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Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
Correspondence
What is the logic, in the CANOE trial (July 10, p 103),1 of taking patients without diabetes and giving them diabetes medicines, which they might be interested in avoiding by avoiding diabetes? We think this regimen is motivated by an implicit preference for an alternative to community and clinical interventions to prevent disease through healthy lifestyles.2,3 After giving up on lifestyle interventions, are pills an attractive alternative? CANOE, and DREAM before it, highlight a major problem of using diabetes medicines to prevent diabetes. The safety of rosiglitazone, used in both trials, is in question and the drug has now been removed from the European market. Whatever benefits might outweigh exposure to this medicine in patients with severe type 2 diabetes do not exist in the case of diabetes prevention. This point is particularly striking when one realises that diabetes is a surrogate outcome for a symptomatic condition (uncontrolled hyperglycaemia) or for elevated cardiovascular risk.4 Furthermore, because the market of healthy people at risk of diabetes is enormous, the number of individuals exposed to harm will be large, as would be the cost of the intervention itself and of caring for the harms it will cause. While high-income countries struggle to balance budgets after the economic depression and seek to restrict healthcare spending, emerging economies— some of which have fared better (eg, Peru)—might be tempted to make the mistakes that high-income nations can no longer afford. The medicalisation of social problems and medicationmediated prevention of risk factors seems counterintuitive and wrong. We declare that we have no conflicts of interest.
*German Malaga, Juan J Miranda [email protected]
www.thelancet.com Vol 376 October 23, 2010
Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima 33, Peru 1
2
3
4
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010; 376: 103–11. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997; 20: 537–44. 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. Montori VM, Isley WL, Guyatt GH. Waking up from the DREAM of preventing diabetes with drugs. BMJ 2007; 334: 882–84.
In the CANOE trial,1 Bernard Zinman and colleagues report that a lowdose combination of rosiglitazone and metformin is more efficacious than placebo for diabetes prevention in patients with glucose intolerance. We wonder whether thinking about this type of treatment as diabetes prevention is misleading: instead of truly preventing disease, the threshold for diabetes treatment is simply being shifted earlier. This message could lead to a perverse mechanism of prescribing hypoglycaemic drugs to non-diabetic people on the basis of surrogate endpoints (results of fasting glucose and glucose tolerance tests are not hard primary endpoints in the same way as is prevention of diabetes complications). Moreover, the idea that glucose concentrations should correlate with better long-term prognosis is not supported by a systematic review that questioned the role of intensive glucose control in patients with type 2 diabetes.2 Finally, we wonder about the choice of rosiglitazone for combination treatment, since emerging data warn about its safety.3,4 Zinman and colleagues’ study, although well designed, is not statistically powered to drive conclusions about rosiglitazone safety. Glucose intolerance and type 2 diabetes can be regarded as a continuum,5 and they are best managed by focusing on global risk reduction
for associated outcomes rather than merely on euglycaemia. Before recommendations for clinical practice are changed, further studies are needed to assess whether the pharmacological treatment of glucose intolerance could affect important outcomes. Science Photo Library
Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
We declare that we have no conflicts of interest.
*Elisa Ceriani, Giorgio Costantino, Giovanni Casazza, Gian Marco Podda, on behalf of GRAM (GRuppo Autoformazione Metodologica) [email protected] Divisions of Internal Medicine II (EC, GCo) and Medical Statistics (GCa), Department of Clinical Sciences, L Sacco Hospital, University of Milan, 20157 Milan, Italy; and Division of Internal Medicine III, Department of Medicine, San Paolo Hospital, University of Milan, Milan, Italy (GMP) 1
2
3
4
5
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010; 376: 103–11. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–72. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007; 298: 1189–95. Graham DJ, Ouellet-Hellstrom R, Macurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010; 304: 411–18. Vickers AJ, Basch E, Kattan MW. Against diagnosis. Ann Intern Med 2008; 49: 200–03.
