Introduction
Obesity, which is defined as a body mass index (BMI) ⩾30 kg/m
2, has been a challenging health problem worldwide. It has become a major contributor to the global disease burden.
1–4 Obesity is a chronic disease and a risk factor for other comorbidities. The recent study of adult BMI trends in 200 countries
5 shows that the prevalence of obesity increased from 3.2% to 10.8% in men and 6.4% to 14.9% in women from 1957 to 2014. The global prevalence of morbid obesity is 0.64% and 1.6% in men and women, respectively. Obesity is also associated with nearly 200 complications, including diabetes, cardiovascular disease, high blood pressure, and stroke, which severely threaten human health.
2
In May 2016, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) announced the clinical practice guidelines for comprehensive medical care of patients with obesity. According to the guidelines for the management of overweight and obese adults, most individuals need to measure body weight frequently and avoid weight gain by adjusting their diet and physical activities.
6 However, long-term cohort studies show that people with obesity, but without any metabolic disorder, remain at risk for various obesity-related complications.
7 Obesity treatment with lifestyle modifications often fails.
8 Therefore, medications also play an important role in obesity management and can help improve health for people who have failed to lose weight by diet and exercise.
9
Five treatment methods have been approved by the US Food and Drug Administration (FDA) for the long-term treatment of obesity. These drugs include orlistat, phentermine + topiramate, lorcaserin, naltrexone + bupropion, and liraglutide. In addition to weight reduction
via orlistat by inhibiting fat absorption, the other drugs all act on the central nervous system pathways, reducing appetite or increasing satisfaction to reduce weight. The side effects of weight loss drug mainly include dizziness, nausea, constipation, insomnia, and other symptoms.
1,9 Phentermine can be used as monotherapy in short term or as fixed-dose combinations with topiramate in long treatment. Naltrexone for weight loss is only used in fixed-dose combinations with bupropion. Orlistat is a long-acting and powerful specific gastrointestinal lipase inhibitor. This drug inhibits the enzymes responsible for the digestion of fat in the human gastrointestinal tract and prevents the absorption of fat in the digestive tract, thereby reducing calorie intake and weight control.
9,10
Many studies support that metformin can promote weight loss in overweight or obesity patients.
11–13 A systematic review that included 946 10–16-year-old obese adolescents demonstrated a significant reduction in BMI [−1.38; 95% confidence interval (CI), −1.93 to −0.82] after metformin treatment.
11 Broad evidence based on clinical trials supports the efficacy and safety profiles of metformin in diabetes and weight gain prevention.
14 In addition, the side effects of metformin are relatively mild. The most common side effect of metformin is gastrointestinal reaction, which decreases with increasing medication period and careful dose escalation.
15 Furthermore, metformin has many advantages, such as improvement of insulin resistance (IR) in people with obesity and alleviation of hyperandrogenism in women with polycystic ovary syndrome (PCOS).
16,17 Therefore, as a possible weight loss-promoting drug, conducting an in-depth study on the potential weight loss benefits of metformin is reasonable.
However, metformin has not been officially approved as a weight-reduction medicine.
4 Different reports indicate inconsistencies in the weight loss effects of metformin. Moreover, no systematic review has been conducted regarding the weight reduction effect of metformin in different populations. The present meta-analysis aimed to further investigate the effectiveness of metformin on weight loss, explore the feasibility and effectiveness of metformin as a potential weight loss medicine, and possibly provide a basis for the establishment of clinical obesity management and obesity management guidelines.
Methods
Search strategy
Studies were identified by searching PUBMED, the Cochrane library, and the Chinese National Knowledge Infrastructure for eligible studies published between January 1, 1998 and March 31, 2019. References cited in the primary articles were also manually searched. Meta-analysis was performed following the PICO format: treatment of obese patients (P) with metformin (I) compared with the placebo/lifestyle/monotherapy (C) outcomes related to weight loss or changes in BMI (O). The basic terms for literature search were as follows: “metformin” and “weight loss” or “weight reduction” and “obesity” and “body mass index” or “BMI”.
Study selection
Randomized controlled trial (RCT) or high-quality case-control, which evaluated the efficacy and safety of metformin was eligible. All titles and abstracts were filtered to exclude unqualified research. The full text of the remaining studies was read for further identification. Metformin monotherapy was selected to eliminate the result interference of combined medication. The selection criteria for the meta-analysis were as follows: (i) intervention with metformin or comparison of metformin with a control, (ii) published RCT, cohort study, and case-control study, (iii) reported changes in BMI before and after treatments, and (iv) metformin treatment at least 1 month and mean dosage report. The exclusion criteria for the meta-analysis were as follows: (a) incomplete research design and extraction failure of effective data, (b) other diseases of patients that affect body weight, and (c) the use of medicine reducing body weight before or during metformin intervention.
