Prevention of Type 2 Diabetes: Evidence and Strategies
Diet
The diet followed in the major diabetes prevention trials discussed above has typically been a weight-reducing diet with decreased fat intake (eg, DPP, Finnish trial) and increased fiber intake (eg, Da Quing, DPP, Finnish trials). However, there has been more emphasis recently on the importance of the quality rather than the quantity of fats in preventing diabetes. For example, in a Spanish study, a non–calorie-restricted traditional Mediterranean diet, enriched with high-fat foods of vegetable origin (olive oil, nuts) decreased the incidence of diabetes by 52% in individuals at high cardiovascular risk after a median follow-up of 4.0 years, and in the absence of significant changes in body weight or physical activity among the groups [33]. These findings were reproduced by other studies. A recent meta-analysis examining the relation between intake of fruits and vegetables and the incidence of diabetes revealed that higher intake of fruit, especially berries, and green, leafy vegetables, yellow vegetables, cruciferous vegetables, or their fiber is associated with a lower risk of T2DM [34].
Exercise
Exercise is thought to improve insulin sensitivity and promote peripheral glucose uptake in normal individuals. Long-term moderate exercise, similar to the exercise recommended in DPP and FDPS, results in increased translocation of insulin-responsive glucose transporter (GLUT-4) from intracellular stores to the cell surface, facilitating glucose uptake [35]. A systematic review of 10 prospective cohort studies published in 2007 showed that, after adjustment for BMI, moderate-intensity physical activity was significantly associated with reduced diabetes incidence [36]. In the FDPS, participants who achieved at least 4 hours of exercise per week had a significant 80% decrease in incidence of diabetes, and this effect was observed even in the group that did not lose weight [23]. In the DQDPS, the greatest reduction in diabetes incidence was observed in the exercise group [22].
In a recent NIH-funded trial designed to examine the relative contribution of exercise alone to the overall beneficial effect of lifestyle changes in the DPP study, a total of 237 adults with IFG were randomly assigned to 4 different groups: low-amount moderate intensity exercise (similar to exercise followed in DPP), high-amount moderate intensity exercise, high-amount vigorous intensity exercise, and a combination of diet, weight loss, and low-amount moderate exercise. Only the diet and exercise group experienced a decrease in fasting glucose, whereas similar improvements in glucose tolerance were observed in both the diet and exercise group and the high-amount moderate-intensity exercise group, suggesting that such an exercise regimen may be as effective as a more intensive multicomponent approach involving diet, exercise, and weight loss for preventing diabetes [37].
Weight Loss
Weight reduction in prediabetic individuals has been consistently associated with reduced incidence of diabetes. Furthermore, the amount of weight loss needed to achieve this benefit seems to be relatively modest and a realistic goal to set for patients. Indeed, in the DPP trial, an average weight loss of only 5.6 kg was associated with a 58% lower incidence of diabetes [24]. Moreover, on further analysis of the DPP trial, and among weight, diet, and exercise, diabetes prevention correlated most strongly with weight loss, with an estimated 16% diabetes risk reduction for every single kilogram of weight reduction [38]. Similarly, within the same lifestyle intervention group in the FDPS, the participants who were able to achieve an initial body weight loss greater than 5% at 1 year had a nearly 70% relative risk reduction in progression to diabetes, when compared to their peers in the intervention group who had less or no weight loss [23].
In summary, numerous randomized controlled studies from various populations have proved that lifestyle modifications, including healthy diet, moderate weight loss, and moderate-intensity exercise, represent a very effective strategy to prevent diabetes in patients at risk, mostly patients with IGT, and this protective effect seems to be sustained over time.
Pharmacologic Interventions
Metformin
Metformin is an antidiabetic agent that works mostly at the liver site by suppressing hepatic glucose production and inhibiting production and oxidation of free fatty acids (FFA), thereby reducing FFA-induced insulin resistance and promoting peripheral glucose uptake [39]. This effect has the potential of preserving beta cell function by reducing the demand for insulin secretion.
In the DPP trial, metformin, although generally less effective than lifestyle changes, was associated with a significant 31% reduction in diabetes incidence (cumulative incidence of 22% in metformin group vs 29% in placebo group) and significant weight reduction (average of 2 kg) [24]. Further analysis of the DPP results showed that metformin efficacy, compared to placebo, was greater in patients who were younger, had higher BMI, and had higher FBG levels. In addition, a DPP substudy of 350 women with history of gestational diabetes and IGT revealed that this group of women, who had a higher risk of progression to diabetes (71% at 3 years) when compared to women with no history of gestational diabetes, despite similar baseline glucose levels, had similar diabetes risk reduction of 50% with both metformin and lifestyle changes [40].