Bernard Zinman and colleagues1 did a double-blind, randomised controlled trial (CANOE) enrolling 207 patients with impaired glucose tolerance who were assigned to rosiglitazone (2 mg) plus metformin (500 mg) twice daily or matching placebo for a median of 3·9 years. They report that combination therapy was associated with a significant reduction in the incidence of type 2 diabetes (relative risk reduction 66%, 95% CI 41–80), albeit with a significant increase in diarrhoea episodes. The magnitude of the relative risk reduction is similar to that (60%) reported in a previous placebocontrolled randomised trial with high-dose rosiglitazone alone.2 The
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1387
What is the logic, in the CANOE trial (July 10, p 103),1 of taking patients without diabetes and giving them diabetes medicines, which they might be interested in avoiding by avoiding diabetes? We think this regimen is motivated by an implicit preference for an alternative to community and clinical interventions to prevent disease through healthy lifestyles.2,3 After giving up on lifestyle interventions, are pills an attractive alternative? CANOE, and DREAM before it, highlight a major problem of using diabetes medicines to prevent diabetes. The safety of rosiglitazone, used in both trials, is in question and the drug has now been removed from the European market. Whatever benefits might outweigh exposure to this medicine in patients with severe type 2 diabetes do not exist in the case of diabetes prevention. This point is particularly striking when one realises that diabetes is a surrogate outcome for a symptomatic condition (uncontrolled hyperglycaemia) or for elevated cardiovascular risk.4 Furthermore, because the market of healthy people at risk of diabetes is enormous, the number of individuals exposed to harm will be large, as would be the cost of the intervention itself and of caring for the harms it will cause. While high-income countries struggle to balance budgets after the economic depression and seek to restrict healthcare spending, emerging economies— some of which have fared better (eg, Peru)—might be tempted to make the mistakes that high-income nations can no longer afford. The medicalisation of social problems and medicationmediated prevention of risk factors seems counterintuitive and wrong. We declare that we have no conflicts of interest.
*German Malaga, Juan J Miranda [email protected]
www.thelancet.com Vol 376 October 23, 2010
Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima 33, Peru 1
2
3
4
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010; 376: 103–11. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997; 20: 537–44. 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. Montori VM, Isley WL, Guyatt GH. Waking up from the DREAM of preventing diabetes with drugs. BMJ 2007; 334: 882–84.
In the CANOE trial,1 Bernard Zinman and colleagues report that a lowdose combination of rosiglitazone and metformin is more efficacious than placebo for diabetes prevention in patients with glucose intolerance. We wonder whether thinking about this type of treatment as diabetes prevention is misleading: instead of truly preventing disease, the threshold for diabetes treatment is simply being shifted earlier. This message could lead to a perverse mechanism of prescribing hypoglycaemic drugs to non-diabetic people on the basis of surrogate endpoints (results of fasting glucose and glucose tolerance tests are not hard primary endpoints in the same way as is prevention of diabetes complications). Moreover, the idea that glucose concentrations should correlate with better long-term prognosis is not supported by a systematic review that questioned the role of intensive glucose control in patients with type 2 diabetes.2 Finally, we wonder about the choice of rosiglitazone for combination treatment, since emerging data warn about its safety.3,4 Zinman and colleagues’ study, although well designed, is not statistically powered to drive conclusions about rosiglitazone safety. Glucose intolerance and type 2 diabetes can be regarded as a continuum,5 and they are best managed by focusing on global risk reduction
for associated outcomes rather than merely on euglycaemia. Before recommendations for clinical practice are changed, further studies are needed to assess whether the pharmacological treatment of glucose intolerance could affect important outcomes. Science Photo Library
Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
We declare that we have no conflicts of interest.
*Elisa Ceriani, Giorgio Costantino, Giovanni Casazza, Gian Marco Podda, on behalf of GRAM (GRuppo Autoformazione Metodologica) [email protected] Divisions of Internal Medicine II (EC, GCo) and Medical Statistics (GCa), Department of Clinical Sciences, L Sacco Hospital, University of Milan, 20157 Milan, Italy; and Division of Internal Medicine III, Department of Medicine, San Paolo Hospital, University of Milan, Milan, Italy (GMP) 1
2
3
4
5
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010; 376: 103–11. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–72. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007; 298: 1189–95. Graham DJ, Ouellet-Hellstrom R, Macurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010; 304: 411–18. Vickers AJ, Basch E, Kattan MW. Against diagnosis. Ann Intern Med 2008; 49: 200–03.
Bernard Zinman and colleagues1 did a double-blind, randomised controlled trial (CANOE) enrolling 207 patients with impaired glucose tolerance who were assigned to rosiglitazone (2 mg) plus metformin (500 mg) twice daily or matching placebo for a median of 3·9 years. They report that combination therapy was associated with a significant reduction in the incidence of type 2 diabetes (relative risk reduction 66%, 95% CI 41–80), albeit with a significant increase in diarrhoea episodes. The magnitude of the relative risk reduction is similar to that (60%) reported in a previous placebocontrolled randomised trial with high-dose rosiglitazone alone.2 The
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1387