Diabetes Mellitus Prevention
Myriam Zaydee Allende-Vigo, MD, MBA, FACP, FACE*
The aim of this study was to review lifestyle modification interventions and pharmacological clinical studies designed to prevent diabetes and provide evidence-based recommendations for the prevention of Diabetes Mellitus. A review of relevant literature compiled via a literature search (PUBMED) of English-language publications between 1997 and 2010 was conducted. It is found that people at increased risk of developing type 2 diabetes mellitus can halt the development of the disease. Lifestyle modification intervention with reduction of 5%–10% of excess body weight and increase in moderate physical activity by 150 min/wk has consistently proven to reduce the appearance of diabetes in different at-risk populations. Pharmacologic interventions have also demonstrated the prevention of the appearance of diabetes in persons at risk. Bariatric surgery has decreased the appearance of diabetes patients in a select group of individuals. The progression from prediabetes to diabetes mellitus can be prevented. Lifestyle modification intervention changes with weight loss and increased physical activity are currently recommended for the prevention of diabetes.
Keywords:prediabetes, prevention diabetes mellitus
INTRODUCTION
Diabetes Mellitus is considered a global epidemic. It is expected that the prevalence of Type 2 Diabetes will reach over 15% of the adult population in the United States and Latin America by 2015.1Type 2 Diabetes is a chronic disease characterized by hyperglycemia with potential adverse consequences. It is the principal cause of nontraumatic amputations of the lower extremities, blindness, and permanent renal failure in the United States.2Diabetes is also considered a coro- nary risk equivalent and an important cardiometabolic risk.3The prevention of diabetes could have a tremen- dous impact on the general well-being and quality of life of individuals.
Glucose is a continuous variable; the threshold for defining normoglycemia and hyperglycemia is
somewhat arbitrarily defined.4It is hypothesized that there is deterioration in susceptible individuals from normoglycemia to prediabetes progressing to diabe- tes.5Prediabetes is an asymptomatic state unassociated with any functional impairment.6 Individuals with prediabetes may progress to diabetes at a variable rate, depending upon genetic or environmental factors.5
People with prediabetes are at an increased risk of developing Type 2 Diabetes Mellitus.6 Although the term prediabetes will be used in this article, the term was officially abandoned by the American Diabetes Association (ADA) in January 2010.7Prediabetes is now known as a category of increased risk for developing Type 2 Diabetes. This term encompasses persons with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or a value of glycated hemoglobin, Hemoglobin A1c between 5.7% and 6.4%. IFG is defined as a fasting glucose value $100 to #125 mg/dL (5.6–6.9 mmole/L). IGT is defined as a 2-hour postprandial glucose $140 to #199 mg/dL (7.8–11.0 mmole/L).8 Studies cited in this article use the term prediabetes referring to individuals with IFG, IGT, or both.
The ability to predict which individuals will progress from prediabetes to diabetes is poor. Prediabetes raises Department of Medicine, University of Puerto Rico Medical
Sciences Campus, San Juan, Puerto Rico.
The authors have no conflicts of interest to declare.
*Address for correspondence: Professor of Medicine and Director, Endocrine Section, Department of Medicine, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan 00936- 5067, Puerto Rico. E-mail [email protected]
the short-term absolute risk of progressing to diabetes 7- to 15-fold.9,10 The prevalence of prediabetes in different populations varies between 5% and 37%.6
The rate of prediabetes progressing to diabetes varies among different populations.6 Individuals with pre- diabetes have hyperglycemia, but levels are lower than the levels defined for diabetes. Testing plasma glucose or A1C levels can identify these individuals.
Suspects of being prediabetic are individuals who are obese, hypertensive, have a family history of diabetes, or belong to certain ethnic groups such as Native Americans or Hispanics. Others at risk are women with a history of gestational diabetes, a poor obstetrical history, or a history of delivering large babies.11
Factors associated with progression of prediabetes to diabetes are elevated levels of fasting plasma glucose, rising levels of fasting plasma glucose, high body mass index (BMI), weight gain, younger age, high plasma insulin levels, decreased insulin response to glucose, dyslipidemia, hypertension, and poor beta cell function.12
Populations at risk for developing diabetes have been studied extensively to delineate strategies to deter its progress. Interventions with lifestyle modification including diet and exercise, pharmacologic interven- tions, and surgery have been studied. Studies have demonstrated that diabetes can be prevented. Studies for the prevention of diabetes will be reviewed.
