Semaglutide vs Metformin: what to choose and for whom

Semaglutide and metformin do not compete «on equal terms»: each has its own patients for whom it is best suited. The editorial team has examined how doctors make decisions in accordance with clinical guidelines, in which situations one drug is logical, in which another or both together, and why for athletes and people without indications neither is a tool.

Who makes the decision and what they take into account

The choice between semaglutide and metformin is the responsibility of a doctor, most often an endocrinologist or family physician. Modern guidelines, notably the annual Standards of Care of the American Diabetes Association (ADA), propose a patient-centred approach rather than a single scheme for everyone.

The doctor takes into account the type and duration of the carbohydrate metabolism disorder, the HbA1c level, body weight, the presence of cardiovascular disease, heart failure and chronic kidney disease, as well as the cost and availability of therapy.

Contraindications are also important: for metformin - significant decline in kidney function; for semaglutide - medullary thyroid cancer or a history of MEN2 syndrome, previous pancreatitis and other circumstances described in the label.

Finally, the doctor assesses whether the person is able to tolerate the gastrointestinal side effects that are inherent to both drugs, and whether they are ready for injections or daily tablets.

Type 2 diabetes: when metformin, when semaglutide

Metformin has historically been the starting drug for type 2 diabetes, and for many patients without additional risk factors it remains a reasonable first step thanks to its efficacy, safety and low cost.

At the same time, modern ADA guidelines emphasize: in people with established atherosclerotic cardiovascular disease or high risk, as well as in obesity, GLP-1 receptor agonists with proven benefit, such as semaglutide, should be considered regardless of whether the patient is taking metformin.

The basis is cardiovascular outcome studies, notably SUSTAIN-6 (Marso et al., 2016), in which semaglutide reduced the incidence of major cardiovascular events in people with type 2 diabetes and high risk.

In practice, the drugs are often combined: metformin as base therapy, semaglutide to strengthen glycemic control, reduce body weight and provide cardiovascular protection. Such a decision is made individually.

Prediabetes and obesity without diabetes

In people with prediabetes, the first line is lifestyle change. The Diabetes Prevention Program (Knowler et al., 2002) showed that an intensive nutrition and physical activity programme reduced the incidence of diabetes by 58%, and metformin by 31% compared with placebo.

The ADA suggests considering metformin for diabetes prevention in certain high-risk groups, for example in younger people with pronounced obesity or in women with a history of gestational diabetes.

In obesity without diabetes, semaglutide at a dose of 2.4 mg per week is registered as a means of weight control in adults with a body mass index of 30 kg/m² or above, or 27 kg/m² or above in the presence of at least one weight-related comorbidity. In STEP 1 the average weight loss was 14.9% versus 2.4% in the placebo group.

For people with obesity and established cardiovascular disease, the SELECT study (Lincoff et al., 2023) added an argument in favour of semaglutide: a 20% reduction in the risk of major cardiovascular events.

Athletes, «cutting» and people without indications

In the fitness community, both drugs are sometimes regarded as a means of «cutting» or «life extension». This use has no medical justification and is associated with risks.

Metformin can blunt adaptation to training. In the MASTERS study (Walton et al., 2019) it reduced the gain in muscle mass from strength training in older people, and Konopka et al. (2019) showed suppression of mitochondrial adaptations to aerobic training.

Semaglutide reduces appetite so much that a person may find it difficult to ensure sufficient protein and energy intake, and part of the lost mass comes from lean tissue. For an athlete this means a risk of losing strength and worsening recovery.

Neither drug, at the time of preparing this material, is on the WADA Prohibited List, but this does not make them «safe supplements». They are not indicated for a healthy person without metabolic disorders.

• For people without indications: it is better to work with nutrition, training and sleep.
• For athletes with diabetes: the choice of therapy is agreed with a doctor taking the training process into account.
• For everyone: do not buy drugs without a prescription and from unverified sources.

Practical steps before talking to a doctor

If you suspect a carbohydrate metabolism disorder or are overweight, it is worth preparing for the consultation so that the decision is as well-founded as possible.

It is useful to have the results of basic tests and to know your own indicators, as well as a list of all medicines and supplements you take.

A list of what is worth gathering:

1. fasting glucose and HbA1c;
2. lipid panel, creatinine and estimated glomerular filtration rate;
3. height, body weight, waist circumference, blood pressure;
4. information about cardiovascular disease, pancreatitis and thyroid disease in personal and family history.

Discuss your goals with your doctor: glucose control, weight loss, heart protection. On these depends whether metformin, semaglutide or their combination will be optimal.

Remember that any pharmacotherapy works best against a background of lifestyle change, not instead of it.

Editorial conclusions

Metformin remains an accessible and time-tested option for many people with type 2 diabetes and for certain groups with prediabetes. Semaglutide is more appropriate when significant weight loss and proven cardiovascular protection are important, and in obesity without diabetes it is precisely semaglutide that has a registered indication.

Often the drugs do not compete but complement one another within an individual regimen determined by a doctor.

For athletes and healthy people without indications, neither drug is a tool for improving physique: the risks outweigh the hypothetical benefit.

We also recommend reading our materials «Semaglutide or metformin: what's the difference», on the effect of GLP-1 drugs on muscle mass and on the tests for monitoring carbohydrate metabolism.

References

1. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes. Diabetes Care. Suppl 1; актуальна редакція.
2. 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.
3. 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.
4. 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.
5. 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.
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. Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880.
8. U.S. Food and Drug Administration. WEGOVY (semaglutide) injection: prescribing information. Silver Spring, MD: FDA.