Insulin Sensitizers for Improving the Endocrine and Metabolic Profile in Overweight Women With PCOS

Chuan Xing; Chunzhu Li; Bing He

Disclosures

J Clin Endocrinol Metab. 2020;105(9) 

In This Article

Results

Literature Identification

The initial search strategy retrieved a total of 5052 studies. After reading the titles, abstracts, and full texts, we selected 14 RCTs, which included a total of 619 women, for inclusion in the analysis. The remaining studies were excluded: 1400 were duplicates, 417 were reviews, 334 were non-RCTs or animal experiments, 2232 failed to meet the inclusion criteria, 553 included unrelated outcomes, 32 combined treatments with other interventions, 2 had no full text available, 5 lacked relevant data, 13 included participants with BMI <25 kg/m2, 23 included participants with age <18 years, and 27 combined with other diseases. The literature screening process and results are shown in Figure 1.

Figure 1.

Flow diagram of studies identified in the systematic review. Abbreviations: BMI, body mass index (kg/m2); RCT, randomized controlled trial.

Characteristics of Included Studies

Table 1 presents the characteristics of included studies. Trials were performed in European,[16–21,26] American,[15,24] and Asian[22,23,25,27,28] countries and were published from 2005 to 2019. Participants in these trials were recruited from outpatient clinics, hospitals, or medical centers and were diagnosed with PCOS according to either the National Institutes of Health or Rotterdam criteria. Participants aged 18 to 49 years were included in all 14 studies. In all, 5 different interventions were included: metformin, GLP-1 receptor agonists, TZDs, metformin + GLP-1 receptor agonists, and metformin + TZDs (shown in Figure 2). Twelve studies evaluated the use of metformin alone, participants received a dosage of metformin ranging from 1.5 g/d to 3 g/d for 12 to 24 weeks. Six studies evaluated GLP-1 receptor agonists alone: 4 studies used liraglutide 1.2 mg/d for 12 weeks, 1 study used liraglutide 3.0 mg/d for 12 weeks, and 1 study used exenatide 20 μg/d for 24 weeks. Four studies evaluated GLP-1 receptor agonists in combination with metformin: 3 used liraglutide 1.2 mg/d in combination with metformin 2.0 g/d for 12 weeks and 1 used exenatide 20 μg/d in combination with metformin 2.0 g/d for 24 weeks. Six studies evaluated TZDs alone: 2 used rosiglitazone 4 mg/d for 24 weeks, 1 used rosiglitazone 4 mg/d for 12 weeks, 1 used pioglitazone 30 mg/d for 24 weeks, 1 used pioglitazone 30 mg/d for 12 weeks, and 1 used pioglitazone 90 mg/d for 12 weeks. Three studies evaluated TZDs in combination with metformin: 1 used pioglitazone 90 mg/d in combination with metformin 1.5 g/d for 12 weeks, 1 used pioglitazone 30 mg/d in combination with metformin 1.0 g/d for 12 weeks, and 1 used pioglitazone 15 mg/d in combination with metformin 3.0 g/d for 24 weeks. For studies included in our meta-analysis, the dropout rate was 7.64% (21/275) for metformin, 11.76% (12/102) for GLP-1 receptor agonists, 8.80% (11/125) for TZDs, 12.86% (9/70) for metformin + GLP-1 receptor agonists, and 2.86% (3/105) for metformin + TZDs.

Figure 2.

Network of eligible comparisons for efficacy. The size of the circles is proportional to sample size, and the width of the lines is proportional to the number of trials. Abbreviations: GLP-1, glucagon like peptide-1 receptor agonist; MET, metformin; TZD, thiazolidinedione.

Quality Assessment of the Included Studies

Quality assessment was evaluated in Figure 3, showing that the lack of blinding was the main cause of potential bias. In trials containing GLP-1 receptor agonists, blinding was not possible because of the different routes of administration of GLP-1 receptor agonists and metformin. In addition, incomplete outcome data was the second cause of potential bias because the number and cause of missing outcome indicators were not consistent between groups. All funnel plots showed minor asymmetry or no publication bias (shown in Figures S1–S10).[55]

Figure 3.

Risk of bias assessment in the RCTs.

Main Outcomes

Improvement of Menstrual Frequency. Data on improving menstrual frequency were reported, with 5 studies showing changes of menstrual cycle frequency (cycles per month) and 5 studies showing the number of menstrual recovery (shown in Table 2 and Figures S11–S12 as menstrual frequency(a) and menstrual frequency(b), respectively).[55] TMA for menstrual frequency(a) revealed that no significant difference among GLP-1 receptor agonists, TZDs, and metformin, while metformin + GLP-1 receptor agonists (WMD 0.02; 95% CI, 0.02–0.02; P = 0.81, I2 = 0%) was more effective than GLP-1 receptor agonists alone. TMA for Menstrual frequency(b) revealed that metformin + TZDs (WMD 4.40; 95% CI, 1.95–9.96; P = 0.80, I2 = 0%) was more effective than metformin alone. Similarly, NMA for Menstrual frequency(b) also revealed that metformin + TZDs (WMD 3.68; 95% CrI, 1.65–8.20) was more effective than metformin.

