QJM Advance Access originally published online on August 19, 2006
QJM 2006 99(9):635-637; doi:10.1093/qjmed/hcl086
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Commentary |
The benefits of insulin therapy following acute myocardial infarction revisited
From the 1Department of Diabetes & Endocrinology, South Manchester University Hospital, Manchester, and 2New Cross Hospital, Wolverhampton, UK
Address correspondence to Dr H. Soran, Specialist Registrar in Endocrinology and Diabetes, Department of Diabetes & Endocrinology, South Manchester University Hospital, Manchester M20 2LR. email: hsoran{at}aol.com
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Introduction |
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 Top Introduction The DIGAMI 2 studyConclusionsReferences |
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The increased mortality and morbidity from cardiovascular disease associated with diabetes mellitus (DM) is well known.1 Patients with DM but no previous myocardial infarction (MI) have a risk of MI similar to that of non-diabetic patients with a previous history of MI,1 and mortality from acute MI in patients with DM is double that in non-diabetic individuals.2,3 Five-year mortality in patients with DM hospitalized with MI is 75%:3 higher than that for many malignant diseases. In spite of more aggressive and interventional therapies for MI, mortality remains significantly higher in patients with DM, compared with those without.4 There are several possible explanations for this increased mortality, including the presence of more severe, extensive and diffuse coronary artery lesions, diabetic cardiomyopathy, diabetic autonomic neuropathy, and the pro-thrombotic tendency in DM.5
The concept of infusing glucose together with insulin and potassium (GIK) to protect ischaemic myocardium was pioneered by Sodi-Pallares et al. more than 40 years ago.6 Many studies lacked statistical power to demonstrate a clear benefit of this intervention compared to controls, and many trials had poor randomization techniques.7 In the DIGAMI study, insulin-glucose intravenous infusion in an acute MI followed by intensive subcutaneous insulin therapy for 3 or more months improved long-term survival compared to the conventional treatment group, with a benefit lasting for at least 3 years.8 The absolute reduction in mortality was 11%, suggesting that one life was saved for every nine treated patients.8 In the DIGAMI study, the greatest mortality reduction was observed in the group that was classified as lowest risk, with an absolute reduction in mortality of 15%. In addition, higher mean glucose values were associated with increased mortality.8 This is in keeping with findings from a latter systematic review9 and another study.10 The clinical implications of the DIGAMI study were not clear; it was not known whether the benefit was related to the initial insulin-glucose infusion, the subsequent subcutaneous insulin treatment, or both. In addition, only half of the patients eligible for entry were randomized over the course of the study. As a result, opinion was divided as to whether the results should be implemented in hospital practice in full,11 or whether we should await the results of further studies.12
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The DIGAMI 2 study |
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TopIntroductionThe DIGAMI 2 studyConclusionsReferences |
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Subsequently, Malmberg et al. embarked on the DIGAMI 2 trial to further investigate their initial findings.13 This study was done in 48 hospitals in Sweden, Norway, Denmark, Finland, Holland and the UK. Patients with diabetes were randomized into three groups: (i) insulin-glucose infusion for 24 h, followed by multi-dose subcutaneous insulin, aiming at a target fasting glucose of 5–7 mmol/l; (ii) insulin-glucose infusion for 24 h, followed by conventional therapy; and (iii) conventional therapy only. However the study at close did not reach the full recruitment of patients. More significantly, the fasting blood glucose target was never reached in group (i) and mean HbA1c did not differ significantly among the three groups. There were no mortality or morbidity differences amongst the three groups, and neither 24-h insulin-glucose infusion nor administration of insulin in the days and months after acute MI appeared to influence the outcome after acute MI. Multivariate logistic regression analysis indicated that the severity of hyperglycaemia was an independent risk factor for adverse outcome.
Disappointingly, the DIGAMI 2 study did not discover whether the hospital insulin or subsequent multi-dose subcutaneous insulin treatment was important. This may have been due to the lack of significant difference in long-term blood glucose between the three arms of the study. Although, a statistically significant difference in blood glucose control was achieved between the first two groups and group three in the acute stage, this difference was smaller than expected, and may not have reached clinical significance. Low recruitment, leading to a 50% reduction in the study power and modifications in the entry criteria to improve recruitment (patients known to have type 2 diabetes and glucose concentration <11 mmol/l were included), may have also played a role. Importantly, the patients investigated in DIGAMI 2 differed significantly from those in the first DIGAMI study. Their levels of admission hyperglycaemia were lower, and this may be the reason for the reduced absolute level of mortality at the end of the study in the three groups. Thus the original DIGAMI trial findings are not entirely contradicted.
