Prediabetes in 2026: Evidence Thresholds for Lifestyle Intervention, Metformin, and Anti-Obesity Pharmacotherapy

Introduction

Prediabetes is a heterogeneous metabolic risk state rather than a single disease phenotype. It may reflect impaired fasting glucose, impaired glucose tolerance, rising glycated hemoglobin, central adiposity, metabolic dysfunction-associated steatotic liver disease, prior gestational diabetes, medication-associated insulin resistance, or early beta-cell dysfunction.

The central clinical question is not simply whether to treat prediabetes. It is which intervention best matches the patient’s glycemic pattern, risk of progression, obesity status, comorbidities, treatment access, preferences, and long-term goals.

The Diabetes Prevention Program established intensive lifestyle intervention and metformin as evidence-based strategies for delaying or reducing the development of type 2 diabetes among high-risk adults. More recently, anti-obesity medications have produced weight loss large enough to alter glycemic trajectories in many adults with obesity and prediabetes. These therapies are clinically important, but they do not erase the distinction among diabetes prevention, obesity treatment, and cardiovascular risk reduction.

A practical approach should therefore avoid presenting lifestyle intervention, metformin, and anti-obesity medications as mutually exclusive competitors. Lifestyle intervention is foundational risk-modifying therapy. Metformin is a selective, low-cost, off-label diabetes-prevention option. Anti-obesity pharmacotherapy is appropriate when obesity meets treatment thresholds and is an important driver of cardiometabolic risk.

Defining Prediabetes and Confirming the Risk State

Prediabetes is defined by one or more of the following laboratory findings:

• A1C of 5.7% to 6.4%

• Fasting plasma glucose of 100 to 125 mg/dL

• Two-hour plasma glucose of 140 to 199 mg/dL following a 75-g oral glucose tolerance test

These criteria identify overlapping but nonidentical populations. Impaired fasting glucose is often associated with hepatic insulin resistance, whereas impaired glucose tolerance more strongly reflects impaired postprandial glucose disposal and peripheral insulin resistance. A1C provides an estimate of average glycemic exposure but can be affected by conditions that alter erythrocyte lifespan or hemoglobin structure. fore escalating treatment, clinicians should confirm that the laboratory result is interpretable and representative. A1C may be misleading in patients with hemoglobin variants, iron deficiency, hemolysis, recent blood loss or transfusion, erythropoietin therapy, advanced kidney disease, pregnancy, or other conditions affecting red blood cell turnover.

Fasting glucose is also subject to biological and preanalytical variability. Acute illness, glucocorticoids, psychological stress, sleep disruption, and specimen-processing delays may affect the result. Repeat testing or confirmation with another diagnostic method is appropriate when findings are unexpected or inconsistent with the broader clinical picture.

Oral glucose tolerance testing may be useful when fasting glucose and A1C are discordant, when postprandial dysglycemia is suspected, or when risk appears higher than fasting measurements suggest. The ADA recommends at least annual testing for the development of diabetes in people with established prediabetes. ediabetes should also prompt a broader cardiometabolic assessment. Relevant factors include:

• Body mass index and central adiposity

• Family history of type 2 diabetes

• Prior gestational diabetes

• Polycystic ovary syndrome

• Hypertension and dyslipidemia

• Obstructive sleep apnea

• Metabolic dysfunction-associated steatotic liver disease

• Chronic glucocorticoid or selected antipsychotic exposure

• Tobacco use and physical inactivity

• Established cardiovascular or kidney disease

The relationship between prediabetes and cardiovascular or kidney outcomes is heterogeneous. Much of an individual’s risk may be driven by coexisting obesity, hypertension, dyslipidemia, smoking, sleep apnea, established cardiovascular disease, or kidney disease rather than by the glycemic category alone.

Albuminuria assessment should therefore be performed when clinically indicated by diabetes, hypertension, known or suspected kidney disease, cardiovascular disease, or other relevant risk factors. Prediabetes by itself does not establish a universal albuminuria-screening requirement.

The management goal is not simply to reduce A1C below 5.7%. It is to reduce progression to type 2 diabetes, address obesity when present, and identify and treat established cardiovascular and kidney risk factors using interventions supported for those specific indications.

Why the Topic Matters Now

Three developments have changed the threshold discussion.

