Diabetes Reduction Assessment Research Articles

Variation at the DPP4 locus influences apolipoprotein B levels in South Asians and exhibits heterogeneity in Europeans related to BMI

Dyslipidaemia, a common feature of type 2 diabetes, is characterised by an increase in atherogenic particles, quantifiable through apolipoprotein B (ApoB) levels. Genetic studies of lipid levels have focused on Europeans; a study in South Asians could identify novel genes. We tested 31,739 single nucleotide polymorphisms (SNPs) from ∼ 2,000 genes in 2,573 South Asians from the epidemiological arm of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study (EpiDREAM) for association with ApoB and we tested two novel associations for replication in 1,181 South Asians from the INTERHEART case-control study. The SNP, rs4664443, within DPP4 was associated with ApoB (p = 7.98 × 10(-5)) in EpiDREAM. The observed association was replicated in the INTERHEART South Asians (one-sided p = 9.65 × 10(-3); combined two-sided p = 4.68 × 10(-6)). The rs4664443 SNP was not associated with ApoB among five other EpiDREAM ethnicities. However, because South Asians had a significantly lower mean BMI compared with other EpiDREAM ethnicities, we tested for and found an interaction between rs4664443 and BMI for ApoB among the Europeans, the largest subgroup in EpiDREAM (p = 4.14 × 10(-3) for interaction), observing an association with ApoB in Europeans with a BMI <25 kg/m(2) (p = 2.35 × 10(-3)), but not with a BMI ≥ 25 kg/m(2) (p = 0.21). The association between rs4664443 and ApoB among all EpiDREAM individuals with BMI <25 kg/m(2) was significant (n = 2,972; p = 1.44 × 10(-5)) compared with those with a BMI ≥ 25 kg/m(2) (n = 11,559; p = 0.81), and there was evidence of association among all genotyped individuals with a BMI <25 kg/m(2), including the INTERHEART South Asians (n = 3,601; p = 9.52 × 10(-7)). Variation at the DPP4 locus is associated with ApoB in South Asians and displays heterogeneity related to BMI in other ethnicities.

Trial update: the Diabetes REduction Approaches with ramipril and rosiglitazone Medications (DREAM) trial

BACKGROUND Diabetes (T2DM) is a worldwide medical and social emergency in the westernized societies. Lifestyle changes, diet and physical activity, have shown a protective effect on the likelihood of developing T2DM and are strongly recommended for primary prevention in people at increased risk for T2DM. However, maintaining adherence to these nonpharmacologic strategies is dishearteningly challenging, and the possible use of drugs to prevent T2DM remains of keen interest. Metformin, glitazones, acarbose and orlistat can reduce the risk of developing T2DM. Recently, post hoc analyses of several clinical studies suggested that ACE-I as well might reduce the risk of T2DM. AIM OF THE STUDY Since none of these trials was designed with this primary end-point, the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Investigators studied the effects of ramipril or rosiglitazone on the risk of T2DM in a randomized trial designed with T2DM as a primary outcome. METHOD Subjects with fasting impaired plasma glucose levels or impaired glucose tolerance, without cardiovascular disease, were randomly assigned, in a 2-by-2 factorial design, to receive either ramipril (up to 15 mg daily) or placebo and either rosiglitazone or placebo. They were followed for a median of 3 years. RESULTS Rates of the primary end points, T2DM or death, were not significantly lower in the ramipril group than in the placebo group. In contrast to ramipril, the use of rosiglitazone resulted in a significant reduction in T2DM or death. DISCUSSION Disappointingly, 14 participants on rosiglitazone developed non-fatal heart failure, compared with 2 cases in the placebo group, and the group gained 3% (2.2 kg) more in body weight than the placebo group. Moreover, we still do not know whether the effect of rosiglitazone on the incidence of T2DM will persist after drug washout. CONCLUSIONS We believe that the high cost of the drug and the study’s negative cardiovascular and body weight outcomes favour a lifestyle strategy in preventing T2DM.