Improvement of Hyperandrogenemia. For improving hyperandrogenemia, outcomes included TT, FT, SHBG, and AND (shown in Table 3 and Figures S13–S16).[55]

Data on decreasing TT were reported in 11 studies. TMA revealed that no significant difference among GLP-1 receptor agonists, TZDs, and metformin while both metformin + GLP-1 receptor agonists (WMD −0.51; 95% CI, −0.63 to −0.39; P = 0.48, I2 = 0%) and metformin + TZDs (WMD −0.37; 95% CI, −0.74 to 0.00; P < 0.00001, I2 = 96%) were more effective than metformin alone. TMA also showed that metformin + GLP-1 receptor agonists (WMD −0.27; 95% CI, −0.48 to −0.06; P = 0.22, I2 = 32%) were more effective than GLP-1 receptor agonists alone. However, NMA showed no significant difference between groups.

As for decreasing FT, TMA revealed that no significant difference on GLP-1 receptor agonists, TZDs, and metformin + GLP-1 receptor agonists when compared with metformin alone while metformin + GLP-1 receptor agonists (WMD −1.84; 95% CI, −2.95 to −0.73; P = 0.48, I2 = 0%) was more effective than GLP-1 receptor agonists alone. The NMA also revealed that metformin + GLP-1 receptor agonists (WMD −1.77; 95% CrI, −3.25 to −0.29) was more effective than GLP-1 receptor agonists.

For increasing SHBG, TMA revealed no significant difference between GLP-1 receptor agonists and metformin, while both metformin + GLP-1 receptor agonists (WMD 10.90; 95% CI, 7.66–14.14, P&I2 not applicable NA) and metformin + TZDs (WMD 4.30; 95% CI, 1.70–6.90, P&I2 NA) were more effective than metformin alone. TMA also showed that metformin + GLP-1 receptor agonists (WMD 7.44; 95% CI, 4.82–10.07; P = 0.38, I2 = 0%) were more effective than GLP-1 receptor agonists alone. Similarly, the NMA revealed that both metformin + GLP-1 receptor agonists (WMD 9.22; 95% CrI, 5.46–12.98) and metformin + TZDs (WMD 4.30; 95% CrI, 0.78–7.82) were more effective than metformin alone and metformin + GLP-1 receptor agonists (WMD 7.80; 95% CrI, 4.75–10.85) was more effective than GLP-1 receptor agonists alone.

For data on decreasing AND, TMA revealed that there was no significant difference among GLP-1 receptor agonists, TZDs, and metformin while metformin + GLP-1 receptor agonists was more effective than metformin (WMD −3.00; 95% CI, −4.99 to −1.01, P&I2 NA) or GLP-1 receptor agonists alone (WMD −2.74; 95% CI, −3.99 to −1.48; P = 0.52, I2 = 0%). NMA also revealed that metformin + GLP-1 receptor agonists was more effective than metformin (WMD −2.53; 95% CrI, −3.96 to −1.09) or GLP-1 receptor agonists alone (WMD −2.70; 95% CrI, −3.91 to −1.50).

Improvement of Glucose Metabolism. For improving glucose metabolism, outcomes included FG and FINS (shown in Table 4 and Figures S17–S18).[55]

Data on decreasing FG were reported in 11 studies. TMA revealed that there was no significant difference between GLP-1 receptor agonists and metformin, while TZDs (WMD 0.07; 95% CI, 0.02–0.11; P = 0.31, I2 = 16%) were less effective than metformin. Both TMA (WMD −0.40; 95% CI, −0.71 to −0.10; P = 0.36, I2 = 0%) and NMA (WMD −0.41; 95% CrI, −0.73 to −0.08) showed that metformin + GLP-1 receptor agonists was more effective than GLP-1 receptor agonists alone.

For data on decreasing FINS, both TMA and NMA revealed no significant difference between groups.

Improvement of Obesity. For improving obesity, outcomes included BMI and WC (shown in Table 5 and Figures S19–S20).[55]

Data on decreasing BMI were reported in 13 studies. NMA revealed no significant difference among GLP-1 receptor agonists, metformin + GLP-1 receptor agonists, and metformin + TZDs, when compared with metformin alone. Both TMA (WMD 1.52; 95% CI, 0.28 to 2.75; P = 0.006, I2 = 69%) and NMA (WMD 1.69; 95% CrI, 0.72–2.66) revealed that TZDs were less effective than metformin.

For data on decreasing WC, both TMA and NMA revealed no significant difference among GLP-1 receptor agonists, TZDs, and metformin, while TMA showed that metformin + GLP-1 receptor agonists (WMD −6.31; 95% CI, −8.27 to −4.35; P = 0.50, I2 = 0%) was more effective than metformin alone.

SUCRA. The SUCRA curve of outcomes illustrated that metformin + GLP-1 receptor agonists was the best intervention for improving menstrual frequency(a) (SUCRA 75.5), FT (SUCRA 90.3), SHBG (SUCRA 99.1), AND (SUCRA 100), FG (SUCRA 85.4), BMI (SUCRA 86.4), and WC (SUCRA 100); metformin + TZDs was the best intervention in improving menstrual frequency(b) (SUCRA 96.1) and TT (SUCRA 85.9), while TZDs were the best intervention for improving FINS (SUCRA 76.8) (shown in Table 6).

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