European Heart Journal Advance Access originally published online on June 13, 2008
European Heart Journal 2008 29(16):2058-2059; doi:10.1093/eurheartj/ehn263
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Cardiovascular prevention in high-risk patients with type 2 diabetes mellitus: when to start it?: reply
Department of Cardiology
Karolinska University Hospital Solna
171 76 Stockholm
Sweden
Tel: +46 8 51 77 21 71
Fax: +46 8 34 49 64
Email: linda.mellbin{at}karolinska.se
Department of Cardiology
Karolinska University Hospital Solna
171 76 Stockholm
Sweden
Department of Cardiology
Karolinska University Hospital Solna
171 76 Stockholm
Sweden
Department of Cardiology
Karolinska University Hospital Solna
171 76 Stockholm
Sweden
Nordic School of Public Health
Göteborg
Sweden
We are grateful for the attention our article on the potential drawback of insulin in patients has attracted, most recently in the letter to the Editor by Drs Garcia and Lopez-Jaramillo. This debate may encourage further efforts to study the proper use of this and other glucose-lowering drugs and serves as an incitement to conduct better trials not only addressing the glucose-lowering potential of these drugs but also and importantly their impact on cardiovascular morbidity and mortality.
We agree with the point raised by the authors of the letter that duration of diabetes certainly may be an important factor for the outcome of our study. In the DIGAMI 2 trial, patients with insulin treatment did indeed have a longer duration of their disease.1 Looking only at patients with newly instituted insulin at discharge, where of a majority were randomized to insulin, the difference was still apparent although less prominent (mean ± SD = 5.6 ± 5.8 years) compared with patients without insulin (4.5 ± 5.7 years; P = 0.016). Aware of this potential confounder, we did, as outlined in the statistics section of our article, apply a propensity score model to control for diabetes duration in a stepwise logistic regression. Other variables in this model were heart failure, hypertension, blood glucose, and the use of lipid-lowering drugs. Although a propensity score model cannot completely rule out some remaining influence of the included confounders ‘the influence of chronic hyperglycaemia’ was taken in consideration. Consequently, it is not a likely explanation of the increased likelihood of subsequent cardiovascular morbidity, especially not in patients with newly instituted insulin.
We do also agree that the formation of advanced glycation endproduct (AGE) may stand behind untoward consequences of longstanding hyperglycaemia and as such responsible for part of the vascular damage related to diabetes.2 Hopefully, this may be counteracted by the early institution of glucose-lowering therapy and one remedy for this is insulin. We share the opinion that, if oral glucose-lowering therapy fails to normalize glycaemia, insulin should be instituted without further delay and that this option often is chosen too late in present all day practice.3 However, in the light of our recent observations from the DIGAMI 2 trial1 and those in the Euro Heart Survey on Diabetes and the Heart,4 we advocate that glucose during such treatment should be kept as normal as possible to balance the potentially negative effects of exogenous insulin against the beneficial effects of avoiding untoward hyperglycaemia.
As mentioned in the letter to the Editor, the outcome of the ORIGIN trial is of great importance to further elucidate benefits and drawbacks with insulin treatment in patients with diabetes and at a high cardiovascular risk. It should, however, be remembered that this trial has recruited patients with impaired glucose tolerance and newly detected or relatively short-lasting diabetes.5 All patients in the DIGAMI 2 study had well-established diabetes and myocardial infarction and may therefore be in a somewhat different situation. Finally and sadly enough, our trial demonstrated how difficult it is, despite a clearly defined treatment targets, to normalize blood glucose in such a population. We may therefore all agree that there is a great need for new and better tools for glucose lowering that combines the ultimate goals, glucose normalization, and cardiovascular disease reduction.
References
- Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L, DIGAMI 2 Investigators. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J (2008) 29:166–176.
[Abstract/Free Full Text] - Brownlee M. Glycosylation products as toxic mediators of diabetic complications. Ann Rev Med (1991) 42:159–166.[CrossRef][Web of Science][Medline]
- Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, Cosentino F, Jonsson B, Laakso M, Malmberg K, Priori S, Östergren J, Tuomilehto J, Thrainsdottir I. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: the Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J (2007) 28:88–136.
[Free Full Text] - Anselmino M, Öhrvik J, Malmberg K, Standl E, Rydén L, on behalf of the Euro Heart Survey Investigators. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the Euro Heart Survey on Diabetes and the Heart. Europ Heart J (2008) 29:177–184.
[Abstract/Free Full Text] - Gerstein HC, Yusuf S, Riddle M, Rydén L, Bosch J, for The ORIGIN Trial Investigators Rationale. Design and Baseline Characteristics for a Large International Trial of Cardiovascular Disease Prevention in People with Dysglycaemia: The ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J (2008) 155:26–32.[Web of Science][Medline]
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