Reducing the Risk of Developing Diabetes

Reducing the Risk of Developing Diabetes

Ramipril

Ramipril

Comparative Effectiveness of Angiotensin‐Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Hypertension on Clinical End Points: A Cohort Study

Roy and colleagues compared the frequency of new-onset diabetes in hypertensive patients in the community treated with an angiotensin receptor blocker or an angiotensin-converting enzyme inhibitor, concluding that incident diabetes was less frequent in the latter group. However, prospective randomized controlled trials are always preferable to cohort studies for determining the effect of drug therapy on clinical outcomes. Consequently, we were surprised that these authors did not cite either of the two large trials that provide robust estimates of the effect of the drugs in question on the development of diabetes mellitus. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research trial (NAVIGATOR)1 showed that valsartan reduced the risk of new-onset diabetes by 14% (95% confidence interval, 8–20%; P<.001), whereas in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM)2 trial, ramipril did not have a significant effect on incident diabetes. These findings suggest that the observations of Roy and colleagues are likely to be spurious and probably reflect unmeasured confounding. The ready availability of health system electronic records aggregated into data warehouses provides a wealth of new information, but large numbers of data cannot substitute for methods that are appropriate for the question.

Journal of Diabetes NEWS

<i>Journal of Diabetes</i> NEWS

Incidence of Diabetes Following Ramipril or Rosiglitazone Withdrawal

OBJECTIVETo examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.RESEARCH DESIGN AND METHODSThe 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone.RESULTSFollowing median (interquartile range) 71 (63–86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo.CONCLUSIONSIn people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.

Type 2 diabetes can be prevented with early pharmacological intervention.

In the U.S., ∼21 × 106 individuals have type 2 diabetes, and twice as many have impaired glucose tolerance (IGT). Approximately 40–50% of individuals with IGT will progress to type 2 diabetes over their lifetime. Therefore, treatment of high-risk individuals with IGT to prevent type 2 diabetes has important medical, economic, social, and human implications. Weight loss, although effective in reducing the conversion of IGT to type 2 diabetes, is difficult to achieve and maintain. Moreover, 40–50% of IGT subjects progress to type 2 diabetes despite successful weight reduction. In contrast, pharmacological treatment of IGT with oral antidiabetic agents that improve insulin sensitivity and preserve β-cell function—the characteristic pathophysiological abnormalities present in IGT and type 2 diabetes—uniformly have been shown to prevent progression of IGT to type 2 diabetes. The most consistent results have been observed with the thiazolidinediones (Troglitazone in the Prevention of Diabetes [TRIPOD], Pioglitazone in the Prevention of Diabetes [PIPOD], Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM], and Actos Now for the Prevention of Diabetes [ACT NOW]), with a 50–70% reduction in IGT conversion to diabetes. Metformin in the U.S. Diabetes Prevention Program (DPP) reduced the development of type 2 diabetes by 31% and has been recommended by the American Diabetes Association (ADA) for treating high-risk individuals with IGT. The glucagon-like peptide-1 analogs, which augment insulin secretion, preserve β-cell function, and promote weight loss, also would be expected to be efficacious in preventing the progression of IGT to type 2 diabetes. Because individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70–80% of their β-cell function, and have an ∼10% incidence of diabetic retinopathy, pharmacological intervention, in combination with diet plus exercise, should be instituted.

Long-term effect of rosiglitazone and/or ramipril on the incidence of diabetes

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial reported that 3years of therapy with rosiglitazone reduced the primary outcome of diabetes or death by 60%. Here we investigated whether an effect on diabetes prevention persists more than 1.5years after therapy has been discontinued. The DREAM On passive follow-up study was conducted at 49 of the 191 DREAM sites. Consenting participants were invited to have a repeat OGTT 1-2years after active therapy ended. A diagnosis of diabetes at that time was based on either a fasting or 2h plasma glucose level of ≥7.0mmol/l or ≥11.1mmol/l, respectively, or a confirmed diagnosis by a non-study physician. Regression to normoglycaemia was defined as a fasting and 2h plasma glucose level of <6.1mmol/l and <7.8mmol/l, respectively. After a median of 1.6years after the end of the trial and 4.3years after randomisation, rosiglitazone participants had a 39% lower incidence of the primary outcome (hazard ratio [HR] 0.61, 95% CI 0.53-0.70; p < 0.0001) and 17% more regression to normoglycaemia (95% CI 1.01-1.34; p = 0.034). When the analysis was restricted to the passive follow-up period, a similar incidence of both the primary outcome and regression was observed in people from both treatment groups (HR 1.00, 95% CI 0.81-1.24 and HR 1.14, 95% CI 0.97-1.32, respectively). Similar effects were noted when new diabetes was analysed separately from death. Ramipril did not have any significant long-term effect. Time-limited exposure to rosiglitazone reduces the longer term incidence of diabetes by delaying but not reversing the underlying disease process.

Diabetes News.

Diabetes News.

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

OBJECTIVEThiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure—outcomes that may have a genetic etiology.RESEARCH DESIGN AND METHODSWe genotyped 4,197 participants of the multiethnic DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965).RESULTSOne SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47–2.42]; P = 5.32 × 10−7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10−4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10−3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05).CONCLUSIONSGenetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.