LIFESTYLE-INTERVENTION STUDIES
Five randomized, controlled trials assessed the effects of lifestyle modification on new-onset diabetes in high-risk individuals. Yamaoka and Tango13conducted a meta-analysis of these 5 trials finding that despite heterogeneity in the specific interventions, lifestyle modification consistently demonstrated a reduction in new-onset diabetes. The relative risk reduction calcu- lated by 3 different models were similar (ie, 55%). The Diabetes Prevention Program (DPP) in the United States was the largest of the 5 trials included in this meta-analysis.12 Other studies included were the Da Qing study in China,14the Finnish Diabetes Prevention study,15 the Indian Prevention Study,16 and the Wein Study in Australia.17
The long-term effect of lifestyle interventions to prevent diabetes was demonstrated in the China Da Qing Diabetes Prevention Study.14In China, 577 adults with IGT were advised to go on a diet, to increase leisure physical activities or diet plus exercise in group-based interventions. Active intervention started in 1986 and lasted until 1992. The combined lifestyle-intervention
groups with diet plus exercise had 51% lower incidence of diabetes and 36% reduction of progression to diabetes.14The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study 20-year follow-up, with 98% of living participants recalled showed that the combined life- style-intervention group with diet and exercise had a 43% lower incidence of diabetes.18
In the prevention of Type 2 Diabetes by lifestyle intervention, a Japanese trial in males with IGT, 356 Japanese males with IGT and 102 control subjects were examined. The goal was to achieve and maintain a BMI , 22 kg/m2 on a healthy diet and perform regular physical activity. The study subjects were able to achieve/maintain $7% reduction of initial body weight with diet and moderate-intensity physical activity $150 min/wk. In this study, the subjects in the intervention group reduced their weight by 2.8 vs.
0.39 kg in controls (P,0.001). The 4-year incidence of diabetes was 9.3% for the subjects in the intervention group vs. 3.0% for those in the control group. The incidence of diabetes was less in individuals who lost more weight, and the reduction on the incidence of diabetes by lifestyle intervention was steeper than the mere reduction in weight, suggesting an independent beneficial effect of the exercise.19
The Indian Diabetes Prevention Program shows that lifestyle modification and Metformin prevent type 2 diabetes in Asian Indian subjects with IGT. This prospective community-based study on 531 middle class working subjects, young individuals with low BMI, high rate of insulin resistance, and a median follow-up of 30 months had as primary outcome the development of diabetes. One group received Metfor- min, 500 mg twice daily. The authors found that the progression of IGT to diabetes in these subjects is high;
these subjects developed the onset of diabetes at a mean age of 45 years. There is a high rate of insulin resistance in these people with a low BMI. The authors found a relative risk reduction of 28.5% of progression of IGT to diabetes. The incidence of diabetes was significantly reduced in both groups: lifestyle modifi- cation or using Metformin 500 mg twice daily. There was no added benefit of combination of both therapies.
There was no change in weight or waist circumference among groups. For every 6 patients treated, 1 case of diabetes was prevented.16
The DPP trial included 3234 individuals in the United States with a BMI $24 kg/m2, IFG, and IGT.
They were randomized to 3 study groups: placebo, intensive diet and lifestyle modification, or Metformin 850 mg twice daily. After an average follow-up of 2.8 years, the incidence of type 2 diabetes was 11 cases per 100 person-years in the placebo group vs. 7.8 in the
Metformin and 4.8 in the lifestyle-intervention groups.
This represented a reduction of 58% in the incidence of diabetes with lifestyle intervention and 31% with Metformin. The effects were similar in both men and women and in all racial and ethnic groups. Intensive lifestyle intervention was also found to be at least as effective in older participants as in younger ones.
Lifestyle intervention was particularly effective with prevention of one case of diabetes for every 7 persons treated for 3 years.12
Based on the findings of these studies, the National Heart, Blood Lung Institute of the United States recommends as the most successful for weight loss and maintenance a combined intervention of a 500- to 1000-cal deficit per day diet, increased physical activity with moderate exercise 30–45 minutes, 3–5 d/wk, with an eventual goal of$30 minutes on most (and preferably all) days of the week, and behavioral treatment.20
PHARMACOLOGIC INTERVENTION STUDIES
Several controlled trials have assessed the effects of pharmacologic intervention on new-onset diabetes in high-risk individuals. In the US DPP study, the benefit of metformin 850 mg twice daily represented a re- duction of 31% in the incidence of diabetes.12After an average follow-up of 2.8 years, the incidence of type 2 diabetes was 11 cases per 100 person-years in the placebo group vs. 7.8 in the metformin group and 4.8 in the lifestyle-intervention group. Lifestyle intervention showed a reduction of 58%. In the DPP follow-up analysis, metabolic syndrome was reduced by 41% in the lifestyle modification group (P,0.001) and by 17%
in the metformin group (P = 0.03), which is not statistically significant. Predictors of regression to normal glucose tolerance in the DPP Study follow-up analysis were lower baseline fasting glucose, younger age, greater insulin secretion, and weight loss.21
In the Indian DPP, there was a relative risk reduction of 28.5% of progression of IGT to diabetes with lifestyle modification and metformin 500 mg twice daily with no added benefit of the combination of both therapies.16
In the Study to prevent NIDDM randomized clinical trial on the use of acarbose for the prevention of type 2 Diabetes Mellitus, 714 patients with IGT, 40–70 years of age, received acarbose for 3 years. This was a double- blind, placebo-controlled randomized trial that showed acarbose significantly increased the reversion of IGT to normal tolerance irrespective of age, BMI, or sex. A 34.6% reduction in the conversion from IGT to diabetes was found. These effects were associated with an
improvement in insulin sensitivity. However, there was a large dropout rate from the acarbose group probably due to the adverse gastrointestinal side effects of the drug.22
In the XENical in the prevention of Diabetes in Obese Subjects (XENDOS) Study, Torgerson et al randomized 3305 patients with a mean BMI of 37 kg/m2, into 2 groups: lifestyle modification plus placebo or lifestyle modification plus orlistat for 4 years. A risk reduction of 37.3% of diabetes over 4 years was found only in the obese individuals with IGT and a reduction by 52%
compared with placebo. At 1 year, mean weight loss was significantly greater with lifestyle modification plus orlistat vs. lifestyle modification alone: 10.6 vs. 6.2 kg (23.3 vs. 13.6 lbs),P,0.001. The difference between the groups remained significant at the end of the study:
5.8 vs. 3.0 kg (12.8 vs. 6.6 lbs),P, 0.001.23There was a greater weight loss in the orlistat group.
