Recommendation

a- Refer adults with overweight/obesity at high risk of type 2 diabetes, to an intensive lifestyle behavior change program for a weight reduction of at least 7% of initial body weight through a healthy reduced-calorie diet and 150 min/week of moderate intensity physical activity. (Strong recommendation, high certainty evidence)

Summary of evidence

Several major randomized controlled trials, including the Diabetes Prevention Program (DPP) trial[i] , the Finnish Diabetes Prevention Study (DPS) [ii] , and the Da Qing Diabetes Prevention Study (Da Qing study) [iii] , demonstrate that lifestyle/ behavioral intervention with an individualized reduced-calorie meal plan is highly effective in preventing or delaying type 2 diabetes and improving other cardio-metabolic markers (such as blood pressure, lipids, and inflammation) [iv] .

The strongest evidence for diabetes prevention in the U.S. comes from the DPP trial1. The DPP demonstrated that intensive lifestyle intervention could reduce the risk of incident type 2 diabetes by 58% over 3 years. Follow-up of three large studies of lifestyle intervention for diabetes prevention showed a sustained reduction in the risk of progression to type 2 diabetes: 39% reduction at 30 years in the Da Qing study[v] , 43% reduction at 7 years in the Finnish DPS 2, and 34% reduction at 10 years[vi] and 27% reduction at 15 years [vii] in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS).

The two major goals of the DPP intensive lifestyle intervention were to achieve and maintain a minimum of 7% weight loss and 150 min moderate-intensity physical activity per week, such as brisk walking.

The DPP lifestyle intervention was a goal-based intervention. All participants were given the same weight loss and physical activity goals, but individualization was permitted in the specific methods used to achieve the goals[viii] . Although weight loss was the most important factor in reducing the risk of incident diabetes, it was also found that achieving the target behavioral goal of at least 150 min of physical activity per week, even without achieving the weight loss goal, reduced the incidence of type 2 diabetes by 44% [ix] .

Rationale for the recommendation

The 7% weight loss goal was selected because it was feasible to achieve and maintain and likely to lessen the risk of developing diabetes. Participants were encouraged to achieve ≥7% weight loss during the first 6 months of the intervention. Further analysis suggests maximal prevention of diabetes with at least 7–10% weight loss9.

The goal for physical activity was selected to approximate at least 700 kcal/ week expenditure from physical activity. For ease of translation, this goal was described as at least 150 mins of moderate intensity physical activity per week, similar in intensity to brisk walking. Participants were encouraged to distribute their activity throughout the week with a minimum frequency of three times per week and at least 10 min per session. A maximum of 75 min of strength training could be applied toward the total 150 min/week physical activity goal8.

Breaking up prolonged sedentary time may also be encouraged, as it is associated with moderately lower postprandial glucose levels[x] ^,[xi]. The preventive effects of physical activity appear to extend to the prevention of gestational diabetes mellitus (GDM) [xii] .

b. Lifestyle modifications: Intensive lifestyle modifications can reduce the incidence of T2DM. Lifestyle modifications include a healthy diet, increased physical activity, and encouraged weight loss for overweight or obese individuals.

c. Body weight management and physical activity Recommendations Refer Individuals with prediabetes to an intensive behavioral lifestyle intervention program with a target to achieve and maintain a 7% loss of their initial body weight. Increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week.

Recommendations

b- A variety of eating patterns can be considered to prevent diabetes in individuals with prediabetes. including Mediterranean diet, low carbohydrate eating plan, low fat, DASH diet (Dietary approaches to stop hypertension ) (Strong recommendation, moderate certainty evidence)

Remarks

Nutrition counseling for weight loss in the DPP lifestyle intervention arm included a reduction of total dietary fat and calories^1,8,9. However, evidence suggests that there are not an ideal percentage of calories from carbohydrates, protein, and fat for all people to prevent diabetes; therefore, macronutrient distribution should be based on an individualized assessment of current eating patterns, preferences, and metabolic goals10. Based on other intervention trials, a variety of eating patterns characterized by the totality of food and beverages habitually consumed[xiii] ^,[xiv] may also be appropriate for individuals with prediabetes13

Summary of evidence

Mediterranean-style and low-carbohydrate eating plans (high in vegetables, fruits, whole grains, beans, nuts and seeds, and olive oil (. [xv] ^{,[xvi],[xvii],[xviii]}. Observational studies have also shown that vegetarian, plant-based (may include some animal products), and Dietary Approaches to Stop Hypertension (DASH) eating patterns are associated with a lower risk of developing type 2 diabetes [xix] ^{, [xx],[xxi],[xxii]}. Evidence suggests that the overall quality of food consumed (as measured by the Healthy Eating Index, Alternative Healthy Eating Index, and DASH score), with an emphasis on whole grains, legumes, nuts, fruits, and vegetables and minimal refined and processed foods, is also associated with a lower risk of type 2 diabetes 21,[xxiii] , [xxiv] , [xxv] . Individualized medical nutrition therapy is effective in lowering A1C in individuals diagnosed with prediabetes [xxvi] .

Recommendation 

c- Pharmacologic Interventions: Prescribe metformin for prevention of T2DM in adult individuals with prediabetes, 25-59 years, those with high BMI ≥35 kg/m2, higher fasting plasma glucose 100 – 125 mg/dL, higher A1C 5.7 – 6.4%, women with prior GDM. (strong recommendation, high certainty  evidence )

Remarks

No pharmacologic agent has been approved by the U.S. Food and Drug Administration for a specific indication of type 2 diabetes prevention. The risk versus benefit of each medication in support of person-centered goals must be weighed in addition to cost, side effects, and efficacy considerations. Metformin has the longest history of safety data as a pharmacologic therapy for diabetes prevention[xxvii] .

Summary of evidence

weight loss through behavior changes in diet and physical activity alone can be difficult to maintain long term6, people at high risk of diabetes may benefit from support and additional pharmacotherapeutics options Metformin was overall less effective than lifestyle modification in the DPP, though group differences declined over time in the DPPOS7, and metformin may be cost-saving over 10 years[xxviii] . In the DPP, metformin was as effective as lifestyle modification in participants with BMI ≥35 kg/m2 and in younger participants aged 25–44 years1. In individuals with a history of GDM in the DPP, metformin and intensive lifestyle modification led to an equivalent 50% reduction in diabetes risk[xxix] . Both interventions remained highly effective during a 10-year follow-up period [xxx] .

By the time of the 15-year follow up (DPPOS), exploratory analyses demonstrated that participants with a higher baseline fasting glucose (≥110 mg/dL vs. 95–109 mg/dL), those with a higher A1C (6.0–6.4% vs. <6.0%), and individuals with a history of GDM (vs. individuals without a history of GDM) experienced higher risk reductions with metformin, identifying subgroups of participants that benefitted the most from metformin[xxxi] . In the Indian Diabetes Prevention Program (IDPP-1), metformin and lifestyle intervention reduced diabetes risk similarly at 30 months; of note, the lifestyle intervention in IDPP-1was less intensive than that in the DPP [xxxii] . Based on findings from the DPP, metformin should be recommended as an option for high-risk individuals (e.g., those with a history of GDM or those with BMI ≥35 kg/m2). Consider periodic monitoring of vitamin B12 levels in those taking metformin chronically to check for possible deficiency [xxxiii] ^,[xxxiv].

Recommendation

d- Prediabetes is associated with heightened cardiovascular risk; therefore, screening for and treatment of modifiable risk factors for cardiovascular disease are suggested. (Strong recommendation, moderate certainty evidence )

Remarks

In people with a history of stroke and evidence of insulin resistance and prediabetes, pioglitazone may be considered to lower the risk of stroke or myocardial infarction. However, this benefit needs to be balanced with the increased risk of weight gain, edema, and fracture. A lower dose may mitigate the risk of adverse effects.

Summary of evidence

People with prediabetes often have other cardiovascular risk factors, including hypertension and dyslipidemia[xxxv] , and are at increased risk for cardiovascular disease [xxxvi] , [xxxvii] . If indicated, evaluation for tobacco use and referral for tobacco cessation should be part of routine care for those at risk for diabetes.

In longer-term follow-up, lifestyle interventions for diabetes prevention also prevented the development of microvascular complications among women enrolled in the DPPOS and in the study population enrolled in the China Da Qing Diabetes Prevention Outcome Study7,[xxxviii] .

The lifestyle intervention in the latter study was also efficacious in preventing cardiovascular disease and mortality at 23 and 30 years of follow-up3^,5. Treatment goals and therapies for hypertension and dyslipidemia in the primary prevention of cardiovascular disease for people with prediabetes should be based on their level of cardiovascular risk. Increased vigilance is warranted to identify and treat these and other cardiovascular disease risk factors[xxxix] . Statins have been associated with a modestly increased risk of diabetes [xl] ^{, [xli], [xlii], [xliii], [xliv]}. In the DPP, statin use was associated with greater diabetes risk irrespective of the treatment group (pooled hazard ratio [95% CI] for incident diabetes 1.36 [1.17–1.58]) 42. In studies of primary prevention of cardiovascular disease, cardiovascular and mortality benefits of statin therapy exceed the risk of diabetes[xlv] , [xlvi]

In studies of primary prevention of cardiovascular disease, cardiovascular and mortality benefits of statin therapy exceed the risk of diabetes45^,46, suggesting a favorable benefit to harm balance with statin therapy.

Recommendation

e- More intensive preventive approaches should be considered in individuals who are at particularly high risk of progression to diabetes, including individuals with BMI ≥35 kg/m2, those at higher glucose levels (e.g., fasting plasma glucose 100–125 mg/dL, 2-h postprandial glucose 140– 199 mg/dL, A1C 5.7 -6.4%), and individuals with a history of gestational diabetes mellitus. (Strongly recommendation, high certainty evidence )

f- Pharmacotherapy should be considered to achieve sustained weight loss, minimize the progression of hyperglycemia, and cardiovascular risk reduction. (strong recommendation, moderate certainty evidence)

Remark

It is important to individualize the risk/benefit of intervention and consider person-centered goals. Risk models have explored risk-based benefit, generally finding the higher benefit of the intervention in those at highest risk9.

Summary of evidence

Individualized risk/benefit should be considered in screening, intervention, and monitoring to prevent or delay type 2 diabetes and associated comorbidities. Multiple factors, including age, BMI, and other comorbidities, may influence the risk of progression to diabetes and the lifetime risk of complications[xlvii] ^,[xlviii]. In the DPP, which enrolled high-risk individuals with impaired glucose tolerance, elevated fasting glucose, and elevated BMI, the crude incidence of diabetes within the placebo arm was 11.0 cases per 100 person-years, with a cumulative 3-year incidence of diabetes of 28.9%1 . Characteristics of individuals in the DPP/ DPPOS who were at particularly high risk of progression to diabetes (crude incidence of diabetes 14–22 cases/100 person years) included BMI ≥35 kg/m2, those at higher glucose levels (e.g., fasting plasma glucose 110–125 mg/dL, 2-h postchallenge glucose 173–199 mg/dL, and A1C ≥6.0%), and individuals with a history of gestational diabetes1^,29^, 30. In contrast, in the community-based Atherosclerosis Risk in Communities (ARIC) study, observational follow-up of older adults (mean age 75 years) with laboratory evidence of prediabetes (based on A1C 5.7–6.4%and/or fasting glucose 100–125 mg/dL), but not meeting specific BMI criteria, found much lower progression to diabetes over 6 years: 9% of those with A1C defined prediabetes, 8% with impaired fasting glucose48.