Pioglitazone and Metformin Similarly Effective in Reducing HbA1c

Yael Waknine

December 13, 2004

Dec. 13, 2004 -- Pioglitazone and metformin as monotherapy for type 2 diabetes are similarly effective in reducing hemoglobin A1c (HbA1c), but they have different effects on fasting plasma glucose (FPG) and plasma lipid levels, according to the results of a long-term randomized trial published in the December issue of the Journal of Clinical Endocrinology and Metabolism. Adverse event profiles for the drugs also differ and should also be taken into account when prescribing.

"Both ß-cell dysfunction and insulin resistance are core defects in the progression of type 2 diabetes and the associated metabolic syndrome," write G. Schernthaner, MD, from the Department of Medicine I at Rudolfstiftung Hospital in Vienna, Austria, and colleagues. "Pioglitazone reduces insulin resistance by enhancing the action of insulin, thereby promoting glucose utilization in peripheral tissues, suppressing glucogenesis, and reducing lipolysis."

The investigators compared the effects of monotherapy in 1,194 therapy-naive patients with poorly controlled type 2 diabetes (mean HbA1c, 7.5% - 11%; reference range was defined as 4.3% - 6.1%) randomized to receive either pioglitazone (up to 45 mg/day; n = 597) or metformin (up to 850 mg three times daily; n = 597) for one year.

For the patients who finished the study (499 in the pioglitazone group and 501 in the metformin group), results at 52 weeks showed similar efficacy between the groups in reducing mean HbA1c from baseline (-1.41% for pioglitazone vs -1.50% for metformin). In both groups, maximal effect was observed at 32 weeks and maintained thereafter. However, pioglitazone therapy resulted in significantly greater mean reductions in FPG from baseline compared with metformin (-45.0 mg/dL [-2.5mmol/L] vs -39.6 mg/dL [-2.2 mmol/L]; P = .016).

Effects on lipid profiles also differed between treatment groups. Treatment with pioglitazone resulted in significantly greater decreases in mean triglyceride (TG) levels (-19% vs -10%, P = .001) and increases in high-density lipoprotein (HDL) cholesterol levels (+6.18 mg/dL [0.16 mmol/L) vs +3.09 mg/dL [0.08 mmol/L]; P = .001) from baseline compared with metformin.

"Pioglitazone treatment reduced TG levels by 19% and increased HDL [cholesterol] by 14%, nearly double the improvements with metformin," the authors point out.

Although low-density lipoprotein (LDL) and total cholesterol (TC) levels increased with pioglitazone therapy, the LDL cholesterol-TC ratio decreased similarly from baseline in both groups (8%; P = .09).

Albumin-to-creatinine ratios were significantly reduced by pioglitazone but remained unchanged with metformin therapy (-19% vs -1%; P = .002).

"Increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that progressively develop in parallel and are strongly associated with increased mortality risk," the authors point out.

Differences in liver function changes and body weight were also observed between groups.

Results of liver tests suggested that although liver function improved from baseline with both therapies, the effects were greater with pioglitazone than with metformin therapy (mean decreases: alanine transaminase [-6.4 U/L vs -2.8 U/L], γ-glutamyltransferase [-9.5 U/L vs -6.4 U/L]). "Because nonalcoholic steatohepatitis is associated with insulin resistance...an improvement in liver function tests might be beneficial in this subset of patients," the authors note.

Treatment with pioglitazone resulted in a 1.9-kg increase in mean body weight at one year compared with a 2.5-kg decrease in those who received metformin. "Metformin treatment resulted in an overall weight decrease in nearly 70% of patients, which may be of particular benefit to overweight patients," the authors comment.

The overall frequency of adverse events was similar between groups, although profiles differed and severe effects were more common in those who received metformin (7.4% vs 4.9%). Edema was the most frequently occurring adverse event with pioglitazone, while gastrointestinal disorders predominated in metformin therapy.

"HbA1c reduction is similar after pioglitazone and metformin monotherapies, but differences in FPG, plasma lipids, and adverse effects between the two compounds may influence decision-making in individual prescribers," the authors conclude. "Differing mechanisms of action also suggest that combination therapy could be complimentary."

The authors report no pertinent financial conflicts of interest .

J Clin Endocrinol Metab. 2004;89:6068-6076

Reviewed by Gary D. Vogin, MD

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