In the Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial, the effect of rosiglitazone on the frequency of diabetes was assessed. In this prospective, randomized controlled trial, 5269 adults over 30 years of age with IGT or IFG were followed up for a median of 3 years and advised on healthy diet. The primary outcome was composite of development of diabetes or death. The diagnosis of diabetes was reduced by 60% in the rosigitazone group.24
In the ACTos NOW for the prevention of diabetes study, a prospective randomized, double-blind 4 years’
study, 602 subjects with prediabetes (IFG + IGT) plus 1 cardiovascular high-risk factor were evaluated for conversion to diabetes and cardiovascular events. The rate of conversion to diabetes was reduced by 81% in the pioglitazone group compared with those taking a placebo. Individuals randomized to take pioglitazone also recovered part of their insulin production, and their bodies became more sensitive to insulin. Forty- two percent of the individuals in the pioglitazone arm returned to normal glucose tolerance at the end of the study vs. 28% of those in the placebo arm.25
Significant weight loss with improvement of hemo- globin A1C levels has been documented with the use of rimonabant.26 In a meta-analysis, Rucker et al27 have documented significant weight loss with the use of orlistat and sibutramine and rimonabant.
In the Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events (NAVIGATOR) Study, a double-blind trial, 9306 participants with IGT and either cardiovascular disease or cardiovascular risk factors were randomized to a 2-by-2 factorial design, to receive nateglinide (up to 60 mg thrice daily) or placebo, with valsartan (up to 160 mg daily) or placebo, in addition to participation in a lifestyle modification
program. The patients were evaluated for 3 coprimary endpoints: the development of diabetes, a core cardio- vascular outcome, and an extended cardiovascular outcome. The participants were followed for a median of 5.0 years for incident diabetes and a median of 6.5 years for vital status. Nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes, the core composite cardiovascu- lar outcome, or the extended composite cardiovascular outcome. The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8%
in the placebo group. The researchers concluded that although nateglinide did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes, valsartan led to a reduction in the incidence of diabetes but did not reduce the rate of cardiovas- cular events.28
At the present time, the US Food and Drug Administration have not approved a single drug for the prevention of diabetes.
BARIATRIC SURGERY INTERVENTION
According to the National Heart Lung and Blood Institute guidelines, weight loss surgery is an option for carefully selected patients when less-invasive methods have failed and the patient is at high risk for obesity- associated morbidity or mortality, such as Diabetes Mellitus.20The Swedish Obese Subject Study included 4047 individuals with a mean BMI of 41 kg/mt2who had large weight losses after gastric surgery. This large weight loss was associated with an 80% reduction in 8 years’ incidence of diabetes, and after 8 years, there was still a 5-fold reduction in diabetes incidence.29
CONCLUSIONS
Based on lifestyle modification and pharmacologic intervention studies for the prevention of diabetes, the ADA recommends that patients with IGT or IFG should be referred to an effective ongoing support program for weight loss of 5%–10% of body weight and for increasing physical activity to at least 150 min/wk (eg, walking). The ADA also recommends that monitoring for the development of diabetes in those with prediabetes should be performed every year. In addition to lifestyle counseling, metformin may be considered in subjects at a very high risk for de- veloping diabetes if individuals have combined IFG and IGT plus A1C $5.7%, arterial hypertension, low high-density lipoprotein cholesterol, elevated
triglycerides, a positive family history of diabetes, or are obese or under 60 years of age.30
Diabetes Mellitus can be prevented in individuals at risk. The consistently proven way to attain this is by lifestyle intervention with weight loss and increased physical activity. There are also proven pharmacologic interventions that can help prevent diabetes, but none of them currently with Food and Drug Administration approval. It is of utmost importance to identify individuals at risk of developing diabetes and start them on preventive measures early. Even though there are effective preventive measures, it has yet to be proven if the growing worldwide diabetic epidemic can be halted and cardiometabolic risk reduced.
ACKNOWLEDGMENTS
I acknowledge the assistance of Jean Turnquist, PhD, professor at the Department of Anatomy of the University of Puerto Rico for reviewing and editing the manuscript.
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