Long-term DPP and DPPOS evidence

The original Diabetes Prevention Program reported a 58% relative reduction in diabetes incidence with intensive lifestyle intervention and a 31% reduction with metformin compared with placebo over a mean follow-up of 2.8 years. Lifestyle participants pursued approximately 7% weight loss and at least 150 minutes per week of moderate-intensity physical activity. llow-up extending beyond 20 years showed persistent but attenuated reductions in diabetes incidence. The separation among treatment groups diminished over time, although the original lifestyle and metformin assignments remained associated with longer diabetes-free survival. ese durable diabetes-incidence findings did not translate into a demonstrated reduction in major cardiovascular events attributable to the original lifestyle or metformin assignments. Aggregate microvascular outcomes also were not significantly different among the randomized groups overall at 15 years. # Broader outcomes associated with lifestyle intervention

A 2026 observational follow-up of Medicare-linked DPP/DPPOS participants found that original assignment to lifestyle intervention was associated with a lower long-term risk of multimorbidity than placebo. Metformin assignment was not associated with a statistically significant reduction.

This analysis should not be interpreted as a new randomized proof of causality. It evaluated a subset of surviving trial participants using observational claims-based follow-up. Nevertheless, it supports continued investigation of the broader health effects of structured lifestyle intervention. # More effective obesity pharmacotherapy

Contemporary obesity pharmacotherapy can produce substantially greater average weight loss than earlier medications. Semaglutide 2.4 mg and tirzepatide have also produced favorable glycemic outcomes among trial participants with overweight or obesity and prediabetes.

These findings are clinically relevant when obesity is present. They do not make prediabetes alone an FDA-approved indication for an anti-obesity medication, and normalization of glucose during treatment should not be described as a cure or as proven prevention of long-term complications.

Lifestyle Intervention: The Default Foundation

Lifestyle intervention remains the reference standard for most adults with prediabetes. In the DPP, lifestyle treatment was structured, coached, goal-directed, and supported over time. It was not limited to brief instructions to eat less and exercise more.

The CDC National Diabetes Prevention Program uses similar core objectives, including:

• Approximately 5% to 7% weight loss

• At least 150 minutes per week of moderate-intensity physical activity

• A structured curriculum

• Coaching by trained personnel

• Ongoing support for maintenance

The clinical threshold for offering lifestyle intervention is broad. Adults with confirmed prediabetes should be offered or referred to an effective preventive intervention, particularly when they have overweight or obesity, rising glycemic measures, prior gestational diabetes, or additional cardiometabolic risk factors. festyle treatment should also be integrated into obesity care when excess adiposity is present. Weight loss, improved cardiorespiratory fitness, better blood pressure control, improved triglycerides, reduced hepatic fat, greater mobility, and improved physical function may be clinically meaningful even when the change in A1C is modest.

These improvements should not be described as proof that lifestyle intervention prevents cardiovascular events in the broad prediabetes population. The DPPOS cardiovascular analysis did not demonstrate fewer major cardiovascular events from the original lifestyle assignment. e principal limitation of lifestyle treatment is implementation. Food insecurity, shift work, caregiving responsibilities, disability, depression, chronic pain, neighborhood safety, time constraints, medication-associated weight gain, and limited insurance coverage can all affect feasibility.

A clinician-facing prescription should identify the actual intervention. Depending on the patient, this may include a recognized diabetes-prevention program, nutrition services, a progressive physical activity plan, obesity-medicine referral, medication review, sleep-apnea evaluation, behavioral support, and measurable follow-up targets.

Lifestyle intervention should not be used as a gatekeeping requirement that indefinitely delays evidence-based obesity treatment. Current obesity guidance supports combining lifestyle treatment with pharmacotherapy when the patient is eligible and the expected benefit justifies treatment. Metformin: Selective, Low-Cost, and Off-Label for Prediabetes

Metformin remains the best-established pharmacologic option for diabetes prevention, but its role is selective. In the United States, metformin is not FDA-approved specifically for prediabetes or diabetes prevention.

The 2026 ADA Standards of Care recommend considering metformin for adults at high risk of type 2 diabetes, particularly those resembling higher-risk DPP participants:

• Age 25-59 years

• BMI of at least 35 kg/m²

• Fasting plasma glucose of approximately 110 mg/dL or higher

• A1C of approximately 6.0% or higher

• Prior gestational diabetes mellitus

tformin is particularly reasonable when prediabetes is persistent and high-risk features are present, when lifestyle intervention has not sufficiently reduced risk, when the patient has prior gestational diabetes, or when cost and extensive clinical experience are important considerations.

