The risk of hypoglycemia is greater in patients who are treatment-naïve or whose HbA1c is <8%. Hypoglycemia may be difficult to recognize in the elderly and in those on concomitant β-blocker therapy. Hypoglycemia is more likely to occur when caloric intake is low, after prolonged exercise, after intake of alcohol, or when multiple antihyperglycemic agents are used. During periods of stress (eg, fever, trauma, infection, or surgery) antihyperglycemic dosage requirements may change.
ALPHA-GLUCOSIDASE INHIBITORS (eg, acarbose): Alpha-glucosidase inhibitors reversibly inhibit membrane-bound intestinal α-glucosidase as well as α-amylase in the pancreas. This action reduces the enzymatic hydrolysis of starches, oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides to delay glucose absorption at the intestinal brush border and blunt the postprandial rise in plasma glucose.
AMYLIN ANALOGUES/AMYLINOMIMETICS: Pramlintide is a synthetic analog of human amylin used in combination with insulin. Amylin is a neuroendocrine hormone, co-secreted with insulin by pancreatic beta cells in response to food intake. Pramlintide mimics the actions of endogenous amylin. It slows gastric emptying without alteration of overall nutrient absorption and suppresses glucagon secretion, which leads to suppression of endogenous glucose output from the liver. Pramlintide also induces feelings of satiety to reduce caloric intake which may be responsible for the associated reductions in weight. Pramlintide alone does not cause hypoglycemia, but increases the risk of insulin-induced hypoglycemia when co-administered with insulin therapy.
BIGUANIDES: Metformin reduces hepatic glucose production and intestinal glucose absorption. It also improves insulin sensitivity and peripheral glucose uptake and utilization. Metformin differs from other antihyperglycemics (eg, sulfonylureas, insulin secretagogues) in that it does not cause hypoglycemia or hyperinsulinemia and is not associated with weight gain; it may produce weight loss. There is a risk of lactic acidosis in patients treated with metformin, especially in the presence of renal and hepatic dysfunction, thus metformin is contraindicated in patients with renal disease or dysfunction and is not recommended in patients with hepatic disease.
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS: Sitagliptin is a DDP-4 inhibitor that slows the inactivation of the incretin hormones. The predominant incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted in response to food intake and contribute to glucose homeostasis by promoting insulin synthesis and secretion as well as reducing glucagon secretion and hepatic glucose production. The incretin hormones are, however, rapidly inactivated by DPP-4. Sitagliptin inhibits this enzyme to prolong endogenous incretin activity. Sitagliptin alone does not cause hypoglycemia, but may increase the risk of insulin-induced hypoglycemia when co-administered with sulfonylureas or other insulin secretagogues.
GLUCAGON: Glucagon is an alternative treatment for severe hypoglycemia if IV glucose cannot be used. Glucagon converts liver glycogen to glucose, thereby increasing blood glucose levels. It is only effective in the presence of sufficient liver glycogen and should not be used in states of starvation, adrenal insufficiency, or chronic hypoglycemia. Intravenous glucagon produces increases in blood pressure and tachycardia that generally resolve quickly, but may require therapy in patients with coronary artery disease or pheochromocytoma.
INCRETIN MIMETICS: Exenatide is a synthetic analog of the incretin hormone GLP-1. Like GLP-1, exenatide binds to and activates the GLP-1 receptor. Exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying . It has also been shown to reduce caloric intake which may be responsible for the associated reductions in weight. Exenatide increases the risk of hypoglycemia when used in combination with sulfonylureas or other insulin secretagogues.
INSULINS: Insulin is used in patients with type 1 diabetes. Insulin is also used in patients with type 2 diabetes who are unable to maintain control of their symptoms either by diet and exercise alone or with the addition of an oral antihyperglycemic agent. Doses should be individualized. Insulin is inactivated if taken orally and is usually given by subcutaneous injection. Insulin preparations are frequently classified by onset, peak, and duration of action.
INSULIN SECRETAGOGUES (eg, nateglinide, repaglinide): Insulin secretagogues stimulate glucose-dependent pancreatic β cell insulin secretion. Similar to the sulfonylureas, these agents induce insulin secretion by blocking ATP-sensitive potassium channels in pancreatic β cells. The β cells then depolarize, resulting in an opening of calcium channels that allows an influx of calcium ions which stimulate insulin secretion. Repaglinide and nateglinide are highly tissue selective with low affinity for heart and skeletal muscle. Like sulfonylureas, insulin secretagogues are associated with a risk of hypoglycemia.
SULFONYLUREAS: Sulfonylureas increase pancreatic β cell sensitivity to glucose. Acute administration of sulfonylureas enhances glucose-dependent pancreatic β cell insulin secretion and may also increase insulin levels by reducing hepatic insulin clearance. Although plasma insulin levels decrease over time with chronic administration, sulfonylureas maintain their antihyperglycemic effect. Sulfonylureas also suppress hepatic glucose production and stimulate release of somatostatin, an inhibitory hormone that slows gastric emptying and suppresses glucagon secretion. Hypoglycemia may occur, especially with longer-acting sulfonylureas, particularly in patients with renal or hepatic insufficiency.
First-generation sulfonylureas (eg, acetohexamide, chlorpropamide) vary considerably in their half-lives. Acetohexamide has a short half life (47 hours) and requires multiple daily dosing whereas chlorpropamide has an extended half life (2448 hours) which can allow for once daily dosing.
Second-generation sulfonylureas (eg, glimepiride, glipizide, glyburide) are about 100 times more potent than first-generation agents. These drugs generally have short-half lives (35 hours), but hypoglycemic effects can last 1224 hours, allowing for once daily dosing. The incidence of hypoglycemia is highest among patients treated with glyburide and lower with glipizide and glimepiride therapy.
THIAZOLIDINEDIONES (eg, pioglitazone, rosiglitazone): Thiazolidinediones increase insulin sensitivity which promotes insulin-dependent glucose disposal and decreases hepatic glucose production. These drugs are potent agonists for peroxisome proliferator-activated receptor-gamma (PPARγ).Activation of PPARγ receptors modifies the expression of insulin responsive genes that regulate glucose and lipid metabolism. Because thiazolidinediones enhance the effects of circulating insulin, these agents require the presence of insulin to produce their antihyperglycemic effects. Thiazolidinediones can cause hepatoxicity and should not be used in patients with liver disease. These agents are also associated with fluid retention, which can cause or exacerbate congestive heart failure.
by
Akshaya Srikanth
Pharm.D Internee
Hyderabad, India
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