Effect of Pharmacological Interventions on Lipid Profiles and C-reactive Protein in Polycystic Ovary Syndrome

A Systematic Review and Meta-Analysis

Mohammed A. Abdalla; Najeeb Shah; Harshal Deshmukh; Amirhossein Sahebkar; Linda Östlundh; Rami H. Al-Rifai; Stephen L. Atkin; Thozhukat Sathyapalan

Disclosures

Clin Endocrinol. 2022;96(4):443-459. 

In This Article

Results

Characteristics of the Included Studies

Overall, 6326 records were found in the electronic database of which 3186 records were initially scanned for eligibility criteria based on titles and abstracts after duplicates were removed. In total, 814 full-text articles were acquired to examine their eligibility, of which 29 RCTs met the eligibility criteria and were therefore included in the meta-analysis (Figure 1).

The 29 RCTs were published until 2020, of which 15 RCTs[19,21,22,26,30,33,39–43,45–47] diagnosed PCOS based on the Rotterdam criteria-2003,[51] 5 RCTs[27–29,32,34] used the National Institute of Health 1990 (NIH, NICHD) criteria;[52] whereas no diagnostic criteria were given for the remaining RCTs (Table 2).

Interventions and Comparisons Details

Nine RCTs (31%) assessed the effect of metformin compared with placebo.[19,25,26,31,32,36,39,44,45] Five RCTs (17%) evaluated the effect of metformin compared with pioglitazone.[37,38,40,41,47] Two RCTs (6.8%) examined the effect of pioglitazone compared with placebo.[21,23] Two RCTs (6.8%) assessed the effect of rosiglitazone compared with metformin.[27,33] Two RCTs (6.8%) evaluated the effect of liraglutide compared with liraglutide added to metformin.[28,29] Two RCTs (6.8%) examined the effect of exenatide compared with metformin.[30,46] Two RCTs (6.8%) assessed saxagliptin compared with metformin.[22,43] Two RCTs (6.8%) evaluated metformin compared with simvastatin.[34,35] Three RCTs (10.3%) evaluated atorvastatin versus placebo.[20,24,42]

Characteristics of the Outcomes Measured

All RCTs evaluated participants at baseline and postintervention. Eleven RCTs (37.9%) reported changes in CRP.[20,24,26,27,30,33,39,42,46] Twenty-six RCTs (89.6%) reported changes in total cholesterol.[19–33,36–38,40–47] Twenty-seven RCTs (93.1%) reported changes in triglycerides.[19–26,28–32,34–37,40–47] Twenty-six RCTs (89.6%) reported changes in HDL.[19,20,22,24–31,33–36,38,40–47] Twenty-five RCTs (86.2%) reported changes in LDL.[19,20,22,24–33,36–38,40–44,46,47] Table 2 shows the descriptive characteristics of the 29 RCTs included in this review.

Assessment of Risk of Bias in the Included Studies

The RoB item for each included RCT and the overall RoB are presented in Figures 1 and 2 in the supplementary material. Briefly, fifteen RCTs (51.72%) were judged to have a high risk of performance bias due to lack of blinding the participants.[19,22,26,28–30,33,37,38,41,43,46,47] One RCT (3.4%) was judged to have a high risk of selective reporting bias.[35] Low risk of bias was judged for the majority of domains among the included RCTs, and an unclear RoB was also judged due to insufficient reporting.

We did not assess for publication bias for the comparisons as there were fewer than 10 RCTs across each outcome.

Effects of Interventions on the Lipid Profiles Outcomes and CRP

The outcomes of the meta-analyses on the impact of pharmaceutical interventions compared with placebo are presented in Figures 2–6 and the comparison with other medications are shown in Table 3.

Figure 2.

Forest plot of comparisons on total cholesterol. (A) Atorvastatin versus placebo, (B) pioglitazone versus placebo, and (C) metformin versus placebo

Figure 3.

Forest plot of comparisons on triglycerides. (A) Atorvastatin versus placebo, (B) pioglitazone versus placebo, and (C) metformin versus placebo

Figure 4.

Forest plot of comparisons on high-density lipoprotein cholesterol. (A) Atorvastatin versus placebo and (B) metformin versus placebo

Figure 5.

Forest plot of comparisons on low-density lipoprotein cholesterol. (A) Metformin versus placebo and (B) atorvastatin versus placebo

Figure 6.

Forest plot of comparisons on C-reactive protein. (A) Atorvastatin versus placebo and (B) metformin versus placebo

Lipid Profiles

TC. Atorvastatin Versus Placebo: In three RCTs, atorvastatin 20 mg QD significantly reduced the mean total cholesterol (SMD: −3.48; 95% CI: −5.74, −1.21, I 2 = 90%) (Figure 2A) (very low-grade evidence).