It may also be appropriate when an oral medication is preferred and modest weight loss or weight neutrality is desirable. Long-term DPPOS analyses support persistent diabetes-incidence reduction and document that some individuals maintain clinically meaningful weight loss with metformin. e expected benefit should be presented realistically. Metformin should not be represented as proven to prevent myocardial infarction, stroke, heart failure, chronic kidney disease, retinopathy, neuropathy, dementia, or mortality in the broad prediabetes population. Its strongest evidence is for delaying or reducing progression to type 2 diabetes in selected high-risk patients.

The ADA also emphasizes that it remains unknown whether beginning glucose-lowering pharmacotherapy before diabetes develops improves long-term health outcomes. No medication other than metformin has sufficient long-term evidence to support routine use solely for diabetes prevention. Obesity pharmacotherapy may nevertheless be appropriate for its obesity indication when eligibility criteria are met. # Metformin safety

Renal function should be assessed before initiation and periodically thereafter.

• Metformin is contraindicated when estimated glomerular filtration rate is below 30 mL/min/1.73 m².

• Initiation is not recommended when estimated glomerular filtration rate is 30-45 mL/min/1.73 m².

• When estimated glomerular filtration rate falls below 45 mL/min/1.73 m² during treatment, the benefits and risks of continuation should be reassessed.

Temporary interruption around iodinated contrast is recommended in patients with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m² and in certain patients with hepatic disease, alcoholism, heart failure, or intra-arterial contrast exposure. Renal function should be reassessed after the procedure according to labeling. ctic acidosis is rare but serious. Risk increases with severe kidney impairment, hypoxic states, sepsis, dehydration, excessive alcohol use, hepatic impairment, and acute illness.

Gastrointestinal intolerance is common, particularly during initiation or rapid dose escalation. Gradual titration and use of an extended-release formulation may improve tolerability.

Long-term metformin treatment can reduce vitamin B12 concentrations. Periodic assessment is appropriate, particularly in patients with anemia, neuropathy, vegetarian or vegan diets, malabsorption, proton pump inhibitor exposure, or other risk factors for deficiency. Anti-Obesity Pharmacotherapy: Treat Obesity, Not a Laboratory Category

Anti-obesity medication is most appropriate when obesity is a therapeutic target in its own right.

Current guidance generally supports considering pharmacotherapy in addition to lifestyle treatment for adults with:

• BMI of at least 30 kg/m², or

• BMI of at least 27 kg/m² with a weight-related complication

Treatment decisions should also consider disease severity, prior response, contraindications, reproductive plans, comorbidities, medication access, cost, expected duration, and patient preferences. ediabetes may strengthen the clinical rationale because it is a weight-related cardiometabolic complication. It should not be presented as a stand-alone FDA-approved indication for obesity pharmacotherapy.

Semaglutide

In STEP program analyses, semaglutide 2.4 mg injection plus lifestyle intervention produced substantial weight loss and increased the likelihood that participants with overweight or obesity and prediabetes had normoglycemia at 68 weeks compared with placebo. These findings describe glycemic status during treatment and should not be characterized as permanent remission or a cure. e STEP 1 extension demonstrated that participants regained approximately two-thirds of their prior weight loss during the year after semaglutide withdrawal, while several cardiometabolic measures moved back toward baseline. This supports viewing obesity pharmacotherapy as potentially chronic treatment rather than a short course. maglutide also has an agent-specific cardiovascular role. In SELECT, semaglutide 2.4 mg reduced major adverse cardiovascular events among adults aged 45 years or older who had established cardiovascular disease and overweight or obesity but did not have diabetes. This finding applies to that defined population and should not be generalized to all adults with prediabetes or to all GLP-1 receptor agonists. rrent Wegovy labeling includes injection and oral formulations. Trial findings and indications should be applied according to the specific formulation, dose, population, and current prescribing information. # Tirzepatide

In SURMOUNT-1, tirzepatide produced substantial weight reduction in adults with obesity or overweight and a weight-related complication. the three-year analysis of participants with obesity and prediabetes, type 2 diabetes developed in 1.3% of tirzepatide-treated participants and 13.3% of placebo-treated participants during 176 weeks of treatment. After an additional 17 weeks off treatment, the corresponding proportions were 2.4% and 13.7%.

