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• W2038863778 abstract "Our increasingly sedentary ‘super size me’ society of dietary excess generates spiralling rates of diabetes mellitus and the metabolic syndrome. More than 8% of adults worldwide have impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and 5% have frank type 2 diabetes.1 Every year 5–10% of the former group will progress to the latter. Coupled with the extensive mortality and morbidity associated with diabetes, the substantial personal and economic cost that these place upon society and the health care system means that strategies to prevent the development of diabetes are increasingly attractive. The question is: ‘Which strategy, at a national and individual level, is most likely to be successful and cost effective?’ This year's meeting of the European Association for the Study of Diabetes in Copenhagen included the presentation of the prospective trial, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study, which addressed this major public health issue — the prevention of type 2 diabetes mellitus. In short, rosiglitazone but not ramipril reduced the incidence of diabetes but both drugs were demonstrably metabolically active, increasing the likelihood of regression to normoglycaemia.2, 3 The DREAM trial was a double-blind, multinational randomised clinical trial with a two-by-two factorial design. Patients were randomly assigned to receive the thiazolidinedione (TZD) rosiglitazone at an 8mg dose or placebo and concurrently assigned to the angiotensin converting enzyme (ACE) inhibitor ramipril at 15mg, or placebo. In all, 24 592 people aged 30 or more were assessed for eligibility with a 75g oral glucose tolerance test and the trial included 5269 patients with IFG or IGT, the accepted ‘pre-diabetic’ states. None of the subjects had cardiovascular disease as it was deemed unethical not to treat these people with open-label ACE inhibitor, based on the results of the HOPE study.4 The median follow up was three years and the primary composite endpoint was incident diabetes or death. The DREAM trial findings were released early on-line in The Lancet and the New England Journal of Medicine.2, 3 The chief points of interest from these trials pertain to the effect of both these medications upon progression to type 2 diabetes, whether they are better than existing medications and strategies and also tolerability, specifically in relation to TZDs' effects on fluid retention and possible heart failure. Thiazolidinediones increase insulin sensitivity by acting on muscle and liver to increase glucose utilisation and decrease glucose production.5 The precise mechanism is yet to be fully elucidated but this class of medication binds to and activates one or more peroxisome proliferator activator (PPAR)-gamma receptors. They preserve insulin secretion and might promote pancreatic betacell health.6-8 They were therefore hypothesised by the DREAM investigators to potentially reduce the frequency of diabetes in high risk individuals. Thiazolidinediones, as a class of medication, lower blood glucose measurements and in the UK are licensed solely for the treatment of diabetes. The hypothesis that an ACE inhibitor may decrease the risk of diabetes emanated from secondary findings of several trials. The Captopril Prevention Project was designed to assess complications and death from cardiovascular disease and noted a 14% lower incidence of diabetes with captopril.9 In the HOPE study, ramipril was found to significantly reduce the diagnosis of self-reported newly diagnosed diabetes by 34%.4 Moreover, a meta-analysis of 12 randomised trials additionally demonstrated a reduction in the risk of diabetes by 27% in patients taking an ACE inhibitor as well as 23% in those patients taking an angiotensin II receptor blocker.10 That these trials had primary endpoints that were cardiovascular in origin but not metabolic could potentially lead to dubiety in terms of ascertainment bias, and hence the two-by-two factorial design of the DREAM study was timely in giving a definitive answer to this important proposal. The primary composite endpoint of incident diabetes or death occurred less frequently with rosiglitazone than with placebo, 11.6% and 26% respectively, giving a hazard ratio (HR) of 0.4 with active treatment (p<0.0001).2 It is important to note several points. Firstly, the rationale of a composite endpoint of death and diabetes may be criticised as both components of the composite endpoint may not carry similar risk reductions. Secondly, death rates were similar in each group and should thus be analysed separately. Thirdly, these findings were recorded during rosiglitazone treatment and the results when the subjects are washed-out of rosiglitazone will be presented later this year at the International Diabetes Federation meeting in Cape Town. This will clarify as to whether rosiglitazone is actually preventing diabetes or simply lowering glucose levels and treating new, as yet undiagnosed, cases of type 2 diabetes mellitus. Furthermore