At the beginning of diabetes treatment: Metformin
Unless contraindicated, we recommend metformin as the initial pharmacotherapy. The goal is to achieve the best possible HbA1c level and counteract further weight gain. HbA1c reflects the average blood glucose level over the past 6–8 weeks. An HbA1c of 6.5% is considered very well controlled. However, it is important to note that an HbA1c target of 6.5% is not appropriate for every patient. Each patient must have an individualized treatment goal. Poor glycemic control is associated with an increased cardiovascular risk. When HbA1c is greater than 7.5%, the risk of developing typical long-term complications of diabetes also rises, such as diabetic retinopathy (eye disease), diabetic polyneuropathy (nerve disease), and diabetic nephropathy (kidney disease).
Because many people are overweight and exercise too little, type 2 diabetes often develops at a younger age. From the age of 40 onward, the risk of developing type 2 diabetes rises sharply in this group. After 5–10 years of poor control, typical complications appear, and patients are still relatively young. More than 50% of dialysis patients are people with type 2 diabetes.
Metformin: As early as possible in type 2 diabetes
Many patients are reluctant to start taking tablets right away. They prefer to first try achieving treatment goals through exercise and weight loss. Even if patients reach their target through lifestyle changes alone, it is still advisable to take metformin. By the time type 2 diabetes is diagnosed, the majority of insulin-producing beta cells are already non-functional. The aim is to preserve as many functional cells as possible, which is achieved by reducing their workload.
That people at increased risk of type 2 diabetes can delay the onset of the disease has long been known. A healthy lifestyle in particular often has the desired effect. A long-term American study now shows that early treatment with metformin could also help.
(September 7, 2025) People at high risk of diabetes can delay the onset of the disease by an average of about three years if they adopt a healthier lifestyle or start treatment with metformin early. This is shown by a U.S. follow-up study, the results of which were recently published in the journal The Lancet Diabetes & Endocrinology1.
Younger people in particular benefit from the drug
Metformin remains the most commonly prescribed drug for the treatment of type 2 diabetes. Among other things, it reduces insulin resistance, which is a typical feature of the disease. With metformin, the body’s own insulin becomes effective again. According to the American study, younger people at high risk of diabetes benefit from this even before the disease actually develops.
More than 3,000 adults with prediabetes took part in the long-term study. Their blood glucose levels were already slightly elevated, but they did not yet have diabetes. At this stage, lifestyle modification was particularly successful. Participants who exercised more and lost weight were 58 percent less likely to develop diabetes within the first three years than those in the control group. According to the DDG, lifestyle intervention delayed diabetes by 3.5 years in half of the group. After 21 years, participants who followed a healthy lifestyle were still 24 percent less likely to develop the disease.
But metformin therapy also had a significant effect: it reduced the risk of diabetes by 31 percent compared to the placebo group in the first three years, and half of the participants enjoyed 2.5 more years free of diabetes. Younger participants in particular (under 45 years of age) benefited from this. Even after more than 20 years, there were still significant differences. In the metformin group, 17 percent fewer people had developed diabetes compared to the placebo group.
Better blood glucose levels reduce the need for insulin, meaning the beta cells have to produce and release less. This relief is supported by metformin in addition to lifestyle changes. Diabetes is a progressive disease. Over the years, more and more beta cells become dysfunctional. Therefore, it makes sense to start metformin as early as possible—even when metabolic control is still good. For certain patient groups, guidelines recommend metformin not only at diagnosis but also for prevention in prediabetes.
Metformin therapy for the prevention of type 2 diabetes should be considered in patients with prediabetes, particularly those with BMI > 35 kg/m², patients younger than 60 years, and women with a history of gestational diabetes.
Prediabetes is defined as HbA1c between 5.7% and 6.4%. These individuals have an increased cardiovascular risk. Therefore, it is recommended to examine and treat additional risk factors such as dyslipidemia and hypertension.
Thanks to modern treatment with statins and ACE inhibitors/ARBs, cardiovascular risk is now only slightly higher compared to patients without diabetes. Today, the leading cause of death in patients with diabetes is no longer heart attack and stroke, but cancer. The risk of developing cancer is elevated not only in patients with manifest diabetes but also in obese individuals and those with prediabetes. Metformin has been shown to reduce cancer risk, which is another reason to start treatment early.
Metformin: Long-standing and proven
Metformin is one of the oldest diabetes medications, after insulin. It reduces glucose production (gluconeogenesis) in the liver, increases insulin sensitivity in muscle, and slows carbohydrate absorption in the gut. Metformin is also known to have a partial incretin effect (see GLP-1 analogues and DPP-4 inhibitors).
In patients with diabetes, the gut microbiome is altered. The microbiome refers to the bacteria in the gut. Experiments in which stool from healthy individuals was transplanted into patients with diabetes have proven that the microbiome contributes significantly to metabolism. All metabolic parameters, including blood glucose and lipids, improved in patients who received stool transplants from healthy donors. Metformin alters the microbiome, shifting it back toward the pattern found in healthy individuals.
Metformin must not be used in cases of severe heart failure, acute myocardial infarction, severe renal insufficiency, or conditions involving respiratory distress such as asthma and chronic obstructive pulmonary disease (COPD). When these contraindications are observed, it is one of the safest drugs available. A feared side effect of metformin is lactic acidosis. This side effect is very rare—occurring once in 50,000 treatment years. It only occurs if contraindications are ignored. With long-term metformin use, vitamin B12 deficiency can occur. Therefore, guidelines recommend monitoring vitamin B12 levels in patients on long-term therapy.
Gradual dose increase of metformin
One challenge with metformin treatment is gastrointestinal tolerance. Therefore, treatment should start with a low dose. It is recommended to begin with 500 mg after dinner (last bite). If tolerated well, after one week 500 mg can be taken both in the morning and evening after meals. The dose should be increased weekly by 500 mg until the optimal dose of 1000 mg in the morning and 1000 mg in the evening is reached. Despite this approach, 10–20% of patients cannot tolerate metformin. In such cases, other antidiabetic agents must be used. Overweight patients benefit particularly from metformin, as it supports weight loss. Moreover, metformin does not cause hypoglycemia. However, hypoglycemia may occur when metformin is combined with insulin or sulfonylureas.
If metformin is not tolerated, an extended-release formulation (Siofor® XR 500 mg/750 mg/1000 mg) can be tried. This has a delayed release over 24 hours and needs to be taken only once daily. The maximum daily dose is 2000 mg.
Metformin as monotherapy or starting directly with combination therapy
Type 2 diabetes is a progressive disease. After some time, monotherapy is no longer sufficient, blood glucose levels rise again, and an additional antidiabetic drug must be introduced. This is the so-called “stepwise therapy of type 2 diabetes.”
Recent studies have shown that when multiple therapies are initiated right at diagnosis, the time until treatment failure can be significantly prolonged.
The Lancet Diabetes & Endocrinology2025, Volume 13, Issue 6, 469 – 481