These results provide strong evidence of reduced diabetes incidence in the studied population over the trial period. They do not establish a general prediabetes indication, permanent prevention after long-term discontinuation, or a class-wide effect for every dual GIP/GLP-1 receptor agonist. rzepatide also has an FDA-approved indication for moderate-to-severe obstructive sleep apnea in adults with obesity. That indication is specific to tirzepatide and should not be attributed to anti-obesity medications generally. # Other anti-obesity medications

Older medications remain options for selected patients, although average weight loss, tolerability, contraindications, and monitoring requirements differ substantially.

Liraglutide 3.0 mg delayed the onset of type 2 diabetes during three years of treatment among adults with obesity and prediabetes in the SCALE Obesity and Prediabetes trial. entermine-topiramate extended release reduced annualized diabetes incidence in a secondary analysis of participants with prediabetes or metabolic syndrome, but reproductive toxicity, sympathomimetic effects, cognitive adverse effects, mood effects, and metabolic complications require careful selection and monitoring. e XENDOS trial found that orlistat added to lifestyle intervention reduced the cumulative incidence of type 2 diabetes over four years among adults with obesity. Its use is frequently limited by gastrointestinal adverse effects, vitamin malabsorption, contraindications, and drug interactions. ltrexone-bupropion may be appropriate for selected patients with obesity, but it should not be used in several common clinical scenarios, including uncontrolled hypertension, seizure disorders, eating disorders, chronic opioid therapy, acute opioid withdrawal, monoamine oxidase inhibitor exposure, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Table 1. Practical Thresholds for Intervention

Strategy	Best-fit clinical setting	Evidence and principal caution
Structured lifestyle intervention	Most adults with confirmed prediabetes	Strong diabetes-prevention evidence and broad risk-factor benefits. Requires structured support rather than brief advice.
Metformin	Persistent high-risk prediabetes, particularly BMI ≥35 kg/m², age 25-59 years, A1C ≥6.0%, fasting glucose ≥110 mg/dL, or prior gestational diabetes	Durable reduction in diabetes incidence and low cost. Off-label for prediabetes; major cardiovascular and microvascular outcome benefit has not been established.
Anti-obesity medication	BMI ≥30 kg/m² or BMI ≥27 kg/m² with a weight-related complication, after individualized assessment	Produces weight loss and may favorably alter glycemic trajectory. Not FDA-approved for prediabetes alone; efficacy and safety are agent-specific.
Global risk management	Hypertension, dyslipidemia, smoking, sleep apnea, kidney disease, MASLD/MASH, or established cardiovascular disease	Addresses risks that may be more clinically important than a small difference in A1C. Benefits should be attributed to the specific evidence-based intervention used.

Safety and Monitoring Considerations

Medication choice should be guided by current labeling, contraindications, comorbidities, reproductive plans, patient goals, cost, access, and expected duration of therapy.

Semaglutide and tirzepatide

Both agents carry boxed warnings concerning thyroid C-cell tumors observed in rodents. They are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Both are also contraindicated after a serious hypersensitivity reaction to the active drug or product excipients. inicians should counsel patients about:

• Nausea, vomiting, diarrhea, constipation, and abdominal pain

• Dehydration and acute kidney injury related to volume depletion

• Gallbladder disease

• Symptoms suggesting acute pancreatitis

• Severe gastrointestinal adverse effects

• Pregnancy and reproductive planning

• Perioperative communication because of delayed gastric emptying and aspiration risk

Neither agent is recommended in severe gastroparesis. A history of pancreatitis warrants individualized consideration, but it is not listed as a formal contraindication in current labeling.

Semaglutide labeling also recommends monitoring for sustained increases in resting heart rate. In patients with type 2 diabetes and a history of diabetic retinopathy, monitoring for retinopathy complications should be considered with either drug. These retinopathy precautions should not be generalized to people with prediabetes who do not have diabetic retinopathy. rzepatide may reduce the effectiveness of oral hormonal contraceptives because of delayed gastric emptying. Patients using oral hormonal contraception should switch to a nonoral method or add a barrier method for four weeks after treatment initiation and for four weeks after each dose escalation. # Phentermine-topiramate extended release

Phentermine-topiramate is contraindicated during pregnancy because of fetal risk. Patients who can become pregnant require pregnancy testing before treatment and monthly thereafter, along with effective contraception. The product is distributed through a risk evaluation and mitigation strategy.

