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Prediabetes is often treated as a single precursor to type 2 diabetes (T2D). That may be useful for screening and prevention, but it does not fully reflect biological reality. People with prediabetes differ markedly in the underlying mechanisms and their risk of developing diabetes. In other words, prediabetes is not a uniform condition but a heterogeneous risk state.

“Lifestyle interventions are and remain the foundation for prediabetes,” said Nikolaos Perakakis, head of the Section of Metabolic Vascular Medicine at the Carl Gustav Carus University Hospital in Dresden, Germany, at the German Diabetes Congress, which took place in Berlin, Germany, on May 13-16, 2026. The problem, Perakakis added, is that adherence to lifestyle programs is limited over the long term; he cited a 2009 study showing that adherence to behavioral weight-loss programs declines over time. Perakakis said it is unlikely that we can do without medications entirely.

Prediabetes: Three High-Risk Subtypes

Data-driven analyses show that six subtypes of a prediabetic metabolic profiles can be distinguished by insulin sensitivity, insulin secretion, liver fat, visceral fat distribution, and genetic T2D risk. Three subtypes are particularly relevant as high risk:

• Prediabetes with fatty liver and marked insulin resistance. This subtype carries a high risk for rapid progression to T2D. Liver fat appears to be not only a marker but also a driver of metabolic deterioration.
• Prediabetes with beta-cell dysfunction. This group may need different long-term prevention strategies than people in whom overweight, fatty liver, and insulin resistance predominate.
• Slow progressors with hyperinsulinemic insulin resistance. This group often develops diabetes only late but already shows early signs of organ damage, especially kidney damage, and has a higher risk for premature death.

Metformin and Incretin-Based Therapies

Metformin remains the primary drug option for pharmacologic management of prediabetes. In the landmark Diabetes Prevention Program, metformin lowered the risk of developing T2D by 31% over 3 years compared with a 58% risk reduction from intensive lifestyle intervention over the same period. Perakakis says metformin appears to help some groups more than others — notably people under 60, those with obesity (BMI above 30 or 35), and women with a history of gestational diabetes. However, metformin has not been shown to reduce diabetes-related complications such as major adverse cardiovascular events, nephropathy, neuropathy, cancer, or death. Newer agents being considered for pharmacologic prevention in high-risk patients include GLP-1 receptor agonists, combined GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists, and SGLT2 inhibitors.

In the STEP 10 trial, semaglutide 2.4 mg, given to people with obesity (BMI ≥ 30) and prediabetes, produced substantially greater weight loss and a higher rate of return to normal blood glucose than placebo. Prediabetes was defined in the study as A1c of 6.0% to ≤ 6.4% and/or fasting plasma glucose (FPG) of 5.5-6.9 mmol/L. Participants had a mean BMI of 40, a mean waist circumference of 120 cm, a mean A1c of 5.9%, and a mean FPG of 5.9 mmol/L; 46% had hypertension, 41% had dyslipidemia, and 10% had cardiovascular disease.

Nearly 81% of patients treated with semaglutide achieved normoglycemia vs 40% on placebo. Overall, 6 months after stopping therapy, 44% of those who had received semaglutide remained normoglycemic. During treatment, mean A1c fell by 0.5 percentage points (P < .0001), and mean FPG fell by 0.6 mmol/L (P < .0001); both measures increased again after treatment ended. “Semaglutide is effective, but when we stop it, values approach baseline again,” Perakakis cautioned.

Tirzepatide Reduces Risk for Overt Diabetes

The SURMOUNT-1 trial showed that tirzepatide in people with prediabetes (A1c, 5.7% to ≤ 6.4%; FPG, 5.6-6.9 mmol/L; oral glucose tolerance test [oGTT] 2-hour value, 140-199 mg/dL) and obesity (BMI ≥ 30 or BMI ≥ 27 with at least one comorbidity) led to substantial weight loss over 3 years and significantly reduced the risk of developing T2D compared with placebo. Fewer participants in the tirzepatide groups were diagnosed with T2D than in the placebo group (1.3% vs 13.3%; P < .001).