In the IDPP study, both lifestyle changes and metformin reduced significantly and similarly the incidence of diabetes in adults with IGT, with no observed added benefit from combining both interventions [26]. It has not been clear, however, how much of this effect of metformin is a result of pharmacologic properties masking hyperglycemia or a true protective and preventive effect. In a washout study in which 1274 DPP participants who did not progress to diabetes underwent an OGTT after 1 to 2 weeks of discontinuing metformin or placebo, the incidence of diabetes was still reduced by 25% in the metformin group, after the washout period, compared to a 31% risk reduction in the primary DPP analysis, suggesting a partially sustained rather than temporary effect of metformin [41]. In the DPPOS long-term follow-up study, metformin (850 mg twice daily as tolerated) was continued in the group initially assigned to metformin in addition to lifestyle counseling [32]. Although the progression to diabetes was similar in all groups during the 5.7-year follow-up period, the cumulative incidence of diabetes at 10 years was still reduced in the metformin group by 18% when compared to control group. Furthermore, the weight loss associated with metformin was also interestingly sustained at 10 years. A meta-analysis echoed this beneficial effect of metformin observed in the DPP trial, reporting a relative risk reduction of new-onset diabetes of 40% with the use of metformin [42].
In summary, metformin has been shown to be effective in preventing diabetes in patients at risk, especially persons with younger age, higher BMI, and history of gestational diabetes and in native Asian Indians. The protective effect of metformin seems to be sustained over the long term in follow-up studies.
Thiazolidinediones
Thiazolidinediones (TZDs) are antidiabetic agents that have been evaluated in diabetes prevention trials. TZDs are peroxisome proliferator-activated gamma receptor (PPAR-γ) agonists that work by augmenting conversion of preadipocytes to adipocytes, which in turn increase adiponectin levels, promoting insulin sensitivity [43]. In addition to their antihyperglycemic properties, TZDs are thought to have a direct protective effect on beta cells, potentially translating into prevention and delay of diabetes [44].
The first study to demonstrate diabetes prevention with a TZD was the TRIPOD study (Troglitazone in Prevention of Diabetes), in which 266 Hispanic women with a history of gestational diabetes were randomly assigned to troglitazone or placebo [45]. Troglitazone use was significantly associated with reduction of progression to diabetes at 1.5-year follow-up when compared to placebo (relative risk reduction of 55%), with a decrease of endogenous insulin requirement at 3 months of therapy and sustained benefit after discontinuation of the TZD, suggesting an effect on beta cell preservation.
Moreover, troglitazone was an investigational drug in the DPP trial from 1996 to 1998, at which time it was discontinued because of associated fatal liver failure in a DPP participant. In the DPP trial, troglitazone was asso-ciated with a remarkable 75% decrease in progression to diabetes at 1 year. Troglitazone was withdrawn from the US market in 2000 because of its association with severe hepatotoxicity.
The international DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medications) trial randomly assigned more than 5000 participants with IFG and/or IGT to rosiglitazone, ramipril, or placebo in a 2 × 2 factorial design [46]. In participants receiving rosiglitazone, the risk for progression to diabetes was reduced by 60% and the likelihood of regression to normoglycemia was increased by 71% when compared to placebo. However, the use of rosiglitazone was associated with an increased risk of new-onset congestive heart failure and a mean weight gain of 2.2 kg, thought to reflect increased subcutaneous gluteal fat deposition, with an observed decreased waist-to-hip ratio.
Interestingly, in a passive follow-up of the DREAM study conducted a median 1.6 years after the end of the trial and 4.3 years after randomization, participants treated with rosiglitazone had a 39% lower incidence of diabetes compared to placebo participants, and 17% more of them regressed from prediabetes to normoglycemia [47]. Nonetheless, there was no difference between the 2 groups when the analysis was restricted to the passive follow-up period, suggesting a time-limited exposure to rosiglitazone reduces the longer-term incidence of diabetes by likely delaying but not reversing the underlying disease process.
