hypoglycemic drugs 49 Pharmacology | Drugs For Diabetes 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 delta-cells produce somatostatin). These hormones play an important role in regulating metabolic activities of the body, particularly glucose homeostasis. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes Diabetes mellitus The incidence of diabetes is growing rapidly in the United States and worldwide. An estimated 30.3 million people in the United States and 422 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. Pharmacology | Drugs For Diabetes The American Diabetes Association (ADA) recognizes four clinical classifications of diabetes: Type 1 diabetes, type 2 diabetes, 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. Pharmacology | Drugs For 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. 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). Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes Causes Loss of β -cell function in type 1 diabetes results from autoimmune-mediated processes that may be triggered by viruses or other environmental toxins. In normal subjects (without diabetes), constant β -cell secretion of insulin 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. Pharmacology | Drugs For Diabetes 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: HbA1c is a marker of overall glucose control and is used to monitor diabetes in clinical practice. Pharmacology | Drugs For Diabetes 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·L the goal of insulin therapy in type 1 diabetes is to maintain blood glucose as close to normal as possible and to avoid wide fluctuations in glucose. The use of home blood glucose monitors facilitates frequent self-monitoring and treatment with insulin. Pharmacology | Drugs For Diabetes 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 diabetes (for example, patients with type 2 diabetes typically are not ketotic), but the long-term clinical consequences are similar. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes In contrast to patients with type 1 diabetes, those with type 2 diabetes are often obese. Obesity contributes to insulin resistance, which is considered the major underlying defect of type 2 diabetes. Pharmacology | Drugs For 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. Pharmacology | Drugs For Diabetes Insulin and Insulin analogs Insulin 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. Insulin secretion is regulated by blood glucose levels, certain amino acids, other hormones, and autonomic mediators. 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. Pharmacology | Drugs For Diabetes 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). Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes 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 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. Pharmacology | Drugs For Diabetes Insulin preparations vary primarily in their onset and duration of activity. 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, although an inhaled insulin formulation is also available. Pharmacology | Drugs For Diabetes 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. Note: In a hyperglycemic emergency, regular insulin is administered intravenously (IV). Pharmacology | Drugs For Diabetes C. Adverse effects Hypoglycemia is the most serious and common adverse reaction to insulin. Other adverse effects include weight gain, local injection site reactions, and lipodystrophy. Lipodystrophy can be minimized by rotation of injection sites. Pharmacology | Drugs For Diabetes Diabetics with renal insufficiency may require a decrease in insulin dose. Due to the potential for bronchospasm with inhaled insulin, patients with asthma, chronic obstructive pulmonary disease, and smokers should not use this formulation. Pharmacology | Drugs For Diabetes Insulin preparations and treatment 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. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes A. Rapid-acting and short-acting insulin preparations Five preparations fall into this category: regular insulin, insulin lispro, insulin aspart, insulin glulisine, and inhaled insulin. 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. Pharmacology | Drugs For Diabetes 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. Inhaled insulin is also considered rapid-acting. Pharmacology | Drugs For Diabetes This dry powder formulation is inhaled and absorbed through pulmonary tissue, with peak levels achieved within 45 to 60 minutes. Rapid- or short-acting insulins are administered to mimic the prandial (mealtime) release of insulins and to control postprandial glucose. They may also be used in cases where swift correction of elevated glucose is needed. Pharmacology | Drugs For Diabetes 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 preceding a meal or within 15 to 20 minutes after starting a meal. Rapid-acting insulin suspensions 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. Pharmacology | Drugs For Diabetes B. Intermediate-acting insulin Neutral protamine Hagedorn (NPH) insulin is an intermediateacting insulin formed by the addition of zinc and protamine to regular insulin. 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. Note: Another name for this preparation is insulin isophane. Pharmacology | Drugs For Diabetes 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 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. Pharmacology | Drugs For Diabetes Insulin detemir 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. Insulin degludec remains in solution at physiologic pH, with a slow release over an extended period. Pharmacology | Drugs For Diabetes It has the longest half-life of the long-acting insulins. As with NPH insulin, insulin glargine, insulin detemir, and insulin degludec are used for basal control and should only be administered subcutaneously. Longacting insulins should not be mixed in the same syringe with other insulins, because doing so may alter the pharmacodynamic profile. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes 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 :S 7%) for most patients, and intensive treatment is more likely to achieve this goal. The frequency of hypoglycemic episodes, coma, and seizures is higher with intensive insulin regimens. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Synthetic amylin analog Amylin is a hormone that is co-secreted with insulin from β cells following food intake. It delays gastric emptying, decreases postprandial glucagon secretion, and improves satiety. Pramlintide is a synthetic amylin analog that is indicated as an adjunct to mealtime insulin therapy in patients with type 1 and type 2 diabetes. Pharmacology | Drugs For Diabetes Pramlintide is administered by subcutaneous injection immediately before 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. Pharmacology | Drugs For Diabetes Glucagon-like peptide receptor agonists Oral intake of 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 glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in response to a meal. Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion. Pharmacology | Drugs For Diabetes Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide are injectable GLP-1 receptor agonists used for the treatment of type 2 diabetes. Liraglutide is also approved to reduce the risk of cardiovascular events and cardiovascular mortality in patients with type 2 diabetes and cardiovascular disease. Two premixed preparations of long-acting insulins and GLP-1 receptor agonists are available: insulin glargine plus lixisenatide and insulin degludec plus liraglutide. Use of these combinations may decrease daily insulin requirements and the number of daily injections. Pharmacology | Drugs For Diabetes Mechanism of action These agents are analogs of GLP-1 that exert their activity by improving glucose-dependent insulin secretion, slowing gastric emptying time, reducing food intake by enhancing satiety (a feeling of fullness), decreasing postprandial glucagon secretion, and promoting β-cell proliferation. Consequently, postprandial hyperglycemia is reduced, HbA1c levels decline, and weight loss may occur. Pharmacology | Drugs For Diabetes Pharmacokinetics GLP-1 receptor agonists are administered subcutaneously, since they are polypeptides. Albiglutide, dulaglutide, liraglutide, and semaglutide are considered long-acting GLP-1 receptor agonists. Albiglutide, dulaglutide, and semaglutide are dosed once weekly, while liraglutide is available as a once-daily injection. Lixisenatide is a short-acting GLP-1 receptor agonist that is dosed once daily. Pharmacology | Drugs For Diabetes Exenatide is available as both a short-acting (dosed twice daily) and extended-release preparation (dosed once weekly). Exenatide should be avoided in patients with severe renal impairment. Pharmacology | Drugs For Diabetes Adverse effects The main adverse effects of the incretin mimetics consist of N, V,D and constipation. GLP-1 receptor agonists have been associated with pancreatitis and should be avoided in patients with chronic pancreatitis. Longer-acting agents have been associated with thyroid C-cell tumors in rodents. Pharmacology | Drugs For Diabetes It is unknown if GLP-1 receptor agonists cause these tumors or thyroid carcinoma in humans, although they are contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. Pharmacology | Drugs For Diabetes Oral hypoglycemic drugs 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. Pharmacology | Drugs For Diabetes Patients with long-standing disease may require a combination of oral agents with or without insulin to control hyperglycemia. The duration of action of some of the oral glucose-lowering drugs and some of the common adverse effects are shown in the figers. Pharmacology | Drugs For Diabetes A. Sulfonylureas These agents are classified as insulin secretagogues, because they promote insulin release from the β cells of the pancreas. The sulfonylureas most used in clinical practice are the secondgeneration drugs glyburide, glipizide, and glimepiride. Pharmacology | Drugs For Diabetes Mechanism of action These agents stimulate 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. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes Pharmacokinetics 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 Adverse effects of the sulfonylureas include hypoglycemia, hyperinsulinemia, and weight gain. They should be used with caution in hepatic or renal insufficiency, since accumulation of sulfonylureas may cause hypoglycemia. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes B. Glinides This class of agents includes repaglinide and nateglinide. Glinides are also considered insulin secretagogues. Mechanism of action Like the sulfonylureas, the glinides stimulate insulin secretion. 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. Pharmacology | Drugs For Diabetes Glinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action and increased risk of serious hypoglycemia. Pharmacokinetics 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 in the liver and are excreted through the bile. Pharmacology | Drugs For Diabetes Adverse effects Although glinides cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas. 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. Pharmacology | Drugs For Diabetes C. Biguanides Metformin, 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, the risk of hypoglycemia is far less than that with sulfonylureas. Pharmacology | Drugs For Diabetes Metformin is also useful in the treatment of polycystic ovary syndrome, as it reduces insulin resistance seen in this disorder. Mechanism of action The main mechanism of action of metformin is reduction of hepatic gluconeogenesis. Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization. Weight loss may occur because metformin causes loss of appetite. 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 Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Pharmacokinetics Metformin is well absorbed after oral administration, is not bound to serum proteins, and is not metabolized. Excretion is via the urine. Adverse effects These are largely gastrointestinal, including NVD. These effects can be reduced by titrating the dose of metformin slowly and administering doses with meals. Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Rarely, potentially fatal lactic acidosis has occurred. Long-term use may be associated with vitamin B12 deficiency, and periodic measurement of vitamin B12 levels is recommended, especially in patients with anemia or peripheral neuropathy. Pharmacology | Drugs For Diabetes D. Thiazolidinediones The thiazolidinediones (TZDs) are also insulin sensitizers. The two agents in this class are pioglitazone and rosiglitazone. Although insulin is required for their action, the TZDs do not promote its release from the β cells, so hyperinsulinemia is not a risk. Pharmacology | Drugs For Diabetes 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. The TZDs can be used as monotherapy or in combination with other glucose-lowering agents or insulin. Pharmacology | Drugs For Diabetes 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 cardiovascular adverse effects. Pharmacology | Drugs For Diabetes Pharmacokinetics Pioglitazone and rosiglitazone are well absorbed after oral administration and are extensively bound to serum albumin. Both undergo extensive metabolism by different CYP450 isozymes. Some metabolites of pioglitazone have activity. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Adverse effects Liver toxicity has occasionally been reported with these drugs, and baseline and periodic monitoring of liver function is recommended. Weight gain can occur because TZDs may increase subcutaneous fat and cause fluid retention. TZDs have been associated with osteopenia and increased fracture risk in women. Note: Fluid retention can worsen heart failure. These drugs should be avoided in patients with severe heart failure. Pharmacology | Drugs For Diabetes Pioglitazone may also increase the risk of bladder cancer. Additionally, rosiglitazone increased risk of myocardial infarction and angina with the use of this agent. Pharmacology | Drugs For Diabetes E. α-Glucosidase inhibitors Acarbose and miglitol 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. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes Pharmacokinetics Acarbose is poorly absorbed. lt is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine. Miglito is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney. Pharmacology | Drugs For Diabetes Adverse effects The most common adverse 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. Pharmacology | Drugs For Diabetes F. Dipeptidyl peptidase-4 inhibitors Alogliptin, linagliptin, saxagliptin, and sitagliptin are oral dipeptidyl peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes. Mechanism of action These drugs inhibit the enzyme DPP4, which is responsible for the inactivation of incretin hormones such as GLP-1. Prolonging the activity of incretin hormones increases release of insulin in response to meals and reduces inappropriate secretion of glucagon. Pharmacology | Drugs For Diabetes DPP-4 inhibitors may be used as monotherapy or in combination with sulfonylureas, metformin, TZDs, or insulin. Treatment guidelines do not recommend the combination of DPP-4 inhibitors with GLP-1 receptor agonists for management of diabetes due to overlapping mechanisms and toxicity. Unlike GLP-1 receptor agonists, these drugs do not cause satiety or fullness and are weight neutral. Pharmacology | Drugs For Diabetes Pharmacokinetics 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 to an active metabolite. The primary route of elimination for saxagliptin and the metabolite is renal. Pharmacology | Drugs For Diabetes 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 the use of DPP-4 inhibitors. Pharmacology | Drugs For Diabetes Agents in this class may also increase the risk of severe, disabling joint pain. Alogliptin and saxagliptin have also been shown to increase the risk of heart failure hospitalizations and should be used with caution in patients with or at risk for heart failure. Pharmacology | Drugs For Diabetes G. Sodium-glucose cotransporter 2 inhibitors Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are oral agents for the treatment of type 2 diabetes. Empagliflozin is also indicated to reduce the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease. Mechanism of action The sodium-glucose cotransporter 2 (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes Pharmacokinetics These agents are given once daily in the morning. Canagliflozin should be taken before the first meal of the day. All drugs are mainly metabolized by glucuronidation to inactive metabolites. These agents should be avoided in patients with renal dysfunction. Pharmacology | Drugs For Diabetes 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. Pharmacology | Drugs For Diabetes Ketoacidosis has been reported with use of SGLT2 inhibitors, and these agents should be used with caution in patients with risk factors that predispose to ketoacidosis (for example, alcohol abuse and caloric restriction related to surgery or illness) Pharmacology | Drugs For Diabetes 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. Figures below summary of the oral antidiabetic agents and GLP-1 receptor agonists and treatment guidelines for type 2 diabetes. Pharmacology | Drugs For Diabetes Pharmacology | Drugs For Diabetes