Treating type 2 diabetes: Targeting the causative factors
Metformin induces weight loss (2–3 kg), preferentially involving adipose tissue in obese patients with type 2 diabetes over 4 to 6 months.22,25 In UKPDS 34, weight gain was similar among those treated with metformin and diet (approximately 2 kg); weight gain over 10 years was less with metformin, however, than with sulfonylurea (approximately 4 kg) or insulin (approximately 6 kg).23 Metformin also significantly improved levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides when compared with glyburide or placebo.22
Risk of lactic acidosis. Lactic acidosis associated with metformin is a rare but serious adverse event, with an estimated prevalence of 3 cases per 100,000.26 The product labeling notes most of these cases have occurred among patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion. Absolute contraindications include renal disease (serum creatinine ≥1.5 mg/dL [males] and ≥1.4 mg/dL [females]), congestive heart failure requiring pharmacological treatment, and acute or chronic metabolic acidosis. It should also be discontinued at the time of radiologic studies using intravascular iodinated contrast materials.
Additional “precautionary conditions” include age ≥80 years (unless measurement of creatinine clearance demonstrates that renal function is not reduced), hepatic disease, cationic drug use, conditions associated with hypoxia (eg, chronic obstructive pulmonary disease [COPD], acute myocardial infarction, dehydration, sepsis), excessive alcohol intake, and surgery, until patient’s oral intake is resumed.
Is the risk overstated? Despite these extensive precautions, published studies show that metformin is commonly prescribed to patients with absolute contraindications.27,28 One recent study observed that 11.2% of Medicare beneficiaries hospitalized with congestive heart failure and concomitant diabetes were treated with metformin.28 In the absence of advanced renal dysfunction, metformin rarely accumulates in the body,29 and accumulation of metformin is rarely reported as a cause of lactic acidosis.30,31 Rather, tissue hypoxia acts as a trigger in most cases. Metformin should therefore be discontinued whenever tissue hypoxia is suspected.31
A recent systematic review and meta analysis found no evidence that metformin was associated with an increased risk of lactic acidosis if the drug was prescribed under study conditions, taking into account contraindications.32 Refinement and clarification of the risk for lactic acidosis in these various populations is needed, to ensure optimal patient safety and to further assess this highly effective medication.
Common adverse effects associated with metformin are diarrhea and nausea, which can be minimized by administering the drug with meals and slowly titrating the dose, or perhaps by using the extended-release formulation.
Thiazolidinediones
Thiazolidinediones (TZDs) include rosiglitazone and pioglitazone. These agents, like metformin, do not increase insulin secretion but depend on the presence of insulin for their activity. TZDs are agonists at peroxisome-proliferator-activated receptor gamma (PPAR-γ) receptors in peripheral tissues such as skeletal muscle, where they increase glucose uptake.15 Thus, their predominant effect is to decrease insulin resistance.
TZDs have similar antihyperglycemic efficacy as sulfonylureas or metformin. They decrease A1c levels by 0.6–1.9 percentage points and lower fasting plasma glucose levels by 50–80 mg/dL.15 They have a slower onset of action compared with other hypoglycemic drugs, and intervals of 3 to 4 weeks should be allowed between doses before increasing the dosage. TZDs also have favorable effects on lipid levels: HDL concentrations increase and triglyceride concentrations decrease with their use.33 It is not known whether they decrease macrovascular or microvascular complications, although such studies are underway.
Adverse effects. TZDs are typically well tolerated, though weight gain of 1–3 kg, edema (4%–5%) and anemia (1%–2%) can occur. Weight gain and edema are more pronounced when TZDs are used in combination with insulin. Anemia is likely due to increased plasma volume rather than any significant hematological effect.
Due to adverse events related to volume expansion, TZDs are not recommended for patients with New York Heart Association class III or IV heart failure. A recent consensus statement from the American Heart Association and the ADA stresses that before administering TZD treatment, the physician should explore the possible presence of cardiac disease, use of other drugs that cause fluid retention, and the pathogenesis of any existing edema or dyspnea.34
Although troglitazone was removed from the market due to its association with hepatocellular injury, pioglitazone and rosiglitazone are not as convincingly associated with liver injury.15 In preapproval clinical studies, less than 0.5% of patients treated with rosiglitzone and pioglitazone had elevations in alanine transaminase (ALT) >3 times the upper limit of normal.
The incidence of hepatitis or acute liver failure from troglitazone was compared with rosiglitazone, pioglitazone, metformin, and glyburide, by analysis of spontaneously reported adverse events to the Food and Drug Administration (FDA) MEDWATCH database during the first 15 months of marketing of each drug.35,36 The incidence of hepatitis per million prescriptions was 21.5, 14.7, 9.4, 2.9, and 4.1, respectively, while the incidence of acute liver failure per 100,000 prescriptions was 4.6, 0.9, 0.8, 0.2, and 0. It appears that postmarketing data support preclinical studies, in that the incidence of acute liver failure is an order of magnitude higher for troglitazone vs. other TZDs.35 However, the FDA recommends avoiding their use in patients with baseline ALT levels >2.5 times the upper limit of normal. The FDA recently reduced the recommended frequency for ALT monitoring for pioglitazone (and is currently considering the same for rosiglitazone). Serum ALT is recommended prior to initiation and then periodically thereafter.