Other contraindications include glaucoma, hyperthyroidism, monoamine oxidase inhibitor use within 14 days, and relevant hypersensitivity. Monitoring should address heart rate, blood pressure, mood, suicidality, cognition, serum bicarbonate, creatinine, potassium, nephrolithiasis risk, and ocular symptoms. Cardiovascular morbidity and mortality benefit has not been established. # Naltrexone-bupropion

Naltrexone-bupropion requires attention to blood pressure and heart rate, seizure risk, eating-disorder history, opioid exposure, monoamine oxidase inhibitors, neuropsychiatric symptoms, and drug interactions. It is contraindicated in pregnancy and should not be combined with other bupropion-containing products. # Orlistat

Orlistat is contraindicated in pregnancy, chronic malabsorption syndrome, cholestasis, and serious hypersensitivity. It can reduce absorption of fat-soluble vitamins, and patients should take an appropriate multivitamin separated from the medication.

Monitoring and counseling should address gastrointestinal adverse effects, rare severe liver injury, oxalate nephropathy, gallstone risk, and interactions involving cyclosporine, warfarin, levothyroxine, antiepileptic drugs, amiodarone, and selected antiretroviral therapies. Table 2. Medication-Specific Safety Snapshot

Medication	Avoid or use caution	Monitoring priorities
Metformin	eGFR <30 mL/min/1.73 m², acute metabolic acidosis, severe acute illness, hypoxia, excessive alcohol exposure	Kidney function, gastrointestinal effects, vitamin B12, anemia, neuropathy
Semaglutide	MTC/MEN2, serious hypersensitivity, pregnancy, severe gastroparesis; individualized caution with prior pancreatitis	Gastrointestinal effects, hydration, kidney function with volume depletion, gallbladder symptoms, resting heart rate, perioperative planning
Tirzepatide	MTC/MEN2, serious hypersensitivity, pregnancy, severe gastroparesis; oral contraceptive interaction	Gastrointestinal effects, hydration, kidney function, gallbladder symptoms, contraception counseling, perioperative planning
Naltrexone-bupropion	Uncontrolled hypertension, seizure disorder, eating disorders, opioid therapy or withdrawal, MAOIs, pregnancy	Blood pressure, heart rate, mood, suicidality, interactions
Phentermine-topiramate ER	Pregnancy, glaucoma, hyperthyroidism, recent MAOI use, relevant hypersensitivity	Monthly pregnancy testing, heart rate, blood pressure, mood, cognition, bicarbonate, creatinine, potassium
Orlistat	Pregnancy, chronic malabsorption, cholestasis, serious hypersensitivity	Gastrointestinal effects, fat-soluble vitamins, kidney and liver symptoms, interacting medications

MTC = medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia syndrome type 2; MAOI = monoamine oxidase inhibitor.

A Practical Clinical Approach

A defensible workflow begins by confirming prediabetes and defining the phenotype. The clinician should determine whether dysglycemia is mild and stable, rising, associated with impaired glucose tolerance, linked to central adiposity, medication-related, or part of a broader obesity-related syndrome.

First layer: Structured lifestyle intervention

Lifestyle treatment should include a measurable weight goal when overweight or obesity is present, a physical activity prescription, an individualized nutrition strategy, sleep and medication review, and referral to a recognized diabetes-prevention or obesity-management program when feasible.

Follow-up should assess:

• Weight and, when useful, waist or other anthropometric measures

• A1C or fasting plasma glucose

• Blood pressure and lipids

• Medication changes

• Physical function

• Barriers to implementation

Second layer: Selective metformin

Metformin is most reasonable when prediabetes is persistent and high-risk features are present, particularly BMI of at least 35 kg/m², age 25-59 years, A1C around or above 6.0%, fasting glucose around or above 110 mg/dL, or prior gestational diabetes.

The discussion should include its off-label status, expected reduction in diabetes incidence, absence of proven broad hard-outcome benefit, kidney thresholds, gastrointestinal effects, and vitamin B12 monitoring.

Third layer: Obesity-directed pharmacotherapy

When a patient meets obesity-treatment criteria, treating obesity may address a more upstream driver of metabolic dysfunction than adding a glucose-focused medication alone.

The decision should address:

• Agent-specific evidence and labeling

• Chronic-treatment expectations

• Adverse-effect management

• Reproductive considerations

• Perioperative communication

• Access and cost

• Effects of discontinuation

• Integration with lifestyle support

Long-term success should not be attributed only to sustained behavioral change. Obesity is a chronic disease, and outcomes may also depend on continued treatment, biologic response, tolerability, adherence, affordability, and management of weight recurrence after medication withdrawal.