Saxagliptin Versus Metformin: In two RCTs, saxagliptin 5 mg QD was compared with metformin 2000 mg QD significantly reduced the mean total cholesterol by 0.15 mmol/L (95% CI: −0.23, −0.08, I 2 = 0%) (Table 3) (very low-grade evidence).

The meta-analysis showed no effect on the mean total cholesterol when pioglitazone and metformin were compared with placebo (Figure 2B,C). Similarly, no effect on mean total cholesterol was found when metformin alone or when metformin was added to liraglutide compared with pioglitazone, rosiglitazone, liraglutide and exenatide (Table 3).

TGs. Atorvastatin Versus Placebo: In two RCTs, atorvastatin 20 mg QD significantly reduced the mean TGs by 0.59 mmol/L (95% CI: −0.72, −0.46, I 2 = 0%) (Figure 3A) (very low-grade evidence).

Pioglitazone Versus Placebo: In two RCTs, pioglitazone 30 mg QD significantly reduced the mean TGs by 0.21 mmol/L (95% CI: −0.39, −0.03, I 2 = 0%) when was compared with placebo (Figure 3B) (very low-grade evidence).

The meta-analysis showed no effect on the mean TGs with metformin alone (Figure 3C) or when metformin was added to liraglutide compared with pioglitazone, liraglutide, exenatide, saxagliptin and simvastatin (Table 3).

HDL-C. Saxagliptin Versus Metformin: In two RCTs, saxagliptin 5 mg QD compared with metformin 2000 mg QD significantly reduced the mean HDL-C by 0.11 mmol/L (95% CI: −0.15, −0.06, I 2 = 7%) (Table 3) (very low-grade evidence).

The meta-analysis did not show any effect on the mean HDL-C when atorvastatin and metformin were compared with placebo (Figure 4A,B). Similarly, no effect was observed with metformin alone or when metformin was added to liraglutide compared with pioglitazone, rosiglitazone, liraglutide, exenatide and simvastatin (Table 3).

LDL-C. Metformin Versus Placebo: In three RCTs, metformin 850 mg BID had no effect on the mean LDL-C (SMD: −0.65; 95% CI: −1.53, 0.22) and in four RCTs metformin 1500 mg QD was also associated with no effect in the mean LDL-C (SMD: −0.23; 95% CI: −0.71, 0.24). Overall, regardless of the administered doses metformin was associated with a significant reduction in the mean LDL-C when compared with placebo (SMD: −0.41; 95% CI: −0.85, 0.03, I 2 = 59%) (Figure 5A) (low grade evidence).

Atorvastatin Versus Placebo: In two RCTs, atorvastatin 20 mg QD significantly reduced the mean LDL-C by 0.91 mmol/L (95% CI: −1.04 to 0.79, I 2 = 0%) when compared with placebo (Figure 5B) (very low-grade evidence).

Rosiglitazone Versus Metformin: In one RCT, rosiglitazone 4 mg QD significantly reduced the mean LDL-C by 0.22 mmol/L (95% CI: −0.36, −0.08) when was compared with metformin 1000 mg QD. In one RCT, rosiglitazone 4 mg QD also significantly reduced the mean LDL-C by 0.48 mmol/L (95% CI: −1.19, 0.23) when was compared with metformin 850 mg BID. Overall, rosiglitazone 4 mg QD significantly reduced the mean LDL-C by 0.23 mmol/L (95% CI: −0.37 to 0.09, I 2 = 0%) when compared with various doses of metformin (Table 3) (very low-grade evidence).

The meta-analysis showed no effect on the mean LDL-C when metformin alone or when metformin was added to liraglutide compared with pioglitazone, liraglutide, exenatide and saxagliptin (Table 3).

CRP. Atorvastatin Versus Placebo: In two RCTs, atorvastatin 20 mg QD was associated with a significant reduction in the mean CRP by 1.51 mg/L (95% CI: −3.26 to 0.24; 65 participants, I 2 = 75%, p = 0.09) (Figure 6A) (very low-grade evidence).

However, the meta-analysis showed no effect on the mean CRP when metformin was compared with placebo (Figure 6B), and no effect with either rosiglitazone or exenatide compared with placebo (Table 3).

Sensitivity Analysis

The effect of each individual RCT on heterogeneity and the strength of the result was reviewed by conducting a sensitivity analysis. Thus, small sample sized RCTs and the one with an overall high RoB were eliminated from the meta-analysis while inspecting their impacts on the collective results. As a result, no substantial effect was found and thus, no RCT was removed from the meta-analysis.

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