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Glucose lowering and diabetes prevention: are they the same? COMMENTARY Published online September 15, 2006
The prevention of type 2 diabetes is a major public-health issue. The results of the Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial,1 show that progression to diabetes in people with impaired glucose regulation can be diminished. The relative risk reduction of rosiglitazone seen in DREAM was similar to that obtained by lifestyle interventions2-5 and much the same as that seen in two previous trials of the now withdrawn thiazolidinedione troglitazone.6,7
Rosiglitazone has been approved as a drug that lowers plasma glucose concentrations and is licensed for use in diabetes. In DREAM, rosiglitazone lowered the 2-h plasma glucose concentration by 1•6 mmol/L in people with abnormal glucose regulation but free of diabetes. In observational studies, a 1 mmol/L difference in 2-h glucose concentrations is associated with a relative risk for progression to diabetes of 0•6.8 Thus, given the glucose lowering seen in the trial, one would expect the trial relative risk to be 0•44, which is within the observed 95% CI of 0•35-0•46 in the trial. In other words, the outcome is no different from that expected from the glucose-lowering effect. Health-care professionals rate diabetes prevention studies as being important much more frequently when results are shown in this way rather than as changes in a continuously distributed measure of glucose, even though the two events are directly related.9 If one accepts that the benefits of diabetes prevention lie in the downstream benefit of reductions in the complications of diabetes, especially cardiovascular disease, then presenting the change in glucose as a continuous variable could be more relevant because it more easily allows calculation of the future effect on diabetes complications, even though large relative-risk reductions might sound more impressive.
The DREAM trial was under-powered to estimate the effect of glucose lowering on cardiovascular disease events, in part because the trial expressly recruited individuals free from such disease. One can estimate the likely effect on cardiovascular disease events with data from observational studies, because each 1•1 mmol/L difference in fasting glucose concentration is associated with a 20% difference in cardiovascular disease risk.10 Thus the difference of 0•5 mmol/L seen in DREAM should lower risk by about 8•6%. This reduction is just outside the lower boundary of the 95% CI recorded in DREAM (0•97-1•94). If this estimate were the true value, the number needed to treat people like those in DREAM for 3 years to prevent one cardiovascular disease event would be 554, which is very high.
In the ProActive trial, another thiazolidinedione drug- pioglitazone-was associated with an increased risk of heart failure.11 This side-effect was much less common in the DREAM population, who were free of pre-existing heart disease. Nevertheless, the risk was seven times greater in those who received rosiglitazone than in those in the placebo group. A more common adverse effect was weight gain. Although this weight gain might be associated with a more favourable distribution of fat, it is a concern. It is difficult to give clear lifestyle messages to overweight individuals with hyperglycaemia, for whom weight loss is at the centre of their therapy, if one prescribes agents that promote weight gain. There is also evidence from longitudinal studies that weight gain is associated with decreased physical activity,12 which would certainly not be advantageous to this population. Since the DREAM trial was short term, we do not know the long-term effects of such weight gain. The likelihood of developing heart failure over the long term is another concern.
A critical issue in diabetes prevention is whether the effect of the intervention lasts only as long as the treatment, or if it is sustained. Such data have not yet been presented. However, data from the troglitazone arm of the Diabetes Prevention Program suggest that the risk returns to the untreated level when the drug is withdrawn.7 The same occurrence is not seen for lifestyle interventions. The extension of the Finnish Diabetes Prevention Study suggests that the benefits of intensive lifestyle intervention are sustained for many years after the intervention period (unpublished data).13 Overall, despite the impressive risk reduction for progression to diabetes, the lack of data on long-term benefits and side-effects, and the high cost of therapy, mean that health-care funders are unlikely to see rosiglitazone as an appropriate agent for individuals with impaired glucose regulation but low absolute cardiovascular risk. Unfortunately, the greater benefits in higher risk individuals would have to be balanced against the likely increased risk of heart failure. Given the prolonged benefits and demonstrable cost effectiveness of intensive lifestyle intervention for people at high risk of diabetes, such interventions should remain the mainstay for the prevention of type 2 diabetes.
*Jaakko Tuomilehto, Nicholas Wareham
Department of Public Health, University of Helsinki, Helsinki, Finland (JT) and MRC Epidemiology Unit, Elsie Widdowson Laboratory, Cambridge, UK (NW)
JT has received research grants from AstraZeneca, Bayer, and Novartis, and has served as a speaker at meetings or advisory panels organised by AstraZeneca, Bayer, Novartis, Novo Nordisk, MSD, Pfizer, Sanofi-Aventis, and Takeda. NW declares that he has no conflict of interest.
1 DREAM trial investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; published online Sept 15. DOI:10.1016/S0140-6736(06)69420-8.
2 Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-50.
3 The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.
4 Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49: 289-97.
5 Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 1991; 34: 891-98.
6 Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic betacell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51: 2796-803.
7 The Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 2005; 54: 1150-56.
8 Forouhi NG, Luan J, Wareham NJ. The descriptive epidemiology of diabetes and pre-diabetes in England. Diabet Med (in press).
9 Muhlhauser I, Kasper J, Meyer G, Federation of European Nurses in Diabetes. Understanding of diabetes prevention studies: questionnaire survey of professionals in diabetes care. Diabetologia 2006; 49: 1742-46.
10 Levitan EB, Song Y, Ford ES, Liu S. Is nondiabetic hyperglycaemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med 2004; 164: 2147-55.
11 Dormandy J, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-89.
12 Petersen L, Schnohr P, Sorensen TI. Longitudinal study of the long-term relation between physical activity and obesity in adults. Int J Obes Relat Metab Disord 2004; 28: 105-12.
13 Herman WH, Hoerger TJ, Brandle M, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 2005; 346: 393-403.
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