Final layer: Global risk management

Prediabetes should prompt attention to blood pressure, LDL cholesterol, smoking, sleep apnea, metabolic liver disease, depression, medication-associated weight gain, physical function, and atherosclerotic cardiovascular disease risk.

Kidney function and albuminuria should be assessed when indicated by the patient’s comorbidities and risk profile. A patient’s near-term clinical risk may be driven more by hypertension, dyslipidemia, smoking, sleep apnea, kidney disease, or established cardiovascular disease than by a small difference in A1C.

Evidence-based treatment of those conditions can reduce cardiovascular and kidney risk. Those benefits should be attributed to the specific intervention and population studied, not to treatment of prediabetes itself.

What Not to Overstate

Regression to normoglycemia is not a cure

A return from prediabetes to normoglycemia during treatment may reflect weight loss, improved insulin sensitivity, medication exposure, behavioral change, or test variability. Risk may return with weight recurrence or medication discontinuation.

Lower diabetes incidence does not prove broad hard-outcome benefit

A reduction in diabetes incidence should not be treated as equivalent to a demonstrated reduction in myocardial infarction, stroke, heart failure, kidney failure, neuropathy, retinopathy, dementia, or mortality.

Semaglutide has cardiovascular outcomes evidence in a specific population with established cardiovascular disease and excess weight. That result should not be assigned to the broad prediabetes population or to the entire GLP-1 receptor agonist class.

Anti-obesity medication does not replace lifestyle support

Pivotal obesity trials generally evaluated pharmacotherapy in conjunction with lifestyle intervention. Pharmacotherapy can augment lifestyle treatment when obesity-treatment criteria are met, but medication discontinuation may be followed by substantial weight recurrence.

Metformin is not obsolete

Metformin produces less average weight loss than contemporary incretin-based obesity medications, but it remains inexpensive, familiar, and supported by long-term diabetes-prevention evidence for selected high-risk phenotypes.

Mechanistic plausibility is not clinical-outcome proof

Weight reduction and improvements in insulin resistance may contribute to better glycemic trajectories. Changes in inflammatory biomarkers, hepatic fat, insulin sensitivity, or other intermediate measures should not be presented as proof of fewer cardiovascular, kidney, microvascular, or mortality events unless clinical outcome data support that conclusion.

Future Directions

Prediabetes management should continue moving beyond a single glucose threshold. Better validated tools are needed to identify:

• Patients likely to progress rapidly

• Patients likely to return to normoglycemia with lifestyle treatment

• Patients most likely to benefit from metformin

• Patients for whom early obesity treatment offers the greatest net benefit

• Patients who should be evaluated for metabolic surgery

• Patients whose dominant risk arises from cardiovascular, kidney, hepatic, or functional disease

Important evidence gaps include the durability of diabetes prevention after long-term discontinuation of obesity medication, comparative effectiveness between metformin and obesity pharmacotherapy in defined prediabetes phenotypes, cost-effectiveness in lower-risk populations, equity of access, and patient-important outcomes beyond diabetes incidence.

Continuous glucose monitoring, digital tools, and advanced risk-prediction methods are being investigated in prediabetes. Their routine use for risk stratification or treatment monitoring is not yet established, and evidence that they improve long-term clinical outcomes remains limited.

Further follow-up is also needed to determine whether early obesity treatment changes cardiovascular, kidney, hepatic, functional, or microvascular outcomes specifically among people with prediabetes.

Conclusion

Prediabetes management in 2026 should be individualized, but not improvised. Structured lifestyle intervention remains the foundation and should be prescribed as active therapy with defined goals and longitudinal support.

Metformin remains a selective, off-label, low-cost option for adults at particularly high risk, including those with BMI of at least 35 kg/m², higher A1C or fasting glucose, younger age, or prior gestational diabetes.

Anti-obesity medications are increasingly relevant when obesity is an important driver of metabolic risk. They should be used according to obesity-treatment indications, agent-specific evidence, and current safety labeling rather than as generic prediabetes drugs.

The practical approach is layered: confirm the risk state, prescribe structured lifestyle intervention, consider metformin when high-risk features are present, use obesity pharmacotherapy when eligibility criteria are met, and manage global cardiometabolic risk with interventions demonstrated to improve the relevant outcomes.

