Prevention of Type 2 Diabetes in Adults With Prediabetes, Impaired Glucose Tolerance, Prior Gestational Diabetes, and High-Risk Phenotypes: A Narrative Review
By Ori Scott, M.Sc. Nutrition
Registered Dietitian (Israel)
Founder, Healthy Habits Coaching
Abstract
Background
Type 2 diabetes mellitus (T2D) is commonly preceded by a variable period of dysglycemia characterized by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), elevated glycated hemoglobin (HbA1c), or combinations of these abnormalities. A history of gestational diabetes mellitus (GDM), obesity, family history, selected cardiometabolic disorders, and other clinical factors further increase risk. The transition from normoglycemia to diabetes is not uniform, and contemporary prevention strategies increasingly emphasize individualized risk assessment.
Objective
To review evidence published from 2021 through September 10, 2026 concerning prevention or delay of T2D in adults with prediabetes, IGT, IFG, previous GDM, and other high-risk phenotypes, with particular attention to medical nutrition therapy (MNT), physical activity, behavioral and psychological support, metformin, obesity pharmacotherapy, and structured diabetes-prevention programs.
Methods
A structured narrative search was developed using PubMed/MEDLINE and Medical Subject Headings (MeSH). Priority was given to professional clinical guidelines, randomized controlled trials, systematic reviews, meta-analyses, and major long-term prevention analyses published during the prespecified five-year period. Current recommendations from the American Diabetes Association (ADA), joint ADA/European Association for the Study of Diabetes (EASD) consensus guidance, and relevant European Society of Cardiology (ESC) guidance were reviewed. Studies were not pooled de novo; therefore, this manuscript is presented as a narrative rather than systematic review.
Results
Current evidence supports structured lifestyle intervention as the foundation of T2D prevention. ADA guidance recommends evidence-based diabetes-prevention programs for adults with overweight or obesity at high risk, with goals of at least 5–7% reduction in initial body weight and at least 150 minutes per week of moderate-intensity physical activity. MNT delivered by a registered dietitian nutritionist improves glycemic, anthropometric, blood pressure, and lipid outcomes. Exercise interventions, including resistance and interval training, improve glucose regulation, although comparative certainty among exercise modalities remains limited. Metformin has the most established pharmacologic prevention evidence and is especially relevant in adults at higher risk, including those aged 25–59 years, those with BMI ≥35 kg/m², fasting plasma glucose ≥110 mg/dL (≥6.1 mmol/L), HbA1c ≥6.0% (≥42 mmol/mol), or previous GDM. Newer obesity medications, particularly semaglutide and tirzepatide, substantially reduce body weight and progression from prediabetes to diabetes in individuals with obesity; however, their strongest current indication is treatment of obesity rather than universal pharmacologic treatment of prediabetes. Women with previous GDM warrant postpartum glucose testing, lifelong surveillance, intensive lifestyle intervention, and selective consideration of metformin.
Conclusions
T2D prevention is most appropriately approached as risk-stratified cardiometabolic care rather than as a uniform response to a single abnormal laboratory result. Lifestyle intervention remains foundational; MNT, structured exercise, behavioral care, treatment of obesity, and metformin should be selected according to individual risk, comorbidities, reproductive history, safety, treatment burden, cost, access, and patient preference.
Keywords: prediabetes; impaired glucose tolerance; impaired fasting glucose; diabetes prevention; gestational diabetes; metformin; medical nutrition therapy; exercise; obesity; behavioral intervention; semaglutide; tirzepatide.
1. Introduction
Prediabetes describes glycemic values above the normal range but below diagnostic thresholds for diabetes. It encompasses several related but physiologically distinct phenotypes, particularly IFG, IGT, and HbA1c-defined dysglycemia. These categories overlap incompletely. Consequently, people grouped under the term “prediabetes” may differ considerably in insulin resistance, β-cell reserve, adiposity, hepatic glucose production, postprandial glucose handling, and future diabetes risk.
The ADA defines prediabetes in nonpregnant adults as fasting plasma glucose of 100–125 mg/dL (5.6–6.9 mmol/L), 2-hour plasma glucose following a 75-g oral glucose tolerance test (OGTT) of 140–199 mg/dL (7.8–11.0 mmol/L), or HbA1c of 5.7–6.4% (39–47 mmol/mol). Diagnostic thresholds for diabetes are fasting plasma glucose ≥126 mg/dL (≥7.0 mmol/L), 2-hour OGTT glucose ≥200 mg/dL (≥11.1 mmol/L), or HbA1c ≥6.5% (≥48 mmol/mol), with confirmatory testing generally required when unequivocal hyperglycemia is absent.
