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Pharmacologic Agents for Diabetes Mellitus, Type 2
AgentMechanism of ActionDosageBenefitsSide EffectsNotes
Insulin (regular insulin; insulin aspart; insulin lispro; insulin glulisine; isophane insulin [NPH]; lente insulin; ultralente insulin; insulin glargine; insulin detemir; insulin lispro, insulin lispro protamine; insulin aspart, insulin aspart protamine; regular insulin, isophane insulin [NPH]; semilente insulin; protamine zinc insulin [PZI])Direct action of hormoneStarting dose is highly variable; weight-based algorithms can be used, with a typical total starting dose of 0.1 to 0.15 units/kg (NPH, lente, or glargine insulin) divided into two dosesInsulin can improve HbA1c by 1%-2%; in some studies, titrated doses can result in all patients achieving HbA1c <7%Hypoglycemia, weight gainMay be used alone or in combination with oral agents
SulfonylureasUpArr pancreatic secretion of insulin in response to glucoseSee table Dosages for Various Types of Sulfonylureas.DnArr HbA1c by 1%-2%Often associated with initial weight gain. Control may deteriorate over time, requiring UpArr doses or additional modes of therapy. First-line agent
Biguanide (Metformin)Suppresses hepatic glucose production and UpArr insulin sensitivity in muscle and liver 500 mg/d; may be UpArr weekly to 2500 mg/d in bid or tid dosaging DnArr HbA1c by 1%-2% (84). May DnArr lipid levels and BP; avoid weight loss; may DnArr macrovascular disease in obese patientsGastrointestinal side effects such as nausea, diarrhea, bloating, and flatulence.

Increased risk of lactic acidosis, primarily in those with renal insufficiency (serum creatinine >1.4 mg/dL), decompensated congestive heart failure, liver failure, and in alcoholics or those who binge drink. Clinicians should avoid the use of metformin in these settings. Furthermore, in clinical situations with a high risk of these situations developing, metformin should be discontinued or used with extreme caution; for example, metformin should be discontinued prior to the use of contrast media in imaging studies
May UpArr mortality when used in combination with sulfonylureas (controversial) (84); overweight patients in a randomized, controlled trial showed 32% reduction in any diabetes-related end point, including 36% reduction in all-cause mortality (84). Combination of glyburide and metformin, glipizide and metformin, and metformin and rosiglitazone are also available
Nonsulfonylurea insulin secretagogue:
Stimulates insulin production; DnArr postprandial hyperglycemiaRepaglinide: 0.5 mg just before meals; can be UpArr to 4 mg qid. Nateglinide: 120 mg just before meals More rapid onset than with sulfonylureas; short-acting; useful in patients who skip meals or drug dosesHypoglycemia, headache with repaglinideGlyburide is more effective at DnArr mean glucose, but repaglinide is more effective at DnArr postprandial glucose and results in less hypoglycemia; can be used as monotherapy; long-term effects on glycemic control are not well defined
Alpha-glucosidase inhibitor (acarbose, miglitol)DnArr postprandial hyperglycemia by DnArr GI absorption of carbohydrates25 mg qd (starting dosage) to tide; titrate to maximum of 100 mg tidDnArr HbA1c by 0.5%-1.0%GI (bloating, flatulence, diarrhea)Less effective than other agents; not generally used as monotherapy in patients with hyperglycemia (HbA1c >9%); qd dosing tends to minimize GI side effects
Thiazolidinediones (rosiglitazone, pioglitazone)UpArr muscle sensitivity to insulinRosiglitazone: 4 mg qd (starting dose), titrate to maximum 8 mg qd or 4 mg bid. Pioglitazone: 15 mg (starting dosage), titrate to maximum 45 mg qdDnArr HbA1c by 1%-2% when added to other agents (102; 168)Weight gain, edema. Need to check LFTs at baseline and whenever clinically indicated thereafter.

The thiazolidinediones can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure, and the thiazolidinedione should be discontinued if any deterioration in cardiac status occurs. Thiazolidinediones should not be used in patients with class III/IV NYHA heart failure.

