Marinella Temprosa

The Effect of Metformin and Intensive Lifestyle Intervention on the Metabolic Syndrome: The Diabetes Prevention Program Randomized Trial

Context Intensive diet and exercise or metformin can prevent the development of diabetes in individuals with impaired fasting glucose, but the effects of these interventions on development of the metabolic syndrome are unknown. Contribution This secondary analysis of Diabetes Prevention Program data showed that lifestyle intervention and metformin each reduced the development of the metabolic syndrome among the 45% of participants who did not have it at baseline. The impact of lifestyle intervention was much more marked than that of metformin. Implications Interventions that prevent diabetes will also reduce the development of the metabolic syndrome. The Editors Considerable attention has recently been paid to the metabolic syndrome, a constellation of risk factors associated with insulin resistance and increased cardiovascular and diabetes risk. The third report of the National Cholesterol Education Programs Adult Treatment Panel now calls for the identification and treatment of this high-risk state and provides a simple set of criteria for diagnosis (1). The World Health Organization (WHO) and the American College of Endocrinology have also provided definitions (2). Although recent studies have provided estimates of the prevalence of the metabolic syndrome in the United States (3, 4), its interrelationship with impaired glucose tolerance is unclear. In particular, it is largely unknown what proportion of participants with impaired glucose tolerance have the metabolic syndrome and whether this varies by ethnicity, age, and sex. Clearly, because an elevated blood glucose level is a common criterion for all definitions, a close association is to be expected. This association may be even stronger in the subgroup of persons with both impaired glucose tolerance and impaired fasting glucose (that is, a fasting plasma glucose level 6.1 to 6.9 mmol/L [110 to 125 mg/dL]). The extent to which we may be able to reduce cardiovascular risk in patients with impaired glucose tolerance by preventing the metabolic syndrome through lifestyle or medication interventions is also unknown. The Diabetes Prevention Program (5, 6) provides a unique opportunity to begin to address these issues. It involves a large sample of more than 3000 participants with impaired glucose tolerance who were carefully followed and randomly allocated to treatment with an intensive lifestyle intervention, metformin, or placebo. In this report, we address 2 questions: the prevalence of the metabolic syndrome at baseline in the trial population (and how this varies by age and sex) and whether the 2 interventions reduced the incidence of new cases of the metabolic syndrome or increased resolution of existing cases compared with placebo. Methods Participants and Procedures Full details of the protocol have been published elsewhere (5, 6). The current report includes 3234 participants seen at baseline. This number includes participants from the 3 treatment arms investigated (that is, standard lifestyle or placebo, intensive lifestyle, and metformin), but not participants from the troglitazone arm, which was discontinued. Individuals were recruited between June 1996 and May 1999 from a variety of sources, including community screenings and household mailings, on the basis of perceived risk for diabetes. Written informed consent was obtained from all participants before screening, consistent with the Declaration of Helsinki and the guidelines of each centers institutional review board. The initial screening step consisted of a fasting glucose measurement. If the participant was eligible, this was followed by a 75-g oral glucose tolerance test. Inclusion criteria were as follows: a fasting plasma glucose level of 5.3 to 7.0 mmol/L (95 to 125 mg/dL) (7.0 mmol/L [125 mg/dL] for Native Americans); a 2-hour plasma glucose level of 7.8 to 11.1 mmol/L (140 to 199 mg/dL) following the glucose load; age of at least 25 years; and body mass index of at least 24 kg/m2 (22 kg/m2 for Asian Americans because of differences in body size in this group). Main exclusion criteria were recent myocardial infarction, symptoms of coronary heart disease, major illness, previous diagnosis of diabetes, use of medications known to impair glucose tolerance, or triglyceride level of at least 6.8 mmol/L (600 mg/dL), as previously detailed (5). Standardized interviewer-administered questionnaires were used to obtain self-reported data on personal medical history, medications, and diet. Self-reported race or ethnicity was classified according to the question used in the 1990 U.S. Census questionnaire (7). Overall, adiposity was assessed by body mass index. Waist circumference was assessed in the standing position midway between the highest point of the iliac crest and the lowest point of the costal margin in the mid-axillary line. All anthropometric measures reflected the average of 2 measurements. Blood pressure was measured twice at 30-second intervals by using a standard mercury manometer. The participant was seated in a chair for 5 minutes before the first measurement was taken, and the mean of the 2 readings was used in the analyses. The metabolic syndrome was defined according to criteria from the National Cholesterol Education Programs Adult Treatment Panel III (1), namely 3 or more of the following conditions: waist circumference greater than 102 cm in men and greater than 88 cm in women; serum triglyceride level of at least 1.7 mmol/L (150 mg/dL); high-density lipoprotein (HDL) cholesterol level less than 1.03 mmol/L (<40 mg/dL) in men and less than 1.3 mmol/L (<50 mg/dL) in women; blood pressure of 130/85 mm Hg or greater; and fasting plasma glucose level of 6.2 mmol/L (110 mg/dL). Participants who were being treated with blood pressurelowering or triglyceride-lowering medications (niacin or fibric acid derivatives) were classified as positive for the respective criterion. We chose the Adult Treatment Panel III (1) criteria because they are commonly used in the United States and are simpler to apply in clinical practice than, for example, the WHO criteria (2). Participants were randomly assigned to receive 1 of 3 interventions: standard lifestyle recommendations plus metformin, 850 mg twice per day; standard lifestyle recommendations plus placebo; or an intensive program of lifestyle intervention. The randomization was done centrally by computer; assignments to the lifestyle group were blinded until randomization, while assignments to the medication groups were blinded until the end of the study. The goals of the lifestyle program were to achieve and maintain a weight reduction of at least 7% of clinical body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. Participants were seen quarterly, when blood pressure was assessed. Fasting glucose levels were determined at the 6-month visits, and fasting lipid levels and waist circumference were measured annually. Further details have been published elsewhere (5, 6). Figure 1 shows the number of participants observed at each annual examination by treatment group. Figure 1. Randomly assigned participants by treatment group and annual visit. Laboratory Methods All of the analytic measurements were performed at the central biochemistry laboratory (Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington). Fasting plasma glucose level was measured on a chemistry autoanalyzer by the glucokinase method. Insulin measurements were performed by using a polyethylene glycolaccelerated double antibody radioimmunoassay method developed in the Diabetes Endocrinology Research Center Immunoassay Core Laboratory (University of Washington, Seattle, Washington). This method is based on the use of an antihuman insulin guinea pig antibody and measures total immunoreactive insulin. The homeostasis model assessment for insulin resistance was calculated as follows (8): Measurements of total plasma cholesterol and triglycerides were performed enzymatically on a chemistry autoanalyzer by using methods standardized to the Centers for Disease Control and Prevention reference methods (9). We obtained HDL fractions for cholesterol analysis by treating whole plasma with dextran sulfate magnesium chloride to precipitate all of the apolipoprotein Bcontaining lipoproteins (10). We calculated low-density lipoprotein cholesterol by using the Friedewald equation (11). In participants with triglyceride levels higher than 4.5 mmol/L (>400 mg/dL), the lipoprotein fractions were separated by using preparative ultracentrifugation of plasma by beta quantification (12). Statistical Analyses Participants were followed for an average of 3.2 years (range, 0.04 to 5.0 years) from the start of the study in June 1996 through 31 July 2001, a period 4 months longer than that reported previously (5). This period was chosen to maximize the available data that were collected during the masked phase of the Diabetes Prevention Program, since unmasking occurred in early August 2001. Random treatment assignments were stratified according to clinical center and were generated by the coordinating center through computer linkup to the field center at time of randomization. Therefore, assignment was unknown until randomization. Assignments to metformin and placebo were double-blinded. The study design and analysis followed the intention-to-treat principle. Nominal (unadjusted) P values and confidence intervals are reported. Logistic regression was used to compare the prevalence of the metabolic syndrome and its components at baseline among the demographic variables. The time to the outcome was assessed by using life-table methods (13). Modified product-limit curves for the cumulative incidence of the metabolic syndrome and for its resolution were compared by using the log-rank test. The estimated cumulative incidence, or resolution, at 3 years and the ris

Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study.

Diabet. Med. 30, 46–55 (2013)

Effect of Progression From Impaired Glucose Tolerance to Diabetes on Cardiovascular Risk Factors and Its Amelioration by Lifestyle and Metformin Intervention The Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group

OBJECTIVE Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program. RESEARCH DESIGN AND METHODS A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status. RESULTS CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia. CONCLUSIONS Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.

The Effect of Progression from Impaired Glucose Tolerance to Diabetes on Cardiovascular Risk Factors and its Amelioration by Lifestyle and Metformin Intervention: The Diabetes Prevention Program Randomized Trial

OBJECTIVE Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program. RESEARCH DESIGN AND METHODS A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status. RESULTS CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia. CONCLUSIONS Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.

Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.

CONTEXT Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. OBJECTIVE To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). DESIGN Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. SETTING Twenty-seven study centers in the United States. PATIENTS DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. INTERVENTION Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). MAIN OUTCOME MEASURES B12 deficiency, anemia, and peripheral neuropathy. RESULTS Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. CONCLUSIONS Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.

Lifestyle and Metformin Treatment Favorably Influence Lipoprotein Subfraction Distribution in the Diabetes Prevention Program

CONTEXT Although intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied. OBJECTIVE The objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program. DESIGN This was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT. PARTICIPANTS Selected individuals with IGT randomized in the Diabetes Prevention Program participated in the study. INTERVENTIONS Interventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity. MAIN OUTCOME MEASURES Lipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured. RESULTS ILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance. CONCLUSION ILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.

Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance

Abstract—The association of insulin resistance and hyperinsulinemia to blood pressure has remained controversial. We examined the association of insulinemia to hypertension and blood pressure using baseline measurements for participants of the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized controlled trial of 3819 participants with impaired glucose tolerance, and is designed to evaluate interventions for the delay or prevention of type 2 diabetes. The relationship between hypertension and insulinemia is described overall and by ethnicity. The effects of demographics (age and gender), adiposity, and glucose on the relationship are also presented. Asian Americans and African Americans had a similarly high prevalence of hypertension as did whites; American Indians had a lower prevalence of hypertension. Among participants not on antihypertensive medications, systolic blood pressure was significantly (but weakly) correlated with fasting insulin (r =0.12), homeostasis model assessment of insulin resistance (HOMA IR;r =0.13), and fasting proinsulin (r =0.10) when adjusted for age and gender (all, P <0.001). Systolic blood pressure showed similar correlations to fasting insulin in each ethnic group. After further adjustment for body mass index, the association of fasting insulin to systolic and diastolic blood pressures weakened considerably but remained significant (systolic:r =0.06, P =0.002; DBP:r =0.06, P <0.001). We conclude that a weak but significant association between insulin, (and proinsulin and HOMA IR) and blood pressure exists but is largely explained by overall adiposity. This association is similar among ethnicities, with the possible exception of Hispanics. The relation between insulin concentrations and blood pressure explains relatively little of the ethnic differences in hypertensive prevalence.

Regression From Prediabetes to Normal Glucose Regulation Is Associated With Reduction in Cardiovascular Risk: Results From the Diabetes Prevention Program Outcomes Study

OBJECTIVE Restoration of normal glucose regulation (NGR) in people with prediabetes significantly decreases the risk of future diabetes. We sought to examine whether regression to NGR is also associated with a long-term decrease in cardiovascular disease (CVD) risk. RESEARCH DESIGN AND METHODS The Framingham (2008) score (as an estimate of the global 10-year CVD risk) and individual CVD risk factors were calculated annually for the Diabetes Prevention Program Outcomes Study years 1–10 among those patients who returned to NGR at least once during the Diabetes Prevention Program (DPP) compared with those who remained with prediabetes or those in whom diabetes developed during DPP (N = 2,775). RESULTS The Framingham scores by glycemic exposure did not differ among the treatment groups; therefore, pooled estimates were stratified by glycemic status and were adjusted for differences in risk factors at DPP baseline and in the treatment arm. During 10 years of follow-up, the mean Framingham 10-year CVD risk scores were highest in the prediabetes group (16.2%), intermediate in the NGR group (15.5%), and 14.4% in people with diabetes (all pairwise comparisons P < 0.05), but scores decreased over time for those people with prediabetes (18.6% in year 1 vs. 15.9% in year 10, P < 0.01). The lower score in the diabetes group versus other groups, a declining score in the prediabetes group, and favorable changes in each individual risk factor in all groups were explained, in part, by higher or increasing medication use for lipids and blood pressure. CONCLUSIONS Prediabetes represents a high-risk state for CVD. Restoration of NGR and/or medical treatment of CVD risk factors can significantly reduce the estimated CVD risk in people with prediabetes.

Lifestyle and Metformin Interventions Have a Durable Effect to Lower CRP and tPA Levels in the Diabetes Prevention Program Except in Those Who Develop Diabetes

OBJECTIVE We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes. RESEARCH DESIGN AND METHODS The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS). RESULTS CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response. CONCLUSIONS Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.

Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium

Background: Despite the reduced incidence of coronary heart disease with intensive risk factor management, people with diabetes mellitus and prediabetes remain at increased coronary heart disease risk. Diabetes prevention interventions may be needed to reduce coronary heart disease risk. This approach was examined in the DPP (Diabetes Prevention Program) and the DPPOS (Diabetes Prevention Program Outcome Study), a long-term intervention study in 3234 subjects with prediabetes (mean±SD age, 64±10 years) that showed reduced diabetes risk with lifestyle and metformin compared with placebo over 3.2 years. Methods: The DPPOS offered periodic group lifestyle sessions to all participants and continued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants with coronary artery calcium (CAC) measurements after an average of 14 years of follow-up. The CAC scores were analyzed continuously as CAC severity and categorically as CAC presence (CAC score >0) and reported separately in men and women. Results: There were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity, 39.5 versus 66.9 Agatston units, P=0.04; CAC presence, 75% versus 84%, P=0.02), but no metformin effect was seen in women. In multivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric, or metabolic factors; by the development of diabetes mellitus; or by use/nonuse of statin therapy. Conclusions: Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes mellitus among men. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00038727.