The clinical relevance of prediabetes extends beyond future glycemic progression. People with dysglycemia frequently have coexisting obesity, hypertension, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, sleep disorders, or elevated cardiovascular risk. Prevention should therefore address the broader cardiometabolic phenotype rather than glucose values alone.
Risk is particularly pronounced after GDM. Postpartum dysglycemia may persist immediately after pregnancy or develop years later, and prior GDM remains an important marker of future T2D susceptibility. Women with previous GDM therefore represent a distinct prevention population rather than a subgroup that should simply be merged with general prediabetes cohorts.
2. Methods
2.1 Review design
This manuscript was designed as a narrative review informed by a structured and reproducible PubMed/MEDLINE search. It was not designed as a formal systematic review because duplicate independent screening, prospective protocol registration, formal risk-of-bias adjudication across all included publications, and PRISMA flow documentation were not undertaken.
The principal evidence window was January 1, 2021 through September 10, 2026. Earlier landmark trials were considered only when summarized in recent guidelines or contemporary long-term analyses and are treated as historical foundations rather than as primary evidence within the review period.
2.2 Information sources
The principal sources were:
PubMed/MEDLINE.
National Library of Medicine MeSH vocabulary.
ADA Standards of Care in Diabetes.
ADA/EASD consensus guidance.
EASD professional guidance and statements.
Relevant ESC diabetes and cardiovascular guidance.
Major peer-reviewed randomized trials, systematic reviews, and meta-analyses indexed in PubMed.
Commercial websites, non-peer-reviewed health blogs, manufacturer promotional material, and unsourced secondary summaries were excluded as evidentiary sources.
2.3 Reproducible PubMed/MeSH strategy
Search A: Prediabetes and T2D prevention
(
"Prediabetic State"[Mesh]
OR "Glucose Intolerance"[Mesh]
OR prediabet*[Title/Abstract]
OR "impaired fasting glucose"[Title/Abstract]
OR "impaired glucose tolerance"[Title/Abstract]
)
AND
(
"Diabetes Mellitus, Type 2/prevention and control"[Mesh]
OR "type 2 diabetes prevention"[Title/Abstract]
OR "diabetes prevention"[Title/Abstract]
)
AND
(
"Life Style"[Mesh]
OR "Nutrition Therapy"[Mesh]
OR "Diet Therapy"[Mesh]
OR "Exercise"[Mesh]
OR "Behavior Therapy"[Mesh]
OR "Metformin"[Mesh]
OR "Hypoglycemic Agents"[Mesh]
OR "Glucagon-Like Peptide-1 Receptor Agonists"[Mesh]
OR lifestyle[Title/Abstract]
OR metformin[Title/Abstract]
OR semaglutide[Title/Abstract]
OR tirzepatide[Title/Abstract]
)
AND
("2021/01/01"[Date - Publication] : "2026/09/10"[Date - Publication])
AND Humans[Mesh]
Search B: Previous GDM and subsequent T2D prevention
(
"Diabetes, Gestational"[Mesh]
OR "gestational diabetes"[Title/Abstract]
)
AND
(
postpartum[Title/Abstract]
OR "Postpartum Period"[Mesh]
)
AND
(
"Diabetes Mellitus, Type 2/prevention and control"[Mesh]
OR "type 2 diabetes"[Title/Abstract]
)
AND
(
"Life Style"[Mesh]
OR "Exercise"[Mesh]
OR "Nutrition Therapy"[Mesh]
OR "Metformin"[Mesh]
OR prevention[Title/Abstract]
)
AND
("2021/01/01"[Date - Publication] : "2026/09/10"[Date - Publication])
AND Humans[Mesh]
Search C: Exercise in prediabetes
(
"Prediabetic State"[Mesh]
OR prediabet*[Title/Abstract]
OR "impaired glucose tolerance"[Title/Abstract]
)
AND
(
"Exercise"[Mesh]
OR "Exercise Therapy"[Mesh]
OR aerobic[Title/Abstract]
OR resistance[Title/Abstract]
OR interval[Title/Abstract]
)
AND
(
randomized controlled trial[Publication Type]
OR meta-analysis[Publication Type]
OR systematic review[Publication Type]
)
AND
("2021/01/01"[Date - Publication] : "2026/09/10"[Date - Publication])
Search D: MNT and dietary intervention
(
"Prediabetic State"[Mesh]
OR prediabet*[Title/Abstract]
)
AND
(
"Nutrition Therapy"[Mesh]
OR "Diet Therapy"[Mesh]
OR "Medical Nutrition Therapy"[Title/Abstract]
OR dietitian[Title/Abstract]
OR "registered dietitian"[Title/Abstract]
)
AND
(
glycemic[Title/Abstract]
OR glucose[Title/Abstract]
OR "type 2 diabetes"[Title/Abstract]
)