The objective is not merely to normalize a laboratory category. It is to reduce the patient’s overall metabolic and cardiovascular risk using interventions matched to the actual clinical phenotype while avoiding unnecessary treatment and unsupported assumptions about long-term benefit.

References

1. American Diabetes Association Professional Practice Committee. (2026). 2. Diagnosis and classification of diabetes: Standards of Care in Diabetes, 2026. Diabetes Care, 49(Supplement 1), S27-S49. https://doi.org/10.2337/dc26-S002. PMID: 41358893.

2. American Diabetes Association Professional Practice Committee. (2026). 3. Prevention or delay of diabetes and associated comorbidities: Standards of Care in Diabetes, 2026. Diabetes Care, 49(Supplement 1), S50-S60. https://doi.org/10.2337/dc26-S003. PMID: 41358891.

3. American Diabetes Association Professional Practice Committee. (2026). 8. Obesity and weight management for the prevention and treatment of diabetes: Standards of Care in Diabetes, 2026. Diabetes Care, 49(Supplement 1). https://doi.org/10.2337/dc26-S008. PMID: 41358882.

4. American College of Physicians. (2026). Pharmacologic treatment of obesity in adults: A living clinical guideline from the American College of Physicians. Annals of Internal Medicine. https://doi.org/10.7326/ANNALS-25-02714. PMID: 42296496.

5. Apolzan, J. W., Venditti, E. M., Edelstein, S. L., Knowler, W. C., Dabelea, D., Boyko, E. J., Pi-Sunyer, X., Kalyani, R. R., Franks, P. W., Srikanthan, P., Gadde, K. M., & Diabetes Prevention Program Research Group. (2019). Long-term weight loss with metformin or lifestyle intervention in the Diabetes Prevention Program Outcomes Study. Annals of Internal Medicine, 170(10), 682-690. https://doi.org/10.7326/M18-1605. PMID: 31009939.

6. Boltri, J. M., et al. (2023). The National Clinical Care Commission report to Congress: Leveraging federal policies and programs to prevent diabetes in people with prediabetes. Diabetes Care, 46(2), e39-e50. https://doi.org/10.2337/dc22-0620. PMID: 36701590.

7. Centers for Disease Control and Prevention. (2024). What is the National Diabetes Prevention Program? Retrieved July 29, 2026, from https://www.cdc.gov/diabetes-prevention/programs/what-is-the-national-dpp.html

8. DailyMed. (2026). Contrave extended-release: Naltrexone hydrochloride and bupropion hydrochloride tablets, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9889a75d-4197-496c-aae1-15c9058c1d1b

9. DailyMed. (2026). Metformin hydrochloride extended-release tablets, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0ef9de1a-b786-4b6c-a250-3f5ac532b16a

10. DailyMed. (2026). Qsymia: Phentermine and topiramate extended-release capsules, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40dd5602-53da-45ac-bb4b-15789aba40f9

11. DailyMed. (2026). Wegovy: Semaglutide injection and tablets, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b

12. DailyMed. (2024). Xenical: Orlistat capsules, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=6240792b-9224-2d10-e053-2a91aa0a2c3e&type=display

13. DailyMed. (2026). Zepbound: Tirzepatide injection, prescribing information. Retrieved July 29, 2026, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b

14. Garvey, W. T., Ryan, D. H., Henry, R., Bohannon, N. J. V., Toplak, H., Schwiers, M., Troupin, B., & Day, W. W. (2014). Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care, 37(4), 912-921. https://doi.org/10.2337/dc13-1518. PMID: 24103901.

15. Goldberg, R. B., Orchard, T. J., Crandall, J. P., Boyko, E. J., Budoff, M., Dabelea, D., et al. (2022). Effects of long-term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Circulation, 145(22), 1632-1641. https://doi.org/10.1161/CIRCULATIONAHA.121.056756. PMID: 35603600.

16. Grunvald, E., Shah, R., Hernaez, R., Chandar, A. K., Pickett-Blakely, O., Teigen, L. M., Harindhanavudhi, T., Sultan, S., Singh, S., & Davitkov, P. (2022). AGA clinical practice guideline on pharmacological interventions for adults with obesity. Gastroenterology, 163(5), 1198-1225. https://doi.org/10.1053/j.gastro.2022.08.045. PMID: 36273831.

17. Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. The New England Journal of Medicine, 387(3), 205-216. https://doi.org/10.1056/NEJMoa2206038. PMID: 35658024.