Data extraction
The extraction and collation of the data were independently conducted by XR and RP for quality. The risk of bias in these studies was assessed by TG and DS. Data were extracted as follows: source of study (first author and publication year), population characteristics (mean age, baseline BMI), methodology design (study design and blind method), and metformin intervention (dose, intervention length); changes of BMI were calculated as differences between the final and initial BMI values (with negative values indicating a decrease).
Statistical analysis
The BMI data were presented in the form of mean ± standard deviation (SD) for statistical analysis. The BMI data were presented in the form of standard error (SE) in the four studies.
18–21 The values were converted into SD based on the following formula: SE = SD/√
N. The baseline BMI was chosen as self-control to compare the changes in BMI before and after treatment. Data from the 21 studies were combined using the random-effects model of STATA 12.0. The results were presented by the weighted mean difference (WMD) for continuous variables with a CI 95%.
I square (
I2) was used to assess heterogeneity across studies, with
I2 values > 50% representing high heterogeneity. Influence analysis was conducted to determine the effect of individual study on the aggregate result. A funnel plot was employed to assess publication bias.
According to guideline for the management of overweight and obesity in adults, obesity is divided into grades I, II, and III with BMI of 30–34.9, 35–39.9, and >40 kg/m2, respectively. Overweight is defined as 25–29.9 kg/m2. Moreover, the dose of metformin was stratified by extracting the data contained in all studies. Low and high doses were defined as <1500 and >1500 mg/d, respectively.
Quality assessment
The quality of each study was assessed using the Cochrane “Risk of bias” tool. The considered factors included seven parts: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcomes, selective reporting, and other biases. DS and TG independently assessed the quality of the included studies.
Discussion
The mechanism of metformin’s effect on body weight may be multifactorial. Long-term follow-up from the Diabetes Prevention Program demonstrates that the primary weight loss mechanism of metformin is improving IR and decreasing food intake.
40 Recent studies highlighted that gastrointestinal physiology and circadian rhythm changes by metformin also regulate fat oxidation and storage in the liver, skeletal muscles, and adipose tissues.
41,42
A recent systematic review found that metformin treatment is associated with BMI reduction (MD −0.86; 95% CI, −1.44 to −0.29) in children and adolescents in comparison with placebo.
12 This finding is a high-quality report of weight management and intervention in children and adolescents; the report indicates that the weight loss effect is different between subgroups (age and male percentage). However, the suitability of the situation in children and adolescents for other populations remains unclear. In addition, a recent study found that orlistat and metformin exhibited similar effects on BMI (WMD −0.65%; 95% CI, −2.03 to 0.73) in women with PCOS.
13 Most results of BMI changes in systematic reviews for metformin based on different populations are similar but different in magnitude.
In the present meta-analysis, baseline BMI was chosen as a self-control to compare the changes in BMI of different populations before and after metformin treatment. Self-control is a common study method that explains the experimental results through the changes of the same population before and after intervention. When studying the effect of metformin on BMI, choosing baseline BMI as self-control can minimize the influence on the result from different control groups. Even if the control group was a lifestyle intervention, the standard of exercise and patient dependence vary significantly.
Overall, a reduction in baseline BMI with metformin therapy for 6 months was calculated at approximately 1 unit in all included populations. Simple obesity patients had the most evident decrease in BMI (WMD −1.31; 95% CI, −2.07 to −0.54,
I2 = 0%). In addition, metformin can relieve diabetes symptoms and reduce BMI (WMD −0.98; 95% CI, −1.25 to −0.72) for T2DM obesity. The present meta-analysis indicated that metformin treatment was beneficial for obesity patients with BMI >35 kg/m
2. This finding was also consistent with the results of studies in other single populations.
4,43–46 A dose comparison considering the weight loss effect of metformin in obese women with PCOS demonstrated that substantial weight reduction is potentially achievable with high doses of metformin.
47 This result is consistent with the current subgroup analysis. This analysis indicates that high-dose metformin treatment was more effective in reducing weight than low dose.
The advantage of the current study lies in its extensive population, comprehensive subgroup analysis, and intuitive results. In general, this study was the first meta-analysis of metformin effectiveness in weight loss that included several populations for comprehensive analysis. Metformin significantly affected simple obesity, and patients with severe obesity showed a significant reduction in BMI.
The present study has several limitations, including the number of studies and incomplete population inclusion. Some unpublished negative results may not be included. The data were analyzed by self-control, although the influence of different degrees of lifestyle intervention in various studies is excluded in theory, there might be some defects. The source data were not complete when using the three-dimensional histogram to demonstrate the effect of metformin on BMI. Therefore, some biases in the meta-analysis may exist, and more in-depth and detailed RCTs are necessary.