Troglitazone or Metformin in Combination with Sulfonylureas for Patients with Type 2 Diabetes?

Safety was assessed on the basis of the results of serum FPG levels, creatinine and liver function tests, and home glucose monitoring. There were no elevations in liver enzymes or serum creatinine in those individuals receiving either troglitazone or metformin. No patient reported hypoglycemic symptoms or blood glucose values of less than 70 mg/dL on more than one occasion. Tolerability was evaluated using a questionnaire of potential side effects that was answered during each study visit. There was one dropout from the trial in the metformin treatment arm, which was attributed to moderate nausea and diarrhea after 1 month of treatment. Six additional participants in the metformin group reported mild nausea and bloating in the first 2 weeks of treatment with metformin; however, no other adverse effects were ascribed to the study medications.

Discussion

There has been much interest in combined pharmacologic therapy for type 2 diabetes, especially when target Hb A1c levels are not achieved with monotherapy. The American Diabetes Association recommends that the goal of treatment in type 2 diabetes is an Hb A1c level of less than 7%, with additional action suggested at values greater than 8%.¹⁸ This small study addressed patients with type 2 diabetes who were already receiving treatment with moderate to maximum doses of a sulfonylurea. The patients in this study were obese (mean BMI = 33 kg/m²) and had uncontrolled diabetes as evidenced by baseline Hb A1c levels. Our results show that metformin and troglitazone had very similar efficacy for those patients in terms of reductions in Hb A1c, FPG, and C-peptide levels when used in combination with a sulfonylurea. Furthermore, safety and tolerability in terms of symptomatic adverse events, hypoglycemia, changes in serum creatinine, and changes in liver enzymes were good for both combinations during the 14 weeks of this clinical trial. Previous studies^9,10,14,16 have shown these combinations effective, but those studies did not directly compare them in a controlled fashion. Troglitazone and metformin are both approved by the FDA for combination therapy with a sulfonylurea. Although metformin is also FDA approved as a monotherapy, it is common practice to start with a sulfonylurea when type 2 diabetes is diagnosed.

The United Kingdom Prospective Diabetes Study (UKPDS) showed metformin to be beneficial as a monotherapy for obese patients with type 2 diabetes, but raised concern about combination sulfonylurea/metformin therapy.¹⁹ In the UKPDS, metformin was shown to reduce overall mortality in obese patients with serum creatinine levels less than 1.5 mg/dL, but increased mortality was associated with the addition of metformin to sulfonylurea therapy. The baseline differences between patients treated with metformin alone and those for whom metformin was added to a sulfonyurea (plus the small number of deaths overall) led the UKPDS investigators to question the validity of this observation. Special precautions are recommended when prescribing metformin,²⁰ mainly because of potential problems with severe lactic acidosis observed in the past with another biguanide (phenformin). Accordingly, metformin is contraindicated in congestive heart failure, in the presence of renal or hepatic insufficiency, during periods of hypoxemia or dehydration, and for heavy alcohol drinkers. It should also be withheld before, during, and after the administration of iodinated intravenous contrast. Tolerability of metformin can be problematic during the dose-titration phase for some patients because of gastrointestinal side effects, but adherence to treatment can be optimized by educating patients that this is usually a transient side effect.

Troglitazone has been associated with elevated hepatic enzymes in approximately 2% of patients in clinical trials; very rare severe or fatal hepatic dysfunction has also been reported.²¹ Accordingly, the manufacturer recommends periodic assay of serum alanine aminotransferase levels (baseline and monthly for the first year of therapy, then quarterly).²² Similar laboratory monitoring is not required for metformin.

Simplicity of a prescribed drug regimen is a consideration for patients, especially with regard to compliance. Metformin requires at least twice-daily administration; troglitazone can be taken once per day. Comparative drug costs are also important to consider. As of 1999, the average wholesale cost in the United States for a 1-month supply of the doses in our study is approximately $142 for troglitazone and $75 for metformin.²³ Newer thiazolidinediones, such as rosiglitazone and pioglitazone, will add competition and continued scrutiny to the efficacy, safety, and costs of this drug class.

Conclusions

Metformin and troglitazone improved glycemic profiles and C-peptide levels with equal success with no significant differences in safety or tolerability. Although our study had sufficient power to detect a clinically meaningful difference in Hb A1c reduction, it was based on a small number of patients and a short study duration. The true test of the effectiveness of these combination therapies must come from large clinical trials of sufficient duration that assess their effects on diabetes-related morbidity and mortality.