18. Jastreboff, A. M., et al. (2025). Tirzepatide for obesity treatment and diabetes prevention. The New England Journal of Medicine, 392(10), 958-971. https://doi.org/10.1056/NEJMoa2410819. PMID: 39536238.

19. Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., Nathan, D. M., & Diabetes Prevention Program Research Group. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine, 346(6), 393-403. https://doi.org/10.1056/NEJMoa012512. PMID: 11832527.

20. Knowler, W. C., Doherty, L., Edelstein, S. L., et al. (2025). Long-term effects and effect heterogeneity of lifestyle and metformin interventions on type 2 diabetes incidence over 21 years in the U.S. Diabetes Prevention Program randomized clinical trial. The Lancet Diabetes & Endocrinology, 13(6), 469-481. https://doi.org/10.1016/S2213-8587(25)00022-1. PMID: 40311647.

21. Le Roux, C. W., Astrup, A., Fujioka, K., Greenway, F., Lau, D. C. W., Van Gaal, L., Ortiz, R. V., Wilding, J. P. H., Skjøth, T. V., Manning, L. S., Pi-Sunyer, X., & SCALE Obesity Prediabetes NN8022-1839 Study Group. (2017). Three years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes. The Lancet, 389(10077), 1399-1409. https://doi.org/10.1016/S0140-6736(17)30069-7. PMID: 28237263.

22. Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., Hardt-Lindberg, S., Hovingh, G. K., Kahn, S. E., Kushner, R. F., Lingvay, I., Plutzky, J., Ryan, D. H., Semple, R. K., & SELECT Trial Investigators. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. The New England Journal of Medicine, 389(24), 2221-2232. https://doi.org/10.1056/NEJMoa2307563. PMID: 37952131.

23. Nathan, D. M., Barrett-Connor, E., Crandall, J. P., Edelstein, S. L., Goldberg, R. B., Horton, E. S., Knowler, W. C., Mather, K. J., Orchard, T. J., Pi-Sunyer, X., Temprosa, M., & Diabetes Prevention Program Research Group. (2015). Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up. The Lancet Diabetes & Endocrinology, 3(11), 866-875. https://doi.org/10.1016/S2213-8587(15)00291-0. PMID: 26377054.

24. Perreault, L., Davies, M., Frias, J. P., Laursen, P. N., Lingvay, I., Machineni, S., Varbo, A., Wilding, J. P. H., Wallenstein, S. O. R., & Le Roux, C. W. (2022). Changes in glucose metabolism and glycemic status with once-weekly subcutaneous semaglutide 2.4 mg among participants with prediabetes in the STEP program. Diabetes Care, 45(10), 2396-2405. https://doi.org/10.2337/dc21-1785. PMID: 35724304.

25. Salive, M. E., Tjaden, A. H., Ames, J. R., Crandall, J. P., Dabelea, D., Hazuda, H. P., Heckman-Stoddard, B. M., Huckfeldt, P. J., Kuo, S., Strotmeyer, E. S., Temprosa, M., Venditti, E. M., & DPP Research Group. (2026). Lifestyle and metformin interventions and risk of multimorbidity in adults with prediabetes. JAMA. Advance online publication. https://doi.org/10.1001/jama.2026.8492. PMID: 42295772.

26. Torgerson, J. S., Hauptman, J., Boldrin, M. N., & Sjöström, L. (2004). XENical in the prevention of diabetes in obese subjects study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care, 27(1), 155-161. https://doi.org/10.2337/diacare.27.1.155. PMID: 14693982.

27. U.S. Food and Drug Administration. (2024). FDA approves first treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight. Retrieved July 29, 2026, from https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or

28. U.S. Preventive Services Task Force. (2021). Screening for prediabetes and type 2 diabetes: U.S. Preventive Services Task Force recommendation statement. JAMA, 326(8), 736-743. https://doi.org/10.1001/jama.2021.12531. PMID: 34427594.

29. Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., Kushner, R. F., & STEP 1 Study Group. (2021). Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine, 384(11), 989-1002. https://doi.org/10.1056/NEJMoa2032183. PMID: 33567185.

30. Wilding, J. P. H., Batterham, R. L., Davies, M., Van Gaal, L. F., Kandler, K., Konakli, K., Lingvay, I., McGowan, B. M., Oral, T. K., Rosenstock, J., Wadden, T. A., & STEP 1 Study Group. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obesity and Metabolism, 24(8), 1553-1564. https://doi.org/10.1111/dom.14725. PMID: 35441470.