Effects of ethnicity on diabetes incidence and prevention: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial

Risk of Type 2 diabetes varies by ethnicity, but whether ethnicity remains important among those who have impaired glucose tolerance or impaired fasting glucose is uncertain. Whether the effect of thiazolidinedione treatment on diabetes prevention in persons with non-diabetic dysglycaemia varies by ethnicity is also not known. We addressed these questions using data collected in the DREAM trial. A 2-by-2 factorial double-blind randomized controlled trial to compare the effects of rosiglitazone and ramipril on the primary outcome of diabetes or death in persons meeting criteria for impaired glucose tolerance or impaired fasting glucose. The effect of these interventions by ethnicity was estimated using Cox regression analysis. Of 5269 adults, 2365 were randomly assigned to rosiglitzone and 2634 to placebo. South Asians showed a higher hazard for the primary outcome compared with Europeans (hazard ratio, 95% confidence interval 2.21, 1.41-3.47) adjusted for age, gender, BMI, waist-hip ratio and geographic region. A lesser increase in risk was seen in Black people (1.37, 1.04-1.81). A significant reduction in risk of the primary outcome with rosiglitazone treatment assignment was seen in all ethnic groups, but the treatment effect significantly differed by ethnicity (P=0.0242), with South Asians experiencing a smaller, and Latinos a larger preventive effect. Ethnicity is an important risk factor for Type 2 diabetes in dysglycaemic persons. All ethnic groups experienced a large significant reduction in diabetes risk because of rosiglitazone. The magnitude of this reduction differed by ethnicity. Given the post hoc nature of this analysis, further confirmation of these findings is needed.

Effect of Rosiglitazone and Ramipril on β-Cell Function in People With Impaired Glucose Tolerance or Impaired Fasting Glucose

OBJECTIVEThe objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed β-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals.RESEARCH DESIGN AND METHODSThe present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. β-Cell function was assessed using the fasting proinsulin–to–C-peptide ratio (PI/C) and the insulinogenic index (defined as 30–0 min insulin/30–0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]).RESULTSSubjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (−0.010 vs. −0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and −0.007 vs. −0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: −0.003 vs. −0.001, P = 0.07).CONCLUSIONSTreatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of β-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved β-cell function.

Dysglycemia and a History of Reproductive Risk Factors

OBJECTIVE—The purpose of this study was to identify reproductive risk factors associated with dysglycemia (diabetes, impaired glucose tolerance, and impaired fasting glucose) in a contemporary multiethnic population.RESEARCH DESIGN AND METHODS—We studied 14,661 women screened with an oral glucose tolerance test for the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial. Reproductive risk factors were compared in normoglycemic and dysglycemic women.RESULTS—Dysglycemia was significantly associated with the number of children born (odds ratio 1.03 per child [95% CI 1.01–1.05]), age (1.05 per year [1.04–1.05]), non-European ancestry (1.09 [1.01–1.17]), preeclampsia/eclampsia (1.14 [1.02–1.27]), irregular periods (1.21 [1.07–1.36]), and gestational diabetes mellitus (GDM) (1.53 [1.35–1.74]). The relationship between GDM and dysglycemia did not differ across BMI tertiles (P = 0.84) nor did the relationships of other risk factors.CONCLUSIONS—Reproductive factors, particularly GDM, are associated with dysglycemia in middle-aged women from many ethnicities. Reproductive factors can be used to counsel young women about their future risk of dysglycemia, whereas in middle age they may help screen for dysglycemia.

Effects of Ramipril and Rosiglitazone on Cardiovascular and Renal Outcomes in People With Impaired Glucose Tolerance or Impaired Fasting Glucose

Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.

Prevention of Type 2 diabetes: fact or fiction?

