Results
Of the 31 trials included for the meta-analysis, we judged that 7 were of good quality, 6 were of fair quality, and 18 were of poor quality.2,5-10,18-41 (See TABLE W1.)
Not enough data to compare TZD vs metformin
As the TZDs had few trials for each drug (5 troglitazone, 2 rosiglitazone, 1 pioglitazone) and not enough of the TZD trials reported data on most parameters, it became unrealistic to perform a statistical comparison of the treatment effect between metformin and the TZDs. Moreover, there were not enough data from TZD trials to analyze the effect of TZDs on any studied parameter. Thus, only data from metformin trials were used in the meta-analysis.
Metformin linked to changes in 3 outcomes
Of the outcomes we evaluated, there were statistically significant changes in three: ovulation rate, LH/FSH ratio, and fasting insulin. (For complete details of our findings, see TABLE.)
After analyzing the ovulation rate in 9 trials, we found a change of –0.18% (95% CI, –0.35 to –0.01; P=.03) from the control group. Our analysis of the LH/FSH ratio in 7 trials revealed a change in value of –0.21 (–0.30 to –0.13; P<.001). We evaluated the fasting insulin levels in 14 trials and found an increase of 30.4 pmol/L (13.9 to 46.8; P<.001).
Insufficient trials (n ≤5) reported on total cholesterol, triglycerides, HDL, LDL, systolic blood pressure, diastolic blood pressure, C-peptide, C-reactive protein, leptin, and Hb A1c. Thus, we did not conduct a meta-analysis for these outcomes.
We intentionally used type I error of 5% for individual tests, not for overall test. If we had adopted multiple testing adjustments, we would have had more conservative results with much wider CIs, which makes it harder to reject the null hypothesis. Specifically, only 2 comparisons (LH/FSH and fasting insulin) would still be significant after multiple testing adjustments, while all marginally significant results would no longer be significant. A second reason to use type I error of 5% for individual (not overall) test is that endpoints are expected to be correlated, since most data were from the same trials.42,43
We did not find any major change in results in the sensitivity analyses we performed. It is worth mentioning, though, that there was significant heterogeneity and variability in the treatment effects from virtually all comparisons we made, though most comparisons revealed no publication bias. When heterogeneity is detected, combining the effects is not always advisable; and when effects are combined, they should be viewed with extreme caution.44-46
At a minimum, we failed to find any homogeneous or consistent treatment effects. Our sensitivity analysis offers additional protection against publication bias or file drawer problems.47
TABLE
Meta-analysis results by outcome
| OUTCOME | NUMBER OF TRIALS | POOLED ESTIMATE OF TREATMENT EFFECT (95% CI)* | P VALUES | SENSITIVITY ANALYSIS** | ||
|---|---|---|---|---|---|---|
| TREATMENT EFFECT* | HETEROGENEITY† | PUBLICATION BIAS‡ | ||||
| Ovulation rate (%) | 9 | –0.18 (–0.35 to –0.01) | .03 | .001 | .92 | –0.18/0.03 |
| Pregnancy rate (%) | 8 | –0.09 (–0.18 to 0.01) | .08 | <.001 | .90 | Unchanged |
| BMI (kg/m2) | 16 | 0.70 (–0.08 to 1.48) | .08 | .05 | .01 | –0.001/1 |
| Waist-to-hip ratio | 13 | –0.02 (–0.05 to 0.02) | .38 | <.001 | .20 | –0.03/0.06 |
| Hirsutism (F-G score) | 7 | –0.26 (–1.64 to 1.12) | .71 | .09 | .76 | Unchanged |
| LH/FSH | 7 | –0.21 (–0.30 to –0.13) | <.001 | .72 | 1 | –0.22/<0.001 |
| Fasting insulin (pmol/L) | 14 | 30.4 (13.9 to 46.8) | <.001 | <.001 | .51 | Unchanged |
| FBG (mmol/L) | 13 | 0.21 (–0.10 to 0.52) | .19 | <.001 | .43 | Unchanged |
| Total testosterone (nmol/L) | 13 | 0.01 (–0.38 to 0.40) | .95 | <.001 | 1 | Unchanged |
| Free testosterone (pg/mL) | 8 | 1.40 (–0.04 to 2.85) | .06 | <.001 | .71 | Unchanged |
| Androstenedione (nmol/L) | 11 | 0.09 (–0.25 to 0.42) | .60 | <.001 | .53 | Unchanged |
| DHEAS (μmol/L) | 14 | –0.48 (–1.20 to 0.24) | .19 | .004 | .58 | –0.91/0.03 |
| *Using Dersimonian and Laird’s random effects model, uncorrected for multiple testing. | ||||||
| †Using Cochran’s Q statistics. | ||||||
| ‡Using Begg and Mazumdar test. | ||||||
| **Pooled estimate/P value, using the trim and fill method. | ||||||
| We did not conduct meta-analysis for endpoints with number of studies ≤5: total cholesterol, triglycerides, HDL, LDL, C-peptide, Hb A1c, leptin, C-reactive protein, systolic blood pressure, and diastolic blood pressure. | ||||||
| LH/FSH, luteinizing hormone to follicle-stimulating hormone ratio; FBG, fasting blood glucose; DHEAS, dehydroepiandrosterone sulfate. | ||||||
Findings don’t support a common practice
Much has been reported in the literature, as well as by the media, regarding the large role that metformin and the TZDs can play in helping to alleviate the alterations caused by the polycystic ovarian syndrome. However, this systematic review of the literature, focusing on randomized controlled trials, failed to find evidence supporting the claims made in the literature, by the media, or offered anecdotally.
Based on our analysis, there is insufficient evidence to assess a difference in effect sizes between the TZDs and metformin. There is also insufficient evidence to assess if either the TZDs or metformin have an effect on lipids, blood pressure, C-peptide, C-reactive protein, leptin, or Hb A1c.
With regard to the analyzed parameters, there were minimal decreases of statistical significance in ovulation rates and LH/FSH, and minimal increase of statistical significance in fasting insulin with metformin. (We cannot account for the paradoxical and unexpected finding of an increase of fasting insulin with metformin, especially since metformin works as an insulin sensitizer.) There was, however, no clinically significant change with metformin in any of the parameters we studied (ovulation rate, pregnancy rate, body mass index, waist-to-hip ratio, hirsutism score, LH/FSH, total cholesterol, fasting insulin, fasting blood glucose, total testosterone, free testosterone, androstenedione, and DHEAS).