the troglitazone arm of the Diabetes Prevention Program suggested that the risk returns to normal when the drug is withdrawn.11 The absolute risk difference between treatment groups of 14.4% means that for every seven people with IFG or IGT who are prescribed rosiglitazone for three years one will be ‘prevented’ from developing diabetes. This reduction in progression to diabetes is similar to that observed with lifestyle approaches11, 12 and is more than with metformin11 and acarbose.13 On the contrary, there was no significant difference in the primary endpoint with ramipril, with events occurring in 18.1% versus 19.5% in the placebo arm. Both medications, however, had a demonstrable metabolic effect in that they increased the likelihood of the secondary outcome of regression to normoglycaemia, compared to placebo with HRs of 1.71 and 1.16 for rosiglitazone and ramipril respectively. A consistent reduction in the primary outcome was seen independent of age, sex, IFG or IGT, geography, and weight and fat distribution. The average weight gain for those patients in the treatment arm was 2.2kg.2 Thus, paradoxically, while incident progression to diabetes may be diminished, overall cardiovascular risk — a primary concern regarding diabetes — may remain static or be increased. Although diet and increasing physical activity may ultimately be the optimal preventative measure, those with higher BMIs may feel unable to pursue increased activity and pragmatically may have more to gain from a pharmacological-based treatment strategy. Given that the HR for those with a BMI of ≥33kg/m2 was 0.32 as compared to an HR of 0.6 for those with a BMI of <28kg/m2,2 subjects with higher BMIs did gain the most. One of the chief concerns in terms of the safety of TZDs is that of fluid retention. Along the nephron, PPAR-gamma is most abundant in the collecting tubules and fluid retention with TZDs is caused by PPAR-gamma stimulation of sodium reabsorption by sodium channels in the luminal membrane of the collecting tubule cells.14 In the PROactive trial, the other licensed TZD pioglitazone was associated with an apparent 11% risk of heart failure compared to 8% in the placebo group, although this was not an adjudicated endpoint and further analysis will be available shortly.15 There were 16 cases of cardiac failure in the DREAM study so drawing large-scale conclusions would be inappropriate, but the fact that the incidence of ‘ cardiac failure’ was lower than that in the PROactive study probably emanates from the fact that this was a study group expressly free from cardiovascular disease. The rate of cardiac failure with rosiglitazone in DREAM is unacceptable in people who are free from cardiovascular disease at baseline, consequently limiting its use in subjects with IGT or IFG to prevent progression to diabetes. The DREAM study was not designed to estimate the effect of glucose lowering upon cardiovascular disease; indeed, the study investigators recruited individuals without such disease. It is reported that each 1.1mmol/L difference in fasting blood glucose concentration is associated with a 20% difference in cardiovascular disease risk,16 and hence the difference observed in the DREAM study with rosiglitazone of 0.5mmol/L would equate to a risk reduction of 8.6%. From this Tuomilehto et al. propose, in the accompanying editorial, that 554 people, like those in the DREAM trial, would need to be treated for three years to prevent one cardiovascular death.17 Therefore, for a preventative medication for a disease associated with significant cardiovascular morbidity and mortality the figures are far from impressive. In summary, though this study suggests that rosiglitazone, with appropriate lifestyle advice, substantially reduces the risk of developing diabetes by approximately two-thirds when remaining on therapy, balancing both the risks and benefits described above advocates that, for every 1000 people treated with rosiglitazone for three years, 144 cases of diabetes will be prevented with an excess of four to five cases of congestive cardiac failure. Ramipril, while successful in improving the regression to normoglycaemia in the study group, had no demonstrable effect upon the primary endpoint, namely progression to type 2 diabetes. Thus, rosiglitazone cannot be recommended for the prevention of type 2 diabetes in patients with IFG/IGT to prevent the onset of type 2 diabetes. For patients with other indications for an ACE inhibitor, the metabolic advantage of regression to normoglycaemia may be considered beneficial, but for both medications it is as yet unclear whether they are superior to either other pharmaceutical regimens (metformin/acarbose)11, 13 or, indeed, diet and exercise.11, 12" @default.
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• W2038863778 title "Thiazolidinediones: the answer to everyone's dreams?" @default.
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• W2038863778 doi "https://doi.org/10.1002/pdi.1016" @default.
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