The growing prevalence of Type 2 diabetes with its high morbidity and excess mortality is imposing a heavy burden on healthcare systems. Because of the magnitude of the problem, obviating diabetes has been a long-standing dream. In the last decade, a number of intervention strategies have been shown to be effective for the prevention of diabetes in high-risk populations with prediabetes. Seven studies have now confirmed that lifestyle modifications, including weight-reducing diets and exercise programs, are very effective in precluding or delaying Type 2 diabetes in high-risk populations with impaired glucose tolerance (IGT). Two major trials are the Diabetes Prevention Study (n = 522) from Finland and the Diabetes Prevention Program (n = 3234) from the US. Both studies have shown that intensive lifestyle intervention could reduce the progression of IGT to diabetes by 58%. Furthermore, four currently-available drugs have been established as being effective in preventing diabetes in subjects with prediabetes. The Diabetes Prevention Program revealed that metformin 850 mg b.i.d. reduced the risk of diabetes by 31%. The STOP-NIDDM (Study To Prevent Non-Insulin-Dependent Diabetes Mellitus) trial (n = 1429) showed that acarbose 100 mg t.i.d. with meals decreased the incidence of diabetes by 36% when the diagnosis was based on 2 oral glucose tolerance tests. The XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) study examined the use of orlistat, an antiobesity drug, as an adjunct to an intensive lifestyle modification program in obese non-diabetic subjects. Orlistat treatment resulted in a 37% decline in the development of diabetes. More recently, the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study (n = 5269) demonstrated that rosiglitazone at 8 mg once/day in subjects with prediabetes (IGT and/or impaired fasting glucose) was effective in reducing the risk of diabetes by 60%. It can be concluded that Type 2 diabetes can be prevented or delayed through lifestyle modifications and/or pharmacologic interventions. This is a fact.

The new clinical trials with thiazolidinediones – DREAM, ADOPT, and CHICAGO: promises fulfilled?

Despite extensive documentation of their insulin-sensitizing and antihyperglycemic effects, the importance and place of the thiazolidinediones in diabetes management remain unclear. Three new controlled clinical trials of thiazolidinediones offer new information on the clinical utility of these agents. During the past year, three new trials of thiazolidinediones were reported. In Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication, rosiglitazone reduced progression to diabetes in prediabetic patients by 60%. A Diabetes Outcome Progression Trial found rosiglitazone to have greater antihyperglycemic durability than metformin and glyburide in patients with recently diagnosed type 2 diabetes. Finally, in the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone, treatment with pioglitazone in patients with type 2 diabetes slowed progression of carotid wall thickness compared with the sulfonylurea glimepiride. These trials support the contention that thiazolidinediones have superior efficacy in improving and stabilizing glycemic control than older antihyperglycemic agents, especially early in the course of type 2 diabetes. Findings from the Carotid Intima-media Thickness in Atherosclerosis using Pioglitazone add to the evidence that these agents have clinically meaningful vasculoprotective effects. Although generally well tolerated, they promote weight gain, limiting their acceptability to some extent, and occasionally lead to a diagnosis of heart failure, mostly in susceptible individuals.

Clinical Implications of the DREAM Study

The following points should be taken into consideration when determining “what circumstances TZDs [thiazolidinediones] should be used in people without documented diabetes,” as questioned by the commentary published in the February issue of Diabetes Care (1). The DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study (2) has limitations that prevent generalizations for individuals with impaired fasting …

A Work in Progress, but a Useful Construct

The metabolic syndrome is a construct that has come into common usage over the last few decades. In 1956, Jean Vague1 first demonstrated that upper-body obesity determined predisposition to diabetes mellitus, atherosclerosis, gout, and renal calculi; however, it was the presentation of this concept by Gerald Reaven in his Banting Lecture in 19882 that initiated the current focus on this entity as a clinical and pathological construct. Dr Reaven suggested that 3 major conditions—non–insulin-dependent diabetes mellitus (type 2 diabetes mellitus), hypertension, and coronary artery disease—had an causal commonality (resistance to insulin-stimulated glucose uptake and hyperinsulinemia) and referred to this constellation of abnormalities as “syndrome X.” He did not include abdominal obesity in the original description, nor did he comment significantly on a potential clinical role for his observations. In fact, his concluding sentences stated, “What remains to be seen is the magnitude of the role that resistance to insulin-stimulated glucose uptake plays in the etiology of human disease. I can only hope that this presentation has outlined the possibilities for future efforts to answer this question.” Response by Kahn p 1818 Since that time, this construct has evolved conceptually and functionally into an entity that many refer to as a “syndrome.” More recently, there have been many questions about the legitimacy of this designation, summarized by Kahn et al3 in a September 2005 position statement for the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Their comments called into question many of the assumptions that underlay the designation of “syndrome,” and they posed the following key questions: How clear is the existing definition of the metabolic syndrome for diagnostic purposes? How useful is the syndrome definition in predicting cardiovascular disease (CVD) risk? Do the individual components of the syndrome convey “risk” …

Diabetes Prevention Between RAAS Inhibition and PPAR-Gamma Stimulation: The Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial

Diabetes Prevention Between RAAS Inhibition and PPAR-Gamma Stimulation: The Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial