Prevention of Type 2 Diabetes

Introduction

According to the National Diabetes Statistics Report, the Centers for Disease Control (CDC) estimates that approximately 38% of adults aged ≥18 years in the United States had prediabetes in 2017-2020, based on fasting glucose or glycosylated hemoglobin (A1C) levels. In 2019, an estimated 90 million US adults had prediabetes, with prevalence rates expected to increase. Worldwide, the International Diabetes Federation (IDF) estimates that in 2021, 541 million adults aged 20-79 (age-adjusted prevalence, 10.2%) had impaired glucose tolerance (IGT). By 2040, the number of adults with IGT is projected to increase to 730 million (age-adjusted prevalence, 11.2%).

Unfortunately, estimates for 2017-2020 indicate that only 19% of US patients with prediabetes are aware of their condition, indicating a need for wider screening. Our knowledge of the early stages of hyperglycemia that presage the diagnosis of diabetes and the encouraging results of major intervention trials clearly show that individuals at high risk can be identified and diabetes delayed, if not prevented. Data from clinical trials strongly suggest that an effort to delay or prevent diabetes is worthwhile.

Diabetes Primary Prevention Trials

Several studies have demonstrated that type 2 diabetes (T2D) can be delayed and perhaps prevented (Table 26-1). These studies used several different interventions, including lifestyle modification, oral antidiabetic agents and basal insulin, in nondiabetic study subjects at high risk for developing T2D.

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Da Qing IGT and Diabetes Study

In this small, early study, 577 individuals with IGT from the city of Da Qing, China, were randomized either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed T2D. The cumulative incidence of diabetes at 6 years was 67.7% in the control group compared with 43.8% in the diet group, 41.1% in the exercise group and 46.0% in the diet-plus-exercise group. In a proportional hazards analysis, the diet, exercise and diet-plus-exercise interventions were associated with 31% (P <0.03), 46% (P <0.0005) and 42% (P <0.005) reductions in risk of developing diabetes, respectively. In a follow-up analysis of the patient population 23 years after the start of the study, the cumulative incidence of diabetes was 89.9% in the control group and 72.6% in the intervention groups (combined in the analysis to increase statistical power; P=0.001).

The Finnish Diabetes Prevention Study (FDPS)

The FDPS randomized 522 middle-aged, overweight subjects (mean BMI, 31 kg/m²) with IGT to either an intensive lifestyle intervention group or a control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, intake of saturated fat, and increasing intake of fiber and physical activity. The mean duration of follow-up was 3.2 years. The cumulative incidence of diabetes after 4 years was 11% in the intervention group and 23% in the control group. During the trial, the risk of diabetes was reduced by 58% (P <0.001) in the intervention group. In a follow-up analysis 13 years after the start of the trial, the cumulative incidence of diabetes in the control group was 64%, compared with 44% in the intervention group (P <0.001).

Diabetes Prevention Program (DPP)

The long-term, National Institutes of Health–funded DPP study was designed to determine whether diabetes could be prevented or delayed in people who had risk factors for developing T2D, namely:

• A family history of T2D
• Having prediabetes (FPG concentration between 100 and 126 mg/dL or a 2-hour OGTT value between 140 and 200 mg/dL)
• Being overweight
• Hypertension or abnormal cholesterol levels
• History of GDM and/or having given birth to a baby weighing >9 lb
• A member of an ethnic group who has a high incidence of diabetes (American Indians, Latinos, Pacific Islanders, Asian Indians and African Americans).

The 3,234, mostly obese (BMI >31 kg/m²), participants in the 3½-year DPP study were randomized into one of four treatment groups. The first group was the intensive lifestyle-change group (goals: exercise at least 150 minutes per week and 7% loss of baseline body weight). The other three groups received metformin (MET) (Glucophage), troglitazone (Rezulin), or placebo, with only minimal lifestyle changes. The DPP is the only study to date that compared lifestyle modifications and pharmacologic interventions.

The DPP ended 1 year early because of the positive results gathered from 25 research institutions around the United States that included >4,000 subjects. Compared with the placebo group, the subjects randomized to the intensive lifestyle-change group reduced their chances of developing T2D by an impressive 58%. In addition, intensive lifestyle changes were effective in all age groups and in both obese and nonobese subjects. Individuals who were given MET with minimal lifestyle changes showed a reduction of 31% in the development of diabetes over the course of study compared with the placebo group. Subanalysis of the results revealed that MET was most effective in younger (<45 years old), heavier (BMI >30 kg/m2) subjects compared with the older, nonobese subjects. There was also a highly significant (approximately 75%) early reduction in the conversion to T2D in the troglitazone group near the end of the first year of the study, although this group was only on medication for an average of 10 months because troglitazone was withdrawn from the study due to liver toxicity. All interventions were more effective in subjects who were randomized earlier in the natural history of their disease (i.e., a 2-hour oral glucose tolerance test (OGTT) value between 140 and 160 mg/dL) compared with the subjects whose initial 2-hour OGTT value was between 180 and 200 mg/dL.

During 10-year follow-up since randomization in the original DPP study, the original lifestyle group lost and then partly regained weight. The modest weight loss with MET was maintained. In the 10-year follow-up study, diabetes incidence rates were similar between treatment groups: 5.9, 4.9, 5.6 per 100 person-years for lifestyle, for MET and for placebo, respectively. The diabetes incidence rates in the 10 years since DPP randomization were reduced by 34% in the lifestyle group and 18% in the MET group compared with placebo. These results indicate that prevention or delay of diabetes with lifestyle intervention or MET can persist for at least 10 years.

Troglitazone in the Prevention of Diabetes (TRIPOD) Study

The TRIPOD study provided several important findings. The first important result was that diabetes could be prevented and delayed with troglitazone (400 mg/day) by 56% compared with the placebo group in a cohort of high-risk, nonpregnant, nondiabetic Hispanic women who had a recent history of gestational diabetes mellitus (GDM). In addition, metabolic studies performed during and after the study demonstrated prolonged preservation of pancreatic or β-cell function in the troglitazone-treated group even after the drug was discontinued. Although troglitazone is no longer on the market, this study suggested that similar benefits may be achieved with the other insulin sensitizers that are available (rosiglitazone [Avandia] and pioglitazone [Actos]).

Study to Prevent Non–Insulin-Dependent Diabetes Mellitus (STOP-NIDDM)

In the 3-year STOP-NIDDM, patients with impaired glucose tolerance (IGT) were randomized to receive either the carbohydrate-absorption inhibitor acarbose 100 mg tid or placebo. By the end of the study, 32% of patients in the acarbose group and 42% of those in the placebo group developed diabetes, corresponding to a risk reduction of ~25% (P = 0.0015). In addition, there was a reduction in cardiovascular (CV) risk in the acarbose-treated group. The results of this study raised some controversy since 4% of patients were excluded from the intention-to-treat analysis because they did not have IGT at screening or had no post-randomization data. Furthermore, 9.3% of the study population had a fasting plasma glucose value at screening that, according to more recent criteria, could be considered diagnostic of diabetes. However, subsequent analysis in which these patients were excluded still found a significant (P = 0.0027) risk reduction with acarbose treatment.

Xenical in the Prevention of Diabetes Mellitus in Obese Subjects (XENDOS) Trial

This double-blind trial randomized 3,305 patients to lifestyle changes plus either the weight-loss agent orlistat 120 mg or placebo three times daily. Participants had a BMI ≥30 kg/m² and normoglycemia (79%) or IGT (21%). After 4 years’ treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37% (P=0.0032). However, subsequent analyses indicated that the difference in diabetes incidence was detectable only in the subgroup of patients with IGT.

Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial

In the DREAM trial, 5269 people with IFG or IGT, or both and no previous CV disease were randomized to receive ramipril (15 mg/day) or placebo, or rosiglitazone (8 mg/day) or placebo, using a 2 × 2 factorial design and were followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death (included because undiagnosed diabetes may be more frequent in those who die than in those who do not).

Ramipril modestly improved glycemic status, including a 9% nonsignificant reduction in the incidence of diabetes and a significant 16% increase in regression to normal glucose levels. In addition, ramipril significantly reduced blood pressure and had a small, favorable effect on liver function. A significantly smaller proportion of patients in the rosiglitazone group than in the placebo group developed the composite primary outcome (11.6% vs 26.0%, respectively, P <0.0001).

Similarly, 10.6% of rosiglitazone-treated patients developed diabetes vs 25% of those that received placebo (P <0.0001), a risk reduction of 62%. Furthermore, the proportion of patients who became normoglycemic by at least 2 years was significantly greater with rosiglitazone than with placebo (50.5% vs 30.3%, respectively; P <0.0001).

While mean body weight increased by ~3% (2.2 kg) with rosiglitazone more than with placebo, there was a favorable effect on the waist/hip ratio with rosiglitazone. In addition, decreases in systolic and diastolic blood pressure with rosiglitazone (1.7 mm Hg and 1.4 mm Hg, respectively) were greater than the decreases with placebo (P <0.0001). CV event rates were similar in both groups, although 14 (0.5%) patients in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (P = 0.01). However, there were no cases of fatal heart failure. At the final visit, 6.8% of subjects in the rosiglitazone group reported peripheral edema vs 4.9% in the placebo group (P = 0.003).

Actos Now for Prevention of Diabetes (ACT-NOW) Trial

The double-blind, placebo-controlled ACT-NOW trial assessed whether pioglitazone can reduce the risk of T2D in adult patients with IGT. A total of 602 patients were enrolled and the median follow-up period was 2.4 years. Conversion to diabetes was confirmed on the basis of the results of repeat testing of fasting glucose and oral glucose tolerance. Annual incidence rates for T2D mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, resulting in a relative risk reduction of 72% for conversion to diabetes in the pioglitazone group (P <0.001) (Figure 26-1). In addition, 48% of the patients in the pioglitazone group converted to normal glucose tolerance compared with 28% of those in the placebo group (P <0.001). A1C decreased by 0.04% with pioglitazone treatment while it increased by 0.20% with placebo (P <0.001). Compared with placebo, there also were significantly greater reductions in fasting glucose with pioglitazone compared with placebo (11.7 mg/dL and 8.1 mg/dL, respectively, P <0.001), as well as 2-hour postprandial glucose (30.5 mg/dL vs 15.6 mg/dL, pioglitazone and placebo, respectively, P <0.001). Other findings included a significantly greater decrease in diastolic BP with pioglitazone vs placebo (2.0 mm Hg vs 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima-media thickening (31.5%, P = 0.047) and a greater increase in the level of HDL-c (7.35 mg/dL vs 4.5 mg/dL, P=0.008). However, weight gain was greater with pioglitazone than with placebo (3.9 kg vs 0.77 kg, P <0.001) and edema was more frequent (12.9% vs 6.4%, P = 0.007).

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Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial

This randomized, double-blind, clinical trial in a total of 9,306 subjects with impaired glucose tolerance and either CV disease or CV risk factors used a 2 × 2 factorial design to assign individuals to treatment with nateglinide vs placebo, or valsartan vs placebo, in addition to participation in a lifestyle-modification program. Participants were followed for a median of 5 years. Treatment with nateglinide did not reduce the incidence of diabetes or the co-primary composite CV outcomes. Although treatment with valsartan resulted in a relative reduction of 14% in the incidence of diabetes, it did not reduce the rate of CV events.

Reduced Diabetes Risk in Other Trials

The ORIGIN trial enrolled over 12,000 subjects over the age of 50 with at least one CV risk factor and either prediabetes (IFG and/or IGT) or early T2D. The primary objective was to determine if insulin replacement therapy targeting normal fasting glucose (<95 mg/dL) with insulin glargine reduces the risk of CV events more than standard-care approaches to glycemic control and, in a factorial design, the impact of omega-3 fatty acids. After a median follow-up of 6.2 years, insulin glargine had a neutral effect on CV outcomes and cancers. However, this study also assessed the progression to T2D in subjects with prediabetes (n=752). In this population, insulin glargine resulted in a 28% relative reduction in the development of diabetes, although it also increased hypoglycemia and modestly increased weight.

The efficacy of phentermine and topiramate extended release (PHEN/TPM ER) on weight loss and metabolic risk reduction were assessed in the CONQUER trial. The 56-week trial enrolled overweight or obese (BMI of between 27 to 45 kg/m²) adult patients with ≥2 weight-related comorbidities, including central adiposity, dyslipidemia, hypertension, or T2D. Patients were randomized to receive lifestyle modifications plus either placebo, 7.5/46 PHEN/TPM ER, or 15/92 PHEN/TPM ER. SEQUEL was a 52-week extension study enrolling patients who completed CONQUER; it assessed the long-term efficacy and safety of PHEN/TPM ER. A sub-group analysis of the 108 weeks of treatment was performed in a separate study, which analyzed the efficacy of PHEN/TPM ER in preventing progression to T2D in a subset of patients who had prediabetes or metabolic syndrome at the beginning of CONQUER. Treatment with 7.5/46 or 15/92 PHEN/TPM ER reduced the annualized incidence rate of T2D in subjects with prediabetes by 48.6% and 88.6% compared with placebo, respectively. The degree of protection against progression to T2D was associated with weight loss: greater weight loss was associated with increased risk reduction.

IRIS was a double-blind, placebo-controlled study that assessed the efficacy of pioglitazone in reducing the risk of stroke or MI after ischemic stroke or transient ischemic attack (TIA) in nondiabetic patients with insulin resistance. The 3,876 patients were 40 years of age and older, had an ischemic stroke or TIA in the 6-month period preceding randomization and were randomized to receive either pioglitazone or the placebo. A significantly lower percentage of patients in the pioglitazone group experienced a primary outcome event (fatal or nonfatal stroke or MI) in comparison to the placebo group (9.0% vs 11.8%, respectively; HR in the pioglitazone group, 0.76; 95% CI, 0.62 to 0.93; P = 0.007). Additionally, the rate of progression to diabetes was significantly lower in the pioglitazone group (HR, 0.48; 95% CI, 0.33 to 0.69; P <0.001). Overall, IRIS determined that pioglitazone therapy directed at improving insulin sensitivity was effective in the prevention of CV events in nondiabetic patients with insulin resistance and cerebrovascular disease.

Several other large-scale clinical trials reported a remarkably consistent reduction in the incidence of T2D in patients with hypertension and/or other CV risk factors treated with either ACE inhibitors (including ramipril) or ARBs for 3 to 6 years. Insulin glargine, a HMG CoA reductase inhibitor (pravastatin) and a thiazolidinedione (pioglitazone) have also been shown to reduce the risk of developing T2D (Table 26-2). However, unlike the DREAM trial, the effect on the incidence of new-onset diabetes was either a secondary end point or a post hoc analysis.

Numerous studies have demonstrated that bariatric surgery is one of the most efficacious modalities for the prevention of T2D. In the large (>4,000 patients) Swedish Obese Subjects trial, bariatric surgery was demonstrated to reduce the risk of T2D by 96% 2 years after the procedure, 84% 10 years after, and 78% 15 years after. Bariatric surgery can also produce high rates of T2D remission, especially if performed early after diagnosis: one meta-analysis found a complete resolution rate of 78.1% (for more information on bariatric surgery in T2D prevention and treatment, see Busetto 2015).