The third large trial assessing the efficacy of a TZD in preventing diabetes was the Actos Now for the prevention of diabetes (ACT NOW) trial, which was a randomized, double-blinded study that assigned 602 patients with IGT to pioglitazone 45 mg daily or placebo [48]. Over a median follow-up of 2.6 years, pioglitazone was associated with a 72% lower annual rate of progression to diabetes (2.1% compared to 7.6 % in placebo group), and a higher rate of conversion to normal glucose tolerance (48%). In addition, pioglitazone had favorable effects on fasting and 2-hour blood glucose, A1C level, diastolic blood pressure, carotid intima thickness, and HDL cholesterol. As in the DREAM trial, an increased incidence of edema and weight gain was observed with pioglitazone.
Unlike the strong evidence supporting TZDs as an approach to diabetes prevention in the US trials, the Indian Diabetes Prevention Program-2 (IDPP-2) trial, which randomized 497 participants with IGT to lifestyle modifications with pioglitazone versus lifestyle modifications with placebo, did not demonstrate a significant reduction in diabetes at 3 years’ follow-up, suggesting a possible ethnicity-related variation in the effect of the medication [49]. In 2011, the French and German medications regulatory agency withdrew pioglitazone from the market because of a potential increase in incidence of bladder cancer with the cumulative use of more than 28 g of pioglitazone. In the United States, the Food and Drug Administration is performing an extensive review of data and advises against the use of pioglitazone in patients with a history of bladder cancer.
In summary, TZDs demonstrated significant efficacy in preventing diabetes in many patients at risk, but their safety concerns, particularly the associated new onset of congestive heart failure and potential increased risk of bladder cancer, might outweigh this benefit.
Combination Metformin and Thiazolidinediones
As metformin and rosiglitazone both have preventive benefits in diabetes, and rosiglitazone is associated with numerous side effects at a higher dose, a combination of metformin and low-dose rosiglitazone was evaluated in in the CAnadian Normoglycemia Outcomes Evaluation (CANOE) trial [50]. A total of 207 patients with IGT were randomly assigned to receive combination metformin (500 mg twice daily) and rosiglitazone (2 mg daily) versus placebo for a median of 3.9 years. The combination therapy was associated with a 66% relative risk reduction of progression to diabetes.
Alpha-glucosidase Inhibitors
Alpha-glucosidase inhibitors are antidiabetic agents that slow oral carbohydrate intestinal absorption, subsequently improving postprandial hyperglycemia, which can eventually reduce glucose toxicity of pancreatic beta cells. In addition, they have been shown to improve insulin sensitivity in individuals with IGT [51] and have been found to exert a favorable protective effect in a prediabetic population [52]. In a multicenter placebo-controlled randomized trial, the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM), 1429 participants with IGT were randomly assigned to receive acarbose 100 mg 3 times a day or placebo for 3 years [53]. As expected, diabetes incidence was significantly decreased by 25% in the acarbose group (relative risk of 32.4% vs 41.5% in acarbose and placebo group, respectively), and acarbose significantly increased reversion to normal glucose tolerance (P < 0.0001). Furthermore, the use of acarbose was associated with a statistically significant 49% decrease in the rate of any cardiovascular event, highlighting the cardiovascular protective effect of improving postprandial hyperglycemia with acarbose. This study had many limitations: a high percentage of participants discontinued treatment (31% in the acarbose group and 19% in the placebo group), most likely related to increased gastrointestinal adverse effects of acarbose. In addition, the diabetes prevention effect does not seem to be sustained: during a 3-month wash-out period where all patients received placebo, incidence of diabetes in the initial intervention group was higher than in the initial placebo group.
In a Japanese multicenter randomized double-blind trial, 1780 patients with IGT were randomly assigned to receive the alpha-glucosidase inhibitor voglibose or placebo [54]. An interim analysis at 48 weeks revealed a significantly lower risk of progression to diabetes in the voglibose group.
Combination Metformin and Acarbose
In a 6-year multicenter British study, the Early Diabetes Intervention Trial (EDIT), 631 participants with IFG were randomly assigned, in a factorial design, to double-blind treatment with acarbose or placebo and simultaneously to metformin or placebo [55]. At 3 years, there was a nonsignificant risk reduction of 8% and 37% in progression to 2 successive fasting plasma glucose values of 140 mg/dL or more in the acarbose and metformin groups, respectively, but a significantly lower 2-hour OGTT glucose in the acarbose group and significantly lower FBG in the metformin group. Interestingly, at 6 years of follow-up, there was no significant difference in relative risk of progression to diabetes with acarbose, metformin, or combination therapy [56]. However, unlike metformin or combination therapy, acarbose was associated with a significant relative risk reduction of diabetes (0.66, P = 0.046) in the subgroup of patients with IGT at baseline, suggesting a possible differential protective effect of certain agents in patients with IGT or IFG.