AND
("2021/01/01"[Date - Publication] : "2026/09/10"[Date - Publication])
Search E: Behavioral and psychological support
(
"Prediabetic State"[Mesh]
OR prediabet*[Title/Abstract]
OR "Diabetes, Gestational"[Mesh]
)
AND
(
"Behavior Therapy"[Mesh]
OR "Motivational Interviewing"[Mesh]
OR "Psychotherapy"[Mesh]
OR "Social Support"[Mesh]
OR "Sleep"[Mesh]
OR depression[Title/Abstract]
OR anxiety[Title/Abstract]
OR behavioral[Title/Abstract]
OR psychological[Title/Abstract]
)
AND
(
prevention[Title/Abstract]
OR adherence[Title/Abstract]
OR lifestyle[Title/Abstract]
)
AND
("2021/01/01"[Date - Publication] : "2026/09/10"[Date - Publication])
2.4 Evidence hierarchy
Preference was given to, in descending order:
current evidence-based clinical practice guidelines;
randomized controlled trials;
systematic reviews and meta-analyses of randomized trials;
major prospective cohort analyses;
high-quality narrative or clinical reviews when needed to contextualize heterogeneous evidence.
A trial demonstrating normalization of HbA1c or fasting glucose was not considered equivalent to a trial demonstrating prevention of incident T2D unless diabetes incidence was directly assessed.
3. Defining the Population at Risk
3.1 Glycemic categories
Prediabetes should not be conceptualized as a binary state. Risk rises along a continuum, and combinations of abnormalities carry more prognostic information than a single borderline result.
Important glycemic phenotypes include:
fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L);
2-hour OGTT glucose 140–199 mg/dL (7.8–11.0 mmol/L);
HbA1c 5.7–6.4% (39–47 mmol/mol);
combined IFG and IGT;
persistent worsening of glycemic markers over time.
ADA guidance emphasizes individualized assessment because age, BMI, glycemic severity, and comorbidities influence progression risk.
3.2 Clinical risk factors
Risk increases further in people with:
first-degree family history of T2D;
previous GDM;
overweight or obesity;
polycystic ovary syndrome;
hypertension;
dyslipidemia;
cardiovascular disease;
low physical activity;
conditions associated with insulin resistance;
progressive rise in fasting glucose or HbA1c.
The rationale for intervention is strongest when multiple high-risk features coexist rather than when a single minimally abnormal biomarker is present.
4. Structured Lifestyle Intervention
Lifestyle intervention remains the central intervention supported across contemporary guidance.
ADA 2026 recommends referral of adults with overweight or obesity at high risk of T2D to an evidence-based prevention program targeting at least 5–7% loss of initial body weight and at least 150 minutes per week of moderate-intensity physical activity.
A 2026 systematic review of diabetes-prevention programs delivered in primary care included 14 studies. The pooled relative risk for diabetes incidence was 0.82, although the 95% confidence interval crossed unity at 0.65–1.02, and certainty for several outcomes was low to moderate. This finding is important because efficacy demonstrated in intensive research settings may be attenuated when translated into routine primary care.
Prevention programs should therefore be assessed not only by theoretical efficacy but also by uptake, retention, feasibility, access, and sustained engagement.
5. Medical Nutrition Therapy
ADA 2026 recommends individualized MNT for people with prediabetes or diabetes and specifically supports referral to a registered dietitian nutritionist with diabetes expertise.
A 2023 systematic review and meta-analysis evaluated 13 randomized trials of dietitian-delivered MNT in adults with prediabetes. Intervention duration ranged from 3 to 24 months. Compared with standard care, MNT reduced HbA1c by a mean of 0.30 percentage points and fasting glucose by 4.97 mg/dL (0.28 mmol/L). Significant improvements were also observed in body weight, BMI, waist circumference, total cholesterol, HDL cholesterol, LDL cholesterol, systolic blood pressure, and diastolic blood pressure. The incidence of T2D itself was not significantly reduced in the pooled analysis, and the certainty of evidence was moderate for fasting glucose and low for HbA1c and diabetes incidence.
This distinction is clinically relevant. MNT has demonstrable cardiometabolic value even where direct evidence for prevention of a diabetes diagnosis is less certain.
5.1 Dietary composition
Current ADA recommendations emphasize individualized eating patterns rather than one mandatory macronutrient distribution. Dietary planning should consider:
total energy intake;
metabolic goals;
cultural and religious food preferences;
food access and cost;
kidney disease;
lipid abnormalities;
gastrointestinal disorders;
eating behavior and disordered eating risk;
long-term sustainability.
ADA 2026 recommends emphasizing nonstarchy vegetables, whole fruits, legumes, lean proteins, whole grains, nuts, seeds, and suitable dairy or nondairy alternatives while minimizing sugar-sweetened beverages, sweets, refined grains, processed foods, and ultraprocessed foods.
A 2024 systematic review of personalized or precision nutrition identified seven randomized trials involving 873 adults with prediabetes or metabolic syndrome. Improvements in HbA1c, postprandial glucose, and waist circumference were reported in several studies, but effects on fasting glucose, insulin resistance, lipids, and blood pressure were inconsistent. The review concluded that the evidence for precision nutrition remains developing and requires larger, more standardized trials.
Accordingly, currently available evidence supports individualized MNT, but does not justify routine use of genetic, microbiome, metabolomic, or other precision-nutrition testing for diabetes prevention.
6. Weight Reduction and Treatment of Obesity
When overweight or obesity is present, weight management becomes a major component of diabetes prevention.
A 5% weight reduction means:
10 lb (4.5 kg) from an initial weight of 200 lb (90.7 kg);
12.5 lb (5.7 kg) from 250 lb (113.4 kg).
A 7% weight reduction means:
14 lb (6.4 kg) from 200 lb (90.7 kg);
17.5 lb (7.9 kg) from 250 lb (113.4 kg).
The objective should be improvement in metabolic health, physical function, and disease risk rather than pursuit of a socially defined body size.
Obesity should be managed as a chronic disease using nutritional therapy, physical activity, behavioral support, and medical treatment when indicated.
7. Physical Activity and Exercise
Exercise improves skeletal-muscle glucose uptake, insulin sensitivity, cardiorespiratory fitness, endothelial function, body composition, and multiple cardiovascular risk factors.
The ADA prevention target remains at least 150 minutes per week of moderate-intensity physical activity.
A 2023 systematic review and meta-analysis of exercise interventions in adults with prediabetes included 20 trials, with 15 contributing to quantitative synthesis. Interval training reduced fasting plasma glucose by approximately 7.25 mg/dL (0.40 mmol/L) compared with control. Resistance training reduced fasting plasma glucose by approximately 6.71 mg/dL (0.37 mmol/L). The authors judged the overall certainty of evidence to be low because of small sample sizes and methodological limitations.
A 2024 network meta-analysis included 24 studies and 1,946 participants. All evaluated exercise approaches were superior to no exercise for at least some glycemic outcomes. Combined moderate-intensity aerobic exercise and low-to-moderate-load resistance training ranked favorably for HbA1c, BMI, body weight, total cholesterol, and LDL cholesterol. Resistance training ranked favorably for fasting glucose, while vigorous-intensity aerobic exercise ranked favorably for 2-hour postprandial glucose.
These analyses do not establish one universally superior prescription. A practical program may include:
moderate-intensity aerobic exercise;
resistance exercise at least several times weekly when medically appropriate;
reduction of prolonged sedentary time;
gradual progression according to baseline fitness and comorbidity.
Exercise prescription should be modified for cardiovascular disease, peripheral neuropathy, severe retinopathy, significant orthopedic disease, pregnancy, postpartum status, or other clinical limitations.
8. Behavioral and Psychological Support
Diabetes prevention is not simply a matter of providing nutritional information. Sustained behavior change depends on self-efficacy, emotional health, environmental support, financial resources, sleep, competing responsibilities, and accessibility of care.
ADA 2026 identifies several evidence-based behavioral strategies, including motivational interviewing, goal setting, action planning, problem solving, self-monitoring, feedback, and social support.
The ADA also recommends screening sleep health in people with prediabetes and individuals at risk for diabetes. Sleep disorders may interfere with glucose regulation, weight management, appetite control, and adherence to health behaviors.
Psychological evaluation should be considered where depression, anxiety, chronic stress, disordered eating, trauma, low self-efficacy, or socioeconomic adversity interfere with prevention efforts.
These issues are particularly important after GDM. A 2025 meta-analysis including 29 studies and 2,442,001 participants found an association between GDM and subsequent postpartum depression, with a pooled relative risk of 1.42. The association does not establish causality, but it strengthens the rationale for psychosocial surveillance in this population.
Behavioral support should therefore be considered a core clinical intervention rather than an optional adjunct for patients perceived as “nonadherent.”
9. Metformin
Metformin remains the medication with the most established evidence base for pharmacologic diabetes prevention.
ADA 2026 recommends considering metformin for adults at high risk of T2D, particularly those aged 25–59 years and those with:
BMI ≥35 kg/m²;
fasting plasma glucose ≥110 mg/dL (≥6.1 mmol/L);
HbA1c ≥6.0% (≥42 mmol/mol);
previous GDM.
A 2024 meta-analysis of 12 randomized trials involving 2,720 participants with prediabetes compared metformin plus lifestyle intervention with lifestyle intervention alone. Addition of metformin was associated with lower T2D incidence, with a relative risk of 0.85 (95% CI 0.75–0.97), and modestly improved HbA1c. Fasting glucose differences were not evident at all follow-up intervals but favored metformin at 12 months.
A separate 2023 meta-analysis directly comparing metformin and lifestyle intervention did not demonstrate a statistically significant difference in incident diabetes between the two strategies, emphasizing that contemporary prevention should not treat medication as a substitute for lifestyle intervention.
9.1 Interpretation
Metformin should not automatically be initiated after a single minimally elevated HbA1c or fasting glucose result. The strength of the indication increases as absolute diabetes risk increases.
A 2026 U.S. modeling analysis using NHANES data estimated a mean 3-year diabetes risk of 18.4% under standard lifestyle recommendations, 14.4% with metformin, and 8.0% with intensive lifestyle intervention. The individualized optimal strategy was intensive lifestyle intervention for 91% of participants in that analytic sample. These estimates were model-based rather than results of a new randomized clinical trial, but they support risk-stratified rather than universal pharmacotherapy.
9.2 Safety
Relevant issues include:
gastrointestinal intolerance;
vitamin B12 deficiency with prolonged use;
kidney function;
treatment burden;
adherence.
Recent evidence continues to support periodic assessment of vitamin B12 in long-term metformin users when clinically indicated.
10. GLP-1 Receptor Agonists and Tirzepatide
A major development in the past five years has been demonstration that effective treatment of obesity can substantially alter progression from prediabetes to T2D.
The critical distinction is between:
treatment of prediabetes itself; and
treatment of obesity in a person who also has prediabetes.
These are not equivalent indications.
10.1 Semaglutide
STEP 10 was a randomized, double-blind trial of semaglutide 2.4 mg weekly in adults with obesity and prediabetes. Participants had BMI ≥30 kg/m² and prediabetes defined according to study criteria. At 52 weeks, mean body-weight change was −13.9% with semaglutide versus −2.7% with placebo. Normoglycemia was achieved in 81% of evaluable participants receiving semaglutide versus 14% receiving placebo. Adverse events leading to discontinuation occurred in 6% and 1%, respectively.
The study provides strong evidence that semaglutide improves weight and glycemic status in people with obesity and prediabetes. It does not establish that semaglutide should be prescribed to every individual with mild prediabetes.
10.2 Tirzepatide
The three-year SURMOUNT-1 analysis included 1,032 participants with obesity and prediabetes. At 176 weeks, mean body-weight change was:
−12.3% with tirzepatide 5 mg;
−18.7% with 10 mg;
−19.7% with 15 mg;
−1.3% with placebo.
Incident T2D occurred in 1.3% of tirzepatide-treated participants versus 13.3% receiving placebo, corresponding to a hazard ratio of 0.07. Seventeen weeks after treatment withdrawal, diabetes had occurred in 2.4% versus 13.7%, respectively. Gastrointestinal adverse events were the most common treatment-related events.
This is among the strongest recent pharmacologic data demonstrating delayed diabetes development in people with obesity and prediabetes.
However, the appropriate interpretation is that effective treatment of obesity substantially modifies diabetes risk. These data should not be generalized to normal-weight individuals with isolated borderline glucose elevation.
11. Previous Gestational Diabetes Mellitus
Women with previous GDM represent a clinically distinct high-risk population.
Postpartum prevention should include:
appropriate postpartum glucose testing;
ongoing diabetes surveillance;
nutritional intervention;
physical activity;
weight management when indicated;
behavioral and psychological support;
consideration of metformin in women with persistent prediabetes and high risk.
11.1 Lifestyle intervention after GDM
A 2024 systematic review and meta-analysis of 17 randomized trials found that postpartum lifestyle intervention after GDM was associated with a nonsignificant 11% reduction in T2D risk overall, with a relative risk of 0.89 (95% CI 0.74–1.07). Lifestyle intervention significantly reduced body weight by approximately 2.9 lb (1.33 kg), BMI by 0.53 kg/m², and waist circumference by approximately 0.54 in (1.38 cm), although significant effects on fasting glucose, 2-hour glucose, and HbA1c were not demonstrated.
This result illustrates an important difference between high-risk postpartum populations and highly controlled prevention trials: childcare, sleep deprivation, lactation, employment, subsequent pregnancy, depression, and access to care may substantially affect adherence and effectiveness.
11.2 Metformin after GDM
Previous GDM is one of the specific high-risk characteristics for which ADA recommends considering metformin when prediabetes is present.
A 2026 randomized trial in 376 women with previous GDM and prediabetes compared lifestyle intervention plus intermittent versus continuous metformin treatment over three years. T2D developed in 11.5% of the intermittent-treatment group and 11.1% of the continuous-treatment group. Intermittent treatment met the study's prespecified noninferiority margin; vitamin B12 deficiency occurred more frequently with continuous treatment, 13.5% versus 3.7%. The authors emphasized that equivalence requires confirmation using a narrower noninferiority margin and more outcome events.
This study is clinically relevant but should not be interpreted as evidence that intermittent metformin has become a universal postpartum standard.
12. Prevention of GDM During Pregnancy Versus Prevention of T2D After GDM
These two questions should be clearly separated.
Preventing GDM in a currently pregnant high-risk woman is not the same as preventing future T2D in a woman who previously had GDM.
A 2024 meta-analysis evaluating prophylactic metformin in high-risk pregnancy included 20 studies involving 3,911 women and reported lower GDM incidence with metformin, pooled RR 0.59. Subgroup findings varied considerably.
A separate large systematic review of 116 studies involving 40,940 participants found reductions in GDM incidence with several dietary, physical activity, combined lifestyle, and pharmacologic approaches. Group-based and health-care-facility-based physical activity programs showed favorable effects in subgroup analyses.
These data remain heterogeneous, and preventive metformin in pregnancy should not be described as universally established standard treatment for all women at elevated GDM risk.
13. European Guidance
European guidance requires careful interpretation.
The 2022 ADA/EASD consensus report provides extensive recommendations concerning person-centered T2D management, lifestyle, weight reduction, cardiovascular risk, and pharmacotherapy, but its principal scope is management of established T2D rather than treatment of prediabetes.
Similarly, the 2023 ESC guideline on cardiovascular disease in diabetes explicitly changed scope relative to the prior 2019 document. The ESC states that because of insufficient clear evidence, the 2023 guideline focuses on cardiovascular disease and established diabetes and leaves prediabetes outside its principal scope.
Consequently, it would be academically inaccurate to imply that there is a recent European guideline containing a detailed drug algorithm for prediabetes equivalent to the ADA prevention section.
The more defensible interpretation is:
ADA currently provides the most explicit contemporary U.S. pharmacoprevention guidance;
EASD-related consensus documents support intensive lifestyle and weight-centered metabolic care but primarily address established T2D;
European cardiovascular guidance emphasizes risk-factor management but does not provide a detailed 2023 prediabetes pharmacotherapy pathway.
14. Summary of Contemporary Evidence
Intervention | Population | Evidence identified, 2021–2026 | Principal outcome | Interpretation |
Dietitian-delivered MNT | Adults with prediabetes | 2023 systematic review; 13 RCTs | HbA1c −0.30%; fasting glucose −4.97 mg/dL (−0.28 mmol/L) | Improves glycemia and cardiometabolic risk; direct diabetes-incidence evidence less certain |
Exercise | Adults with prediabetes | 2023 meta-analysis; 20 trials | Interval training FPG approximately −7.25 mg/dL (−0.40 mmol/L); resistance training approximately −6.71 mg/dL (−0.37 mmol/L) | Beneficial, but comparative certainty among modalities is low |
Combined aerobic/resistance exercise | Adults with prediabetes | 2024 network meta-analysis; 24 studies, n=1,946 | Favorable ranking for several glycemic and cardiometabolic measures | Reasonable combined approach; ranking is not equivalent to definitive superiority |
Metformin + lifestyle | Prediabetes | 2024 meta-analysis; 12 RCTs, n=2,720 | RR for T2D 0.85 | Modest additional prevention benefit beyond lifestyle |
Semaglutide 2.4 mg | Obesity + prediabetes | STEP 10, 2024 | Weight −13.9%; normoglycemia 81% vs 14% | Strong obesity-treatment effect with substantial glycemic improvement |
Tirzepatide | Obesity + prediabetes | SURMOUNT-1, 2025 | T2D 1.3% vs 13.3% at 176 weeks | Very large reduction in diabetes progression during treatment |
Postpartum lifestyle | Previous GDM | 2024 meta-analysis; 17 RCTs | RR 0.89, 95% CI 0.74–1.07 | Improves anthropometric outcomes; pooled diabetes reduction not statistically significant |
Intermittent vs continuous metformin | Previous GDM + postpartum prediabetes | 2026 RCT, n=376 | T2D 11.5% vs 11.1% | Noninferior within the trial's prespecified margin; requires confirmation |
Primary-care prevention programs | Prediabetes/high-risk adults | 2026 meta-analysis; 14 studies | RR 0.82, 95% CI 0.65–1.02 | Real-world effectiveness may be smaller than efficacy in intensive research programs |
Evidence:
15. Risk-Stratified Prevention Framework
A useful clinical framework is to stratify rather than treat all prediabetes identically.
Lower-risk dysglycemia
Examples include:
isolated HbA1c near 5.7% (39 mmol/mol);
no progressive glycemic deterioration;
no previous GDM;
absence of obesity or major cardiometabolic risk factors.
Preferred approach:
confirm abnormality where clinically appropriate;
individualized MNT;
physical activity;
smoking avoidance;
sleep assessment;
periodic glycemic monitoring.
Medication is not automatically required.
Higher-risk prediabetes
Features may include:
fasting glucose ≥110 mg/dL (≥6.1 mmol/L);
HbA1c ≥6.0% (≥42 mmol/mol);
IGT;
combined IFG and IGT;
BMI ≥35 kg/m²;
previous GDM;
worsening glucose trajectory;
multiple cardiometabolic risk factors.
Preferred approach:
structured diabetes-prevention program;
MNT;
≥150 minutes/week moderate physical activity;
resistance training where appropriate;
active treatment of obesity;
behavioral support;
consideration of metformin.
Obesity plus prediabetes
Where obesity itself meets criteria for medical treatment, anti-obesity pharmacotherapy can be considered according to current obesity-treatment indications. Semaglutide and tirzepatide have demonstrated substantial effects on weight and glycemic progression, but should not be described as mandatory treatment for prediabetes itself.
16. Monitoring
Monitoring should extend beyond HbA1c.
Reasonable outcome measures include:
fasting plasma glucose, mg/dL followed by mmol/L;
HbA1c, % followed by mmol/mol;
2-hour OGTT glucose when indicated;
body weight, lb followed by kg;
waist circumference, inches followed by cm;
blood pressure, mmHg;
lipid profile, mg/dL followed by mmol/L where reported;
physical activity;
dietary intake;
sleep;
psychological well-being;
medication tolerance and adherence;
quality of life.
In patients receiving metformin long term, vitamin B12 status should be considered when anemia, neuropathy, prolonged exposure, or other risk factors are present.
17. Areas of Uncertainty
Several important gaps remain.
First, “reversion to normoglycemia” is not synonymous with permanent prevention of T2D.
Second, many anti-obesity drug studies demonstrate benefit while treatment is maintained. Long-term durability after withdrawal is incompletely defined.
Third, IGT, IFG, and HbA1c-defined prediabetes are frequently pooled despite physiological differences.
Fourth, lifestyle efficacy demonstrated in specialist trials is not always reproduced in primary care. The 2026 primary-care meta-analysis found no statistically significant reduction in diabetes incidence in the pooled estimate.