Taken together, the results of these trials add further evidence that the development of diabetes can be delayed and possibly prevented.

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Who Should Be Screened

Prediabetes increases the risk of progressing to T2D by 3- to 10-fold. These patients are also at increased risk of developing complications typically associated with frank diabetes, including CVD and microvascular disease. For these reasons, screening for prediabetes in at-risk patients has been proposed. According to the 2022 ADA Standards of Medical Care guidelines, screening for prediabetes and diabetes should be conducted in individuals 35 years of age and older by measuring FPG, A1C, or 75-g 2-hour OGTT. Screening should also be considered for people who are <35 years of age and are overweight (BMI ≥25 kg/m²) if they have another risk factor, such as a high-risk race or ethnicity, a first-degree relative with diabetes, history of gestational diabetes or CVD, physical inactivity, hypertension, dyslipidemia, or other clinical conditions associated with diabetes. Asian-Americans should be considered for screening at a lower BMI of ≥23 kg/m². Women who were diagnosed with gestational diabetes should undergo lifelong screening at least every 3 years. Screening is also recommended in people with HIV regardless of age or BMI. Testing for prediabetes in children and adolescents can also be considered in those who are overweight or obese and who have additional risk factors for diabetes. If testing reveals normal results, screening should be repeated every 3 years (at a minimum).

The ADA define individuals with prediabetes as those with one of the following abnormal laboratory values:

• FPG 100 mg/dL to 125 mg/dL
• 2-h PG in the 75-g OGTT 140 mg/dL to 199 mg/dL
• A1C 5.7% to 6.4%.

Although the results of the prevention trials discussed above are encouraging, broader implementation of screening has been slowed by concern over the cost effectiveness of early interventions in high-risk patients. This concern was addressed in the analysis of the 10-year cost-effectiveness data from the DPP/DPPOS studies, which demonstrated that intensive lifestyle intervention is indeed cost effective and MET is marginally cost-saving, or at least cost-neutral, compared with placebo. Even when the direct nonmedical costs of the interventions are considered, the interventions are cost effective.

Patients with IGT, IFG or an A1C of 5.7% to 6.4% should be counseled on lifestyle changes, with goals similar to those in the DPP (7% weight loss and moderate-intensity physical activity for at least 150 minutes per week). Several nutritional patterns, including Mediterranean, low-carbohydrate and plant-based diets, may lower the risk of progressing to T2D. Since the natural history of prediabetes is variable, with some patients progressing to T2D, some remaining in the prediabetes state and others regressing to normal glucose regulation, laboratory values can be measured annually to track progression to frank diabetes. ACE/AACE recommend annually measuring FPG, A1C, or in patients suspected of progressing, 2-hour post-challenge glucose tolerance testing. ACE/AACE also recommend annual assessment of microalbuminuria, fasting lipid concentrations and blood pressure. More frequent monitoring is recommended in patients at high risk, such as those that meet several prediabetes criteria.

Summary

Treating prediabetes with FDA-approved medication that is typically reserved for T2D is merely being proactive, since the diagnostic boundaries between prediabetes and diabetes are somewhat arbitrary. Early initiation of therapy with both pharmacologic and nonpharmacologic therapy will most likely have the best chance of slowing or preventing disease progression. As discussed above, several agents have been shown to decrease the incidence of diabetes, including MET, thiazolidinediones (TZDs), acarbose and others. However, MET has the strongest evidence base in younger heavier subjects and has also demonstrated long-term safety when used for diabetes prevention. TZDs are extremely effective but do have more side effects.

The 2022 ADA guidelines recommend that MET therapy for prevention be considered in patients with prediabetes, especially in patients aged 25–59 years with BMI ≥35 kg/m², higher fasting plasma glucose (e.g., ≥110 mg/dL) and higher A1C (e.g., ≥6.0%), as well as in women with a history of gestational diabetes.