After 17 weeks without treatment or placebo, 2.4% of participants on tirzepatide and 13.7% on placebo had developed T2D. Nearly 90% of patients on various tirzepatide doses reached normoglycemia compared with almost 60% in the placebo group; Perakakis attributed the placebo-group improvement to lifestyle interventions. After stopping therapy, however, the gains in normoglycemia diminished. “Tirzepatide is effective at achieving normoglycemia and preventing progression to T2D, but those effects wane after treatment stops,” he said.

Can incretin-based therapies reduce the risk for diabetes-related complications in people with prediabetes? A post hoc analysis of the SELECT trial found that semaglutide lowered cardiovascular events and overall mortality in patients who were overweight or obese, had preexisting cardiovascular disease, and had prediabetes — and the benefit held regardless of baseline A1c or changes in A1c. The A1c-stratified analysis included 17,604 participants (mean age, 61.6 years; 72.3% male). Baseline A1c was < 5.7% in 33.5%, 5.7% to < 6.0% in 34.6%, and 6.0% to < 6.5% in 31.9%. Semaglutide’s reductions in cardiovascular events and mortality were consistent across these A1c groups.

SGLT2 Inhibitors

SGLT2 inhibitors have proven very effective in treating T2D and in slowing the progression of diabetic kidney disease. Perakakis cited a meta-analysis of four studies in patients with prediabetes, heart failure, or chronic kidney disease (CKD) that showed benefits with SGLT2 inhibitors. In that analysis, prediabetes was defined as A1c ≥ 5.7% and < 6.5%.

The analysis included 5655 participants with prediabetes. SGLT2 inhibitors were associated with a significantly lower risk for new-onset diabetes (relative risk, 0.79; 95% CI, 0.68-0.93). The relative risks for new-onset diabetes were 0.68 for dapagliflozin and 0.87 for empagliflozin. The results suggest a potential benefit of SGLT2 inhibitors in high-risk groups with prediabetes. “With SGLT2 inhibitors, you get about a 20% reduction in the risk of developing T2D — in adults with prediabetes and heart failure or chronic kidney disease,” Perakakis summed up.

LIFETIME: SGLT2 Inhibitor Trial

Perakakis reported that a prospective study called LIFETIME is currently under way at four German diabetes research centers to investigate an SGLT2 inhibitor (dapagliflozin 10 mg plus lifestyle counseling vs placebo plus lifestyle counseling) for prediabetes. Men and women aged 35-75 years with BMI ≥ 20 are being enrolled. Prediabetes is defined as FPG of 100-125 mg/dL or an oGTT 2-hour value of 140-199 mg/dL. Endpoints include the frequency of remission of hyperglycemia, reduction in urine albumin-to-creatinine ratio, changes in estimated glomerular filtration rate, and remission of CKD. “So the study is looking at whether SGLT2 inhibitors can play a role in diabetes-related complications in patients with prediabetes,” Perakakis said.

Although pharmacologic options exist for treating prediabetes, several questions remain. The most important question, Perakakis said, is, “Who do we want to treat at all? The incidence of prediabetes is high — 10%-12%. But it is unrealistic to treat all patients pharmacologically, especially younger populations who would need treatment for many years,” he said. Therefore, consideration is being given to defining high-risk groups within people with prediabetes using parameters such as:

• Higher A1c (> 6.0%)
• Higher BMI (> 30)
• Presence of comorbidities (positive cardiovascular disease history, arterial hypertension, or dyslipidemia)
• Based on biomarker risk profiles

To identify potential biomarkers associated with the course of prediabetes, a study compared proteomic and metabolomic profiles of people whose prediabetes either progressed to diabetes within a year or reverted to normoglycemia. Two proteins were identified: elevated levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with a higher risk for diabetes 1 year later.

Perakakis believes that blanket pharmacologic treatment for all people with prediabetes is not advisable. Rather, he said, it is crucial to better identify high-risk individuals and treat them more selectively.

This story was translated from Medscape’s German edition.