The FDA's joint Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Committee concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. This conclusion was based on several independently conducted meta-analyses showing an increase in the relative risk of myocardial infarction, angina, or sudden death among patients taking rosiglitazone. Presentations by FDA staff members suggested that a subgroup of patients with type 2 diabetes who are at higher risk for these events includes those with long-term nitrate use and those receiving concomitant insulin therapy. The FDA committee report acknowledged that there were several caveats inherent in the meta-analyses, including the facts that most of the clinical trials lasted only 6 months (although the two largest trials, which contributed most of the end points, were longer), that there were relatively few myocardial events overall, and that differences existed in adjudication of ischemic events. Ultimately, the committee voted to recommend that rosiglitazone not be removed from the market but rather that label warnings and extensive educational efforts be instituted immediately. The committee also requested further studies, but noted that none of the several proposed analyses of the ongoing clinical trials is likely to define an absolute risk for myocardial ischemic events in patients with diabetes who are taking this drug (110; 109)

The FDA has received postmarketing reports of new onset and worsening diabetic macular edema in patients receiving rosiglitazone. In most cases, the patients also reported concurrent peripheral edema. In some cases, macular edema resolved or improved after discontinuation of therapy, and in one case macular edema resolved after dose reduction.

An FDA alert has been issued regarding safety data indicating an increased risk for fractures of the upper arm, hand, and foot in women taking rosiglitazone and pioglitazone as compared to those taking metformin or glyburide.

As monotherapy, most useful in patients with mild hyperglycemia; as adjunct, most useful to patients on insulin (insulin dosage must be DnArr by 10%-25% to avoid hypoglycemia), sulfonylureas, or metformin
ExenatideGlucose-dependent enhancement of inulin secretion, suppression of inappropriately high glucagon secretion, slowing of gastric emptying, reduction of food intake5 µg sc 60 min before morning and evening meals; increase to 10 µg after 1 monthDnArr HbA1c by ~1%
DnArr weight
Nausea, vomiting

In October 2007, the FDA reported that it had reviewed 30 postmarketing reports of acute pancreatitis in patients taking exenatide. In some cases, an association between exenatide and acute pancreatitis has been suspected. Health care professionals should be alert to the signs and symptoms of acute pancreatitis and instruct patients taking exenatide to seek prompt medical care if they experience unexplained, persistent, severe abdominal pain, which may or may not be accompanied by vomiting. If pancreatitis is suspected, exenatide should be discontinued. Amylin Pharmaceuticals has agreed to include information about acute pancreatitis in the precautions section of the product label
May only be used in combination with metformin, a sulfonylurea, or a combination of metformin and sulfonylurea
PramlintideModulation of emptying, prevention of the postprandial increase in plasma glucagon, and increased satiety60 µg sc just before each major meal (>=250 kcal or containing >30 g carbohydrate); increase as tolerated to 120 µgDnArr HbA1c by ~0.5%
DnArr weight
NauseaUse in patients with suboptimal glycemic control on insulin with or without concurrent metformin-sulfonylurea therapy. Because of its effect on gastric emptying, pramlintide may delay the absorption of concomitantly administered oral drugs and reduce their peak plasma concentrations
DPP-IV inhibitors (Sitagliptin)Prevent the rapid degradation of incretin hormones, thereby resulting in increased postprandial levels of active incretin hormons, GLP-1 and GIP. By enhancing incretin action, DPP-IV inhibitors lower blood glucose in a glucose-dependent manner, enhance β-cell mass, and promote satiety100 mg qd; 50 mg daily if creatinine clearance is 30-50 mL/min; and 25 mg daily if creatinine clearance is <30 mL/minDnArr HbA1c by ~0.7%NoneMay be used as monotherapy or in combination with metformin or thiazolidinediones in patients with type 2 diabetes

bid = twice daily; BP = blood pressure; DPP-IV = dipeptidyl peptidase-IV; GI = gastrointestinal; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; LFT = liver function test; NYHA = New York Heart Association; qd = once daily; qid = four times daily; sc = subcutaneous; tid = three times daily.