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Diabetes - Contraindications Pharmacologic options - side effects Several classes of oral pharmacologic agents and parenteral insulin are available for the treatment of type 2 diabetes. Sulfonylureas were the first type of oral therapy to be developed: Tolbutamide (Orinase) was introduced in the United States more than 40 years ago, and six other sulfonylureas are now available (table 2). In 1996 two other type of oral andidiabetic agents received US Food and Drug Administration (FDA) approval: the biguanide metformin (Glucophage) and the alpha-glucosidase inhibitor acarbose (Precose). Since then, another alpha-glucosidase inhibitor, miglitol (Glyset), has also been approved by the FDA; the manufacturer apparently does not intend to market the drug in the United States in the near future, but it will soon be available for use in Europe. The newest oral drug for type 2 diabetes is the insulin-sensitizing agent troglitazone (Rezulin), a thiazolidinedione approved by the FDA in 1997.
Sulfonylureas: These agents act as insulin secretagogues, binding to specific receptors in the plasma membrane of the pancreatic beta cell that trigger the release of insulin and C-peptide. The first-generation sulfonylureas are effective in reducing hyperglycemia at dosages of 100 mg or more per day; dosing once or twice daily is sufficient for all of these agents except tolbutamide, which may require more frequent dosing. The most common adverse effects noted with these agents are fluid retention resulting in hyponatremia, alcohol-induced flushing of the skin, and competition with drugs such as aspirin and trimethoprim for binding with serum albumin. Compared with first-generation agents, second-generation sulfonylureas can achieve the same degree of glycemic control with a much lower dosage, and largely because of this, they have a lower incidence of adverse effects.About 50% of patients receiving sulfonylurea therapy achieve glycemic control, but 20% do not respond (Primary failures). In another 3% to 10% of patients each year, type 2 diabetes becomes refractory to sulfonylurea therapy (secondary failures); progressive failure of beta cell function causes some of these failures, but the majority are due to poor compliance with nutrition therapy and exercise programs. Among the adverse effects associated with sulfonylurea-induced insulin secretion are weight gain, hyperinsulinemia, and hypoglycemia. Strict attention to diet and physical activity can minimize weight gain, and the incidence of hypoglycemic episodes can be reduced by adjusting the dosage.
Biguanides: Metformin is the only biguanide approved by the FDA for the treatment of type 2 diabetes. It reduces hyperglycemia primarily by lowering hepatic glucose output, and it also increases peripheral glucose disposal in muscle and adipose tissues. Metformin is not active in the absence of insulin. In most patients taking metformin, insulin levels remain unchanged or decrease.Metformin is appropriate for patients who have not achieved glycemic control with nutrition therapy, and exercise. It may be prescribed as monotherapy or in combination with a sulfonylurea; the hyperinsulinemia and weight gain associated with sulfonylurea therapy may be attenuated by the addition of metformin to the regimen. The initial dose of metformin is normally either one 500-mg tablet with morning and evening meals or one 850-mg tablet with breakfast; the maximum dosage is 2,550 mg per day. Anorexia, nausea, and abdominal discomfort are frequent adverse effects of metformin therapy; though disconcerting to the patient, these effects can contribute to weight loss and thereby actually benefit the obese patient. Because of a risk of lactic acidosis, metformin is contraindicated in patients with renal insufficiency, impaired hepatic function, congestive heart failure, sepsis, abnormal creatinine clearance beyond the age of 80 years, or any condition likely to cause central hypoxia or reduced peripheral perfusion. It should not be used during acute illness requiring hospitalization or within 48 hours of radiologic studies involving the use of iodinated contract materials. The 20 deaths due to lactic acidosis during the first year metformin was on the market were predominantly among patients who had contraindications to the use of the agent.
