Semaglutide or Metformin: what's the difference

Semaglutide and metformin are the two drugs most often discussed today in the context of type 2 diabetes and excess weight. Both lower glucose levels, but they work in completely different ways and have different clinical capabilities. The editorial team examines what this difference consists of from a pharmacological and evidence-based standpoint.

Two generations of diabetes treatment

Metformin belongs to the biguanide class and has been used in clinical practice since the mid-20th century. For decades it was the first-line drug for type 2 diabetes thanks to its efficacy, low cost, neutral effect on body weight and the absence of hypoglycemia risk with monotherapy.

Semaglutide is an agonist of glucagon-like peptide-1 (GLP-1) receptors, a modern peptide drug. It is available as once-weekly subcutaneous injections and in tablet form for daily use. In addition to diabetes, at a higher dose it is approved for the treatment of obesity.

Both drugs are prescription-only. Their use is determined by the diagnosis, comorbidities, kidney function and tolerability, not merely by a desire to lose weight or lower glucose.

Unlike many substances our blog examines, these drugs have a powerful evidence base from large randomized trials, which allows them to be compared substantively.

Mechanisms of action

The main effect of metformin is a reduction in glucose production by the liver (gluconeogenesis). At the cellular level it affects mitochondrial function and the cell's energy state, which is associated with activation of AMP-activated protein kinase (AMPK). An important role is also played by its action in the intestine, notably changes in the microbiota and the secretion of gut hormones.

Semaglutide mimics the hormone GLP-1, which is released in the intestine after eating. It enhances glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying and acts on the appetite centres in the brain, reducing hunger and food intake.

The glucose-dependence of semaglutide's action means that it stimulates insulin only when glucose is elevated, so on its own it rarely causes hypoglycemia. Metformin also does not stimulate insulin secretion and with monotherapy practically does not cause hypoglycemia.

The key difference for body weight is the central effect on appetite. It is precisely this that explains why semaglutide leads to significantly greater weight loss than metformin.

Effect on glucose and body weight

Both drugs effectively lower the level of glycated hemoglobin (HbA1c) in type 2 diabetes, but in clinical studies semaglutide usually provides a greater reduction than metformin at standard doses.

As for body weight, the difference is fundamental. In the STEP 1 study (Wilding et al., 2021), in people with obesity or overweight without diabetes, semaglutide at a dose of 2.4 mg per week together with lifestyle change reduced body weight by an average of 14.9% over 68 weeks versus 2.4% in the placebo group.

Metformin has a more modest effect. In the Diabetes Prevention Program DPP (Knowler et al., 2002), in the metformin group the average weight loss was small - about 2 kg - whereas intensive lifestyle change gave a greater result.

At the same time, metformin has shown the ability to reduce the risk of developing diabetes in people with prediabetes: in the DPP, by 31% compared with placebo, versus 58% in the intensive lifestyle-change group.

Heart, blood vessels and other long-term effects

For metformin the classic evidence is UKPDS 34 (1998): in overweight people with type 2 diabetes it reduced the risk of diabetes-related complications and mortality compared with conventional therapy. However, this study was conducted before the era of modern drugs.

Semaglutide has data from modern cardiovascular outcome studies. In SUSTAIN-6 (Marso et al., 2016), in people with type 2 diabetes and high cardiovascular risk, it reduced the incidence of major cardiovascular events compared with placebo.

The SELECT study (Lincoff et al., 2023) showed that in people with overweight or obesity and established cardiovascular disease, but without diabetes, semaglutide reduced the risk of major cardiovascular events by 20%.

For people who train, there is another aspect: in the MASTERS study (Walton et al., 2019), metformin blunted the gain in muscle mass in response to strength training in older people. Semaglutide, in turn, leads to the loss not only of fat mass but also of part of the lean mass, which is discussed in the literature.

Safety and side effects

The most common side effects of metformin are diarrhea, nausea, a metallic taste, abdominal discomfort; extended-release forms are better tolerated. With prolonged use, vitamin B12 deficiency is possible, so periodic monitoring is recommended.

A rare but serious complication of metformin is lactic acidosis, the risk of which increases with severe renal insufficiency, hypoxia and alcohol excess. That is why the drug is contraindicated in significant decline of kidney function.

Semaglutide most often causes gastrointestinal symptoms - nausea, vomiting, diarrhea, constipation, especially during dose escalation. Among the more serious risks are gallstone disease and pancreatitis. The label contains a warning about medullary thyroid cancer, detected in rodent studies, and a contraindication for people with this cancer or a history of MEN2 syndrome.

In brief about the main differences in safety:

• metformin: monitoring of kidney function and vitamin B12 level;
• semaglutide: monitoring of gastrointestinal tolerability, the risk of pancreatitis and gallstone disease;
• both: not prescribed on one's own, require a doctor's supervision.

Editorial conclusions

Metformin and semaglutide are drugs of different generations with different mechanisms. Metformin reduces glucose production by the liver, is cheap and time-tested, but has little effect on body weight. Semaglutide acts through the GLP-1 system, substantially reduces weight and has modern data on reducing cardiovascular risk.

Neither of them is a «drug for cutting»: both have clear medical indications and contraindications and require monitoring.

The question of choosing between them is the subject of a separate conversation with an endocrinologist, which takes into account the diagnosis, comorbidities and treatment goals.

We also recommend reading our materials «Semaglutide vs metformin: what to choose and for whom», on the side effects of semaglutide and on how GLP-1 drugs affect muscle mass.

References

1. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.
2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844.
3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221–2232.
4. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
5. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865.
6. Walton RG, Dungan CM, Long DE, et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: a randomized, double-blind, placebo-controlled, multicenter trial: the MASTERS trial. Aging Cell. 2019;18(6):e13039.
7. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes. Diabetes Care. Suppl 1; актуальна редакція.