The Influence of Metformin on Weight
Introduction
Type 2 diabetes mellitus has reached epidemic proportions worldwide and is closely associated with the rising prevalence of obesity. Approximately 80–90% of people with type 2 diabetes are overweight or obese. Because of this close relationship, the term diabesity—derived from diabetes and obesity—has been used in the medical literature since the 1970s.
Obesity contributes to insulin resistance and worsens hyperglycemia in patients with diabetes. Therefore, diabetes management should always include lifestyle interventions aimed at weight reduction, while glucose-lowering medications should ideally promote weight loss or, at minimum, remain weight neutral.
Weight reduction has been shown to improve insulin sensitivity and lower blood pressure, while also reducing endothelial dysfunction, inflammatory and procoagulant markers, and serum cholesterol and triglyceride levels. [1]
Not all antidiabetic medications have the same effects on body weight. Sulfonylureas (SUs), thiazolidinediones (TZDs), and meglitinides are associated with weight gain, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors are generally weight neutral. In contrast, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors promote weight loss. [1,2]
The effect of metformin on body weight remains less clearly defined. International diabetes guidelines have differed in their interpretation of the available evidence. The 2012 joint statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) described metformin as weight neutral. [2] In contrast, the 2013 recommendations of the American Association of Clinical Endocrinologists (AACE) recognized metformin as having weight-reducing properties. [3]
This article reviews the mechanisms through which metformin may influence body weight, summarizes evidence from clinical studies, and discusses practical aspects of metformin therapy.
Mechanism of Action of Metformin
Metformin is one of the oldest and most widely prescribed glucose-lowering medications, yet its molecular mechanisms have not been completely elucidated.
Several mechanisms have been proposed. Metformin is believed to inhibit mitochondrial respiratory chain complex I, activate adenosine monophosphate-activated protein kinase (AMPK), suppress glucagon-induced cyclic adenosine monophosphate (cAMP) production, and inhibit activation of protein kinase A (PKA). [4]
By improving insulin sensitivity, metformin reduces the postprandial hyperglycemia commonly seen in patients with diabetes, which results from delayed insulin secretion and a delayed insulin peak. [5] Improved postprandial glycemic control may also reduce carbohydrate cravings and decrease episodes of overeating, particularly foods rich in carbohydrates. [6]
Metformin also suppresses hepatic gluconeogenesis, thereby reducing hepatic glucose production. In patients with diabetes, gluconeogenesis is estimated to be approximately three times higher than in healthy individuals, and metformin therapy reduces this process by about one-third. In addition, metformin decreases intestinal glucose absorption. [7]
Together, these effects reduce the amount of glucose available for storage as adipose tissue.
Unlike weight loss achieved through calorie restriction alone, weight reduction during metformin therapy appears to occur predominantly through loss of adipose tissue rather than lean muscle mass. [7]
By improving peripheral insulin sensitivity, metformin also reduces pancreatic insulin secretion. Lower circulating insulin levels may decrease stimulation of insulin receptors in abdominal adipose tissue, potentially reducing energy storage and visceral fat accumulation.
Interestingly, metformin has also been shown to promote weight loss in obese individuals without insulin resistance, as assessed by normal HOMA or Matsuda indices, and even in those with normal glucose metabolism. [8] These observations suggest that mechanisms beyond improved insulin sensitivity contribute to its effects on body weight.
Metformin has also been associated with appetite suppression, leading some investigators to propose that it possesses anorectic properties. [9]
Experimental studies have demonstrated reductions in leptin concentrations within adipose tissue and in the circulation, suggesting that metformin may improve leptin sensitivity by reducing leptin resistance. [10,11]
Furthermore, several studies have reported increased concentrations of glucagon-like peptide-1 (GLP-1) during metformin therapy, which may represent another mechanism contributing to weight loss. [12,13]
What Do Research Findings Show?
Clinical studies suggest that metformin monotherapy has a neutral or only modest effect on body weight compared with placebo during the first year of treatment for type 2 diabetes. (14) However, when metformin is compared with other glucose-lowering medications that are associated with weight gain, the difference becomes clinically meaningful.
