Role for insulin in acute myocardial infarction: ruled out or hard to prove?

Iwan C.C. van der Horst and Felix Zijlstra

Department of Cardiology
University Medical Center Groningen
PO Box 30001
9700 RB Groningen
The Netherlands
Tel: +31 50 3612355
Fax: +31 50 3611347
E-mail address:
i.c.c.van.der.horst{at}thorax.umcg.nl

The only large randomized trials to investigate treatment focused on hyperglycaemia in MI patients were the Diabetes Insulin– Glucose in Acute Myocardial Infarction (DIGAMI) studies. In the first DIGAMI, the combination of insulin–glucose infusion followed by intensive insulin treatment resulted in both better glucose control and a reduction in hospital mortality from 11.1 to 9.1% (NS) and an absolute mortality reduction of 7.5% after 1 year.1 However, DIGAMI 2 could not confirm either the beneficial effect of early or sustained insulin treatment.2 During the first 24 h, intensive insulin treatment resulted in a decrease in glucose level from 12.7 to 9.1 mmol/L vs. 12.7 to 10.0 mmol/L in control patients.

Is the role for insulin in acute MI ruled out? Yes, based on the current literature there is no evidence to support insulin treatment. Nevertheless, positive effects of insulin during myocardial ischaemia have been described in experimental studies.3 They depend on the influence on reduced fatty acid oxidation, increased glucose oxidation, and diminished apoptosis of myocardial cells to induce myocardial survival. These effects, however, could only be obtained soon after the initiation of myocardial ischaemia.4 Furthermore, there is a large amount of clinical evidence to support the concept that hyperglycaemia has an unfavourable effect.2,5,6 Hyperglycaemia during MI is short lived and strict glucose control should be obtained as soon as possible after symptom onset. Unfortunately, in the DIGAMI 2, the time delay between hospital admission and randomization, i.e. insulin treatment, averaged 8.6 h.

Is the role for insulin hard to prove? Yes, in MI patients, it is not easy to obtain glucose levels within the set range of 7.0–10.0 mmol/L within 24 h after admission.1,2,7,8 In critically ill patients, strict glucose was obtained,9 although it took ~24 h to reach target levels.10

Another striking aspect of the DIGAMI 2 study may be important to explain the results. Only one out of five hyperglycaemic/diabetes patients was treated with either coronary artery bypass grafting or primary percutaneous coronary intervention. To finally answer the question whether or not insulin therapy is of benefit in acute MI, MI patients should be treated with optimal modern reperfusion therapy and randomized to early, goal-directed insulin treatment. For instance, aiming of a glucose level of 7.0 mmol/L within 4 h after presentation and a more strict control thereafter.

References

  1. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin–glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57–65.[Abstract]
  2. Malmberg K, Ryden 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, Waldenstrom A; 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]
  3. Opie LH, Jonnesen A, Yellon DM. The glucose hypothesis: updated or outdated? Role of insulin. Cardiovasc J S Afr 2004;15:S1.
  4. Eberli FR, Weinberg EO, Grice WN, Horowitz GL, Apstein CS. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res 1991;68:466–481.[Abstract/Free Full Text]
  5. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359:2140–2144.[CrossRef][ISI][Medline]
  6. Timmer JR, van der Horst IC, Ottervanger JP, Henriques JP, Hoorntje JC, de Boer MJ, Suryapranata H, Zijlstra F; Zwolle Myocardial Infarction Study Group. Prognostic value of admission glucose in non-diabetic patients with myocardial infarction. Am Heart J 2004;148:399–404.[CrossRef][ISI][Medline]
  7. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E, Ahmed R, Xie C, Kazmi K, Tai J, Orlandini A, Pogue J, Liu L; CREATE-ECLA Trial Group Investigators. Effect of glucose–insulin–potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA 2005;293:437–446.[Abstract/Free Full Text]
  8. van der Horst IC, Zijlstra F, van't Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ, Zwolle Infarction Study Group. Glucose–insulin–potassium infusion in patients treated with primary angioplasty for acute myocardial infarction: the glucose–insulin– potassium study: a randomized trial. J Am Coll Cardiol 2003;42:784–791.[Abstract/Free Full Text]
  9. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367.[Abstract/Free Full Text]
  10. van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–366.[CrossRef][ISI][Medline]




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