Alpha-Glucosidase Inhibitors: Another approach to the treatment of type 2 diabetes is the use of an alpha-glucosidase inhibitor (acarbose or miglitol), either as mono-therapy or in combination with other oral agents or insulin. These agents act by competitively inhibiting carbohydrate-digesting enzymes (sucrase, glucoamylase, maltase, isomaltase) found in the brush border of the villi of the small intestine, effectively delaying glucose absorption and decreasing post-prandial hyperglycemia and hyperinsulinemia. They are taken at the beginning of each meal. Like metformin, alpha-glucosidase inhibitors used as monotherapy are not associated with insulin-induced hyperinsulinemia, hypoglycemia, or weight gain; in fact, the addition of acarbose to a tolbutamide regimen may decrease postprandial hyperinsulinemia and attenuate tolbutamide-induced weight gain.Mild-to-moderate gastrointestinal symptoms of abdominal discomfort, borborygmi, flatulence, and diarrhea are common with use of acarbose or miglitol; they are caused by the presence in the colon of complex carbohydrates that have not been digested in the small intestine and thus must be digested by bacteria in the colon. These symptoms can be minimized by slow upward adjustment of the dose, and they usually improve after several weeks of therapy, probably as the result of an adaptive increase in glucosidase activity in lower parts of the small intestine. The small proportion of acarbose that is absorbed (<2%) is metabolized by the kidneys; caution is therefore advised in patients with renal dysfunction (creatinine level, >2.0 mg/dL). Use of alpha-glucosidase inhibitors should be avoided entirely in patients with inflammatory or obstructive bowel disease. The recommended initial dosage or acarbose or miglitol is 25 mg three times a day, with each dose taken at the start of a main meal. The dosage may be adjusted upward at 4- to 8-week intervals, based on 1-hour postprandial blood sugar levels and tolerance. The maximum dosage in the United States is 100 mg three times a day should not ordinarily be considered for patients weighing 60 kg or less, because there is an increased risk of elevated serum transaminase levels when acarbose or miglitol is given to such patients.
Thiazolidinediones: The thiazolidinediones are a new class of insulin-sensitizing drugs that include the agent troglitazone, which has FDA approval for use in patients with type 2 diabetes, either as monotherapy or with insulin or a sulfonylurea. The precise mechanism of action of troglitazone has not been defined, but the drug appears to interact with specific receptors on insulin-sensitive cells to regulate gene expression.Troglitazone therapy reduces fasting and postprandial plasma glucose levels as well as hyperinsulinemia, and the effects are generally dose related. Troglitazone significantly improves insulin sensitivity by increasing insulin-dependent glucose disposal and reducing hepatic glucose output. It also exerts a beneficial effect on the lipid profiles of patients with type 2 diabetes, lowering increased levels of triglycerides and raising levels of high-density lipoprotein cholesterol. Studies are currently in progress to determine the effects of troglitazone in patients with insulin resistance, including polycystic ovary syndrome, impaired glucose tolerance, obesity, and syndrome X. For monotherapy, the initial dosage of troglitazone is usually 400 mg once daily with breakfast. For patients not responding to 400 mg once daily, after 6 to 8 weeks the dosage may be increased to 600 mg once daily, the maximum recommended dosage. Whether a dosage of 600 mg results in better control of glycemia than lower dosages is not clear; the data available are conflicting. For patients receiving concomitant sulfonylurea or insulin therapy, the initial dosage of troglitazone is 200 mg once daily with breakfast, with continuation of the current sulfonylurea or insulin dosage. The dosage or troglitazone may be increased after about 2 to 4 weeks to a usual dosage of 400 mg once daily. The dosage of a concomitant sulfonylurea may need to be lowered to optimize therapy. The dosage of concomitant insulin may be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL. Further adjustments in insulin dosage may be required. Since serious liver injury has been reported in a small number of patients, the FDA recommends measuring liver enzyme levels at the start of therapy; every month for the first 6 months of treatment, every other month for the next 6 months, periodically thereafter, and any time symptoms of liver dysfunction develop. Patients with significant liver enzyme elevations should stop taking the drug.
Insulin: Multiple daily injections of insulin are effective in achieving glycemic control in nearly all patients with type 2 diabetes. Exogenous insulin compensates for the lack of endogenous insulin, which is no longer produced in adequate amounts by the pancreas in response to glucose stimulation. About 40% of patient with type 2 diabetes use insulin.Managing the care of insulin-treated patients is often a difficult and complex process. Insulin is available in several formulations with varying onsets of action and peaks of effectiveness; an implantable insulin pump is also available. For optimal glycemic control to be maintained, the patient's fasting and postprandial glycemia must be taken into account in devising an insulin regimen; as many as four injections per day may be required, timed to coincide with meals and/or bedtime. Patients taking insulin must monitor their blood glucose levels often and know how to recognize and treat episodes of hypoglycemia. These are not ideal conditions for the compliance needed to achieve optimal glycemic control. For type 2 diabetes patients who retain some insulin-secreting capacity, oral antidiabetic agents may provide a means of achieving glycemic control without using exogenous insulin. However, in some patients who do not achieve their therapeutic goals with oral agents, insulin may be added to the regimen as combination therapy. |
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