A 2011 review of 12 randomized clinical trials found that patients treated with sulfonylureas gained an average of 2.7 kg more than those treated with metformin. (15) The difference became greater with longer treatment duration. In eight studies lasting up to 24 weeks, the average weight difference between metformin and sulfonylureas was 1.9 kg (95% confidence interval [CI] 1.4–2.5 kg), whereas in the remaining four studies lasting longer than 24 weeks, the average difference increased to 3.6 kg (95% CI 3.1–4.1 kg). (15)
Switching patients from sulfonylureas to metformin resulted in an average weight loss of 3.8 kg, while no significant weight changes were observed in patients who continued sulfonylurea therapy. (16)
Metformin also demonstrated a weight advantage over thiazolidinediones (TZDs). In eight randomized comparative studies lasting up to one year, the average weight difference favored metformin by 2.6 kg (95% CI 1.2–4.1 kg). (15) In the four-year ADOPT (A Diabetes Outcome Progression Trial), the difference was even greater, with patients receiving rosiglitazone weighing an average of 6.9 kg more than those treated with metformin (95% CI 6.3–7.4 kg). (17)
Three randomized studies comparing metformin with dipeptidyl peptidase-4 (DPP-4) inhibitors consistently reported greater weight reduction with metformin, with an average between-group difference of approximately 1.4 kg. (18–20)
Similarly, two randomized studies comparing metformin with meglitinides found an average weight advantage of 2.0–3.4 kg in favor of metformin. (21,22)
Combination therapy has also been evaluated. Compared with combinations containing thiazolidinediones, sulfonylureas, or DPP-4 inhibitors, metformin monotherapy was associated with lower weight gain or greater weight loss, with differences of –2.2 kg, –2.3 kg, and –0.2 kg, respectively. (15)
A positive relationship has also been observed between metformin dose and body weight, with higher metformin doses associated with greater weight reduction during combination therapy.
Patients receiving metformin plus meglitinides experienced slightly greater weight gain (approximately 0.9 kg) than those receiving metformin alone. (22,23)
Among metformin-based combination regimens, the greatest tendency toward weight gain has been observed with metformin plus TZDs. This combination produced approximately 0.9 kg more weight gain than metformin plus sulfonylureas and 0.3–1.5 kg more weight gain compared with metformin plus sitagliptin, which was associated with weight reductions ranging from 0.4 to 1.2 kg. (15)
The greatest weight reduction has been reported with combinations of metformin and GLP-1 receptor agonists. Compared with metformin plus TZDs, the average weight difference was 2.7 kg, while compared with metformin plus DPP-4 inhibitors, the difference was 2.4 kg. (24,25)
Two randomized studies comparing metformin plus GLP-1 receptor agonists with metformin plus sulfonylureas also demonstrated significantly greater weight loss in the GLP-1 groups, with average reductions of 3.8 kg and 12.3 kg, respectively. (26,27)
Adding metformin to insulin therapy also helps limit weight gain compared with insulin alone. A 2004 Cochrane meta-analysis reported that patients receiving basal insulin plus metformin gained 3.7 kg less weight than those receiving insulin monotherapy. This benefit was observed with both basal and basal-bolus insulin regimens. (28) Subsequent studies have confirmed these findings. (29–31)
The beneficial effect of metformin on body weight has been demonstrated both when combined with basal insulin and with rapid-acting insulin. (28,32)
Overall, available evidence indicates that metformin monotherapy generally has a neutral or only modestly favorable effect on body weight compared with placebo. However, compared with sulfonylureas, thiazolidinediones, meglitinides, and DPP-4 inhibitors, metformin treatment is consistently associated with substantially less weight gain—up to 6 kg in some patient populations. Metformin also attenuates weight gain when combined with other glucose-lowering medications or insulin.
Although these weight differences may initially appear modest, even small increases in body weight have been associated with reduced treatment adherence and a greater likelihood of discontinuing therapy. (34,35) Conversely, even modest weight loss—approximately 5% of body weight—significantly reduces cardiovascular risk, which is particularly important in patients with type 2 diabetes.
Practical Recommendations
(Based on the Lithuanian reimbursement guidelines for outpatient diabetes treatment)
- If there are no contraindications, initiate metformin in all newly diagnosed patients with type 2 diabetes, regardless of body weight, together with lifestyle modification and dietary intervention.
- Before adding a second glucose-lowering medication, increase the metformin dose to the maximum tolerated level.
- Unless contraindicated, continue metformin as the foundation of therapy when combining oral glucose-lowering medications at any stage of treatment.
- When prescribing metformin together with insulin therapy, always consider the drug's contraindications.
Prepared by Dr. Laura Šiaulienė
Reprinted from Lietuvos gydytojo žurnalas (Lithuanian Doctor's Journal).
Literature references are available from the editorial office.
LT/Met/2014/07
