European Heart Journal Advance Access originally published online on March 18, 2008
European Heart Journal 2008 29(8):1076-1077; doi:10.1093/eurheartj/ehn117
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Glucose, insulin, and coronary heart disease: reply
Department of Cardiology
Karolinska Hospital
Stockholm S171 76
Sweden
Department of Cardiology
Karolinska Hospital
Stockholm S171 76
Sweden
Department of Cardiology
Karolinska Hospital
Stockholm S171 76
Sweden
Department of Cardiology
Karolinska Hospital
Stockholm S171 76
Sweden
Tel: +46 85 177 2171
Fax: +46 8 344964
Email: lars.ryden{at}ki.se
We appreciate that our articles on potentially negative effects of insulin treatment have attracted interest that initiates a discussion on possible explanations to this seemingly unexpected finding. We agree that the analysis of inflammatory markers and cytokines may shed some further light on this issue. Such studies are under way in a fairly large subgroup of the DIGAMI 2 patients. That insulin may relate to increased release of inflammatory cytokines in diabetic patients with coronary artery disease has recently been reported by Antoniades et al.1 We do, however, not believe that, as suggested ‘the negative results could be due to higher serum glucose levels in the insulin group since glucose has proinflammatory actions...’. The data presented were obtained at comparable levels of glycemic control since, as stated in the statistics section, an adjustment for updated glucose levels during the complete period of follow-up was included in the comparison of different glucose lowering treatments. Thus, the difference between metformin (favourable impact) and insulin (negative impact) cannot be explained by lower glucose levels during the former than the latter treatment modality. We share the assumption that the outcome of insulin treatment might have been more favourable if glucose control had been more efficient than that achieved a fasting glucose of 8.0–8.3 mmol/L.2 We did indeed suggest that: ‘if insulin is used for glucose control, it is important that the treatment target is normoglycemia in order to balance the favourable impact of glycemic control against potentially harmful effects of insulin in itself’. This hypothesis is presently tested in the ongoing Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial.3
In this context we would also like to comment upon the very thoughtful editorial4 that accompanied our articles in the European Heart Journal. We agree with most of what was written but would like to underline one thing of great importance that seems to have been overlooked. Like the authors of the editorial and the letter to the Editor, our original thought was that the observation of a harmful effect of insulin, despite meticulous statistical adjustments and the application of a propensity score, was influenced by confounders. This is why we finally focused only on patients who never had been treated with insulin before but who, according to the protocol in DIGAMI 2, were randomized to receive this drug or not.
The negative impact of insulin was if anything even more apparent in this rather large subgroup [n = 245; HR for myocardial infarction or stroke 2.22 (95% CI 1.46–3.35; P = 0.0002)]. Thus, although made in epidemiological and survey analyses, our observations need to be taken seriously. The demand for prospective, outcome trials on the impact of glucose lowering agents seems to be mandatory. In such studies, there will be ample room for mechanistic observations, e.g. that are interesting but presently speculative and perhaps of less immediate clinical relevance.
References
- Antoniades C, Tousoulis D, Marinou K, Papageorgiu N, Bosinakou E, Tsioufis C, Stefinidi E, Latsiois G, Tentolouris C, Siasos G, Stefanidis C. Effect of insulin dependence on inflammatory process, thrombotic mechanisms and endothelial function, in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clin Cardiol (2007) 30:295–300.[CrossRef][Web of Science][Medline]
- Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K, Laakso M, Torp-Pedersen C, Waldenström A, and the DIGAMI 2 investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J (2005) 26:650–661.
[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]
- Radke PW, Schunkert H. Glucose-lowering therapy after myocardial infarction: more questions than answers. Eur Heart J (2008) 29:141–143.
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