Fifth, postpartum intervention remains especially difficult because of competing caregiving, sleep, lactation, socioeconomic, and mental-health demands.
Sixth, evidence for microbiome-guided nutritional or pharmacologic prevention remains insufficient for routine clinical use.
Seventh, reduction of glucose concentrations or conversion to normoglycemia should not automatically be interpreted as evidence of reduced cardiovascular events, microvascular disease, or mortality unless those outcomes were directly measured.
18. Discussion
The last five years have not displaced lifestyle intervention from the center of diabetes prevention. Instead, they have clarified that prevention should be individualized according to metabolic risk and underlying disease.
MNT is clinically effective and improves multiple cardiometabolic outcomes. Exercise produces measurable improvement in glucose regulation, although evidence does not establish one universally superior modality. Behavioral support is necessary because maintenance of dietary and activity changes depends on psychological, social, and environmental conditions.
Metformin continues to occupy a unique position because it has extensive prevention experience, low cost, long-term familiarity, and current guideline support for selected high-risk patients. Recent meta-analysis confirms a modest additional reduction in T2D incidence when metformin is added to lifestyle intervention.
At the same time, contemporary obesity pharmacotherapy has altered the prevention landscape. The magnitude of diabetes-risk reduction observed with tirzepatide in people with obesity and prediabetes is substantially larger than effects generally reported with metformin. However, comparing those findings without considering population differences would be misleading. Tirzepatide and semaglutide trials enrolled people with obesity and treated obesity intensively. The results therefore support management of obesity as a major diabetes-prevention strategy rather than universal replacement of metformin in all prediabetes.
GDM represents another situation in which absolute risk is sufficiently high to justify more active prevention. Nevertheless, postpartum treatment should be individualized. The emerging 2026 evidence concerning intermittent metformin is promising but not yet sufficient to redefine standard practice.
The principal implication is that prevention should be escalated according to risk. A person with one borderline HbA1c measurement should not receive the same intervention as a person with combined IGT, severe obesity, previous GDM, and progressive fasting hyperglycemia.
19. Conclusions
The evidence published from 2021 through September 2026 supports a multidimensional strategy for prevention or delay of T2D.
Structured lifestyle intervention remains the foundation of care. Evidence-based programs should incorporate individualized MNT, regular physical activity, reduction of sedentary behavior, and behavioral strategies that improve adherence and long-term maintenance.
Metformin remains the most established pharmacologic preventive option and is most strongly supported for high-risk adults, particularly younger adults with substantial obesity, higher fasting glucose or HbA1c, and women with previous GDM.
Semaglutide and tirzepatide substantially alter glycemic progression in people with obesity and prediabetes, with the three-year tirzepatide data demonstrating a marked reduction in incident diabetes. These findings support early and effective treatment of obesity as a component of diabetes prevention but do not justify indiscriminate use of incretin-based therapy for all people with prediabetes.
Post-GDM prevention requires special attention. Lifestyle intervention, surveillance, psychological support, and selective use of metformin should be integrated into longitudinal care rather than restricted to the immediate postpartum period.
Current evidence therefore favors risk-stratified prevention rather than uniform pharmacologic treatment of prediabetes.
20. Obesity-Specific Guidance
Obesity should be recognized as a chronic disease requiring long-term management.
For individuals with obesity and dysglycemia:
nutrition therapy should be individualized;
physical activity should be prescribed according to functional capacity;
behavioral and psychological factors should be actively addressed;
anti-obesity pharmacotherapy should be considered when clinically indicated;
treatment goals should include glycemic status, cardiometabolic risk, physical function, quality of life, and treatment sustainability rather than weight alone.
Stigmatizing or moralizing descriptions of body size, eating behavior, or medication use are inappropriate.
21. Bibliography
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McGowan BM, Bruun JM, Capehorn M, et al. Efficacy and safety of once-weekly semaglutide 2.4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial. Lancet Diabetes Endocrinol. 2024;12(9):631-642. doi:10.1016/S2213-8587(24)00182-7. PMID: 39089293.
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Yu H, Sun J, Hu H. Prophylactic administration of metformin reduces gestational diabetes mellitus incidence in the high-risk populations: a meta-analysis. Ir J Med Sci. 2024;193(1):199-209. doi:10.1007/s11845-023-03380-z. PMID: 37248332.
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