In other randomized controlled trials investigating the influence of intensive insulin therapy on the outcome of acutely ill patients in the context of intensive care and after cardiac surgery, where the variation in blood glucose control between different study arms was actually achieved, outcomes were indeed significantly better.7–9,14
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Conclusions |
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TopIntroductionThe DIGAMI 2 studyConclusionsReferences |
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In the DIGAMI 2 trial, patients with type 2 DM did not show improved survival following an acute MI from insulin treatment (either acutely introduced or long-term) compared with conventional management. However several factors, mentioned above, may account for this outcome, which should be interpreted as ‘no result’, rather than a negative result.
In an intensive care study, Van den Berghe et al. indicated that it was the tight glycaemia control in particular, rather than the amount of insulin administered, that explained the mortality benefit in their intensive insulin therapy group.15 However, a role for insulin therapy, independent of its blood-glucose-lowering effect, cannot be completely ruled out.16–18 There is an increasing body of evidence to suggest that preventing hyperglycaemia and subsequent glucose toxicity is an effective, safe and practicable way of reducing mortality and morbidity in both post acute MI and other acutely ill patients.8,9,12,14,15 Due to funding and logistic difficulties, further multicentre randomized controlled trials are unlikely, at least in the near future. Nevertheless, there is a local need to develop protocols. With the current available evidence, out-of-hospital routine subcutaneous insulin may not be necessary, provided that the desired glycaemic control can be attained using lifestyle modifications and oral hypoglycaemic agents. However, in hospital, insulin-glucose infusion as per the DIGAMI protocol appears justified in patients with acute MI and blood glucose concentrations >11 mmol/l.
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References |
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TopIntroductionThe DIGAMI 2 studyConclusionsReferences |
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1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and non diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229–34.
2. Herlitz J, Malmberg K, Karlson BW, Ryden L, Hjalmarson A. Mortality and morbidity during a five year follow-up of diabetes with myocardial infarction. Acta Med Scand 1988; 224:31–81.[Web of Science][Medline]
3. Herlitz J, Bang A, Karlson BW. Mortality, place and mode of death and reinfarction during a period of five years after acute myocardial infarction in diabetic and non-diabetic patients. Cardiology 1996; 87:423–8.[Web of Science][Medline]
4. Brogan GX, Peterson ED, Mulgund J, Bhatt DL, Oham EM, Gilber WB, et al. Treatment disparities in the care of patients with and without diabetes presenting with non–ST-segment elevation acute coronary syndromes. Diabetes Care 2006; 29:9–14.
5. Aronson D, Rayfield E, Cheseboro JH. Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction. Ann Intern Med 1997; 126:296–306.
6. Sodi-Pallares D, Testelli MR, Fishleder B. Effects of intravenous infusion of potassium-insulin-glucose solution on the electrocardiographic signs of myocardial infarction. A preliminary clinical report. Am J Cardiol 1962; 9:116–81.[CrossRef][Web of Science][Medline]
7. Fath-Ordoubadi F and Beatt K. Glucose-insulin-potassium therapy for treatment of myocardial infarction: an overview of randomized placebo-controlled trials. Circulation 1997; 96:1074–7.
8. Malmberg K. for the DIGAMI study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Br Med J 1997; 314:1512–15.
9. Capes S, Hunt D, Malmberg K, Gerstein H. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000; 355:773–8.[CrossRef][Web of Science][Medline]
10. Bolk J, van der Ploeg T, Cornel JH, Arnold AE, Sepers J, Umans VA. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol 2001; 79:207–14.[CrossRef][Web of Science][Medline]
11. Lawrence IG and Davies MJ. Diabetes and myocardial infarction: do we have time to wait? Pract Diabetes Int 1999; 16:43–6.
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13. Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. 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; 26:650–61.
14. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359–67.
15. Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, et al. Outcome benefit of intensive insulin therapy in critically ill: insulin dose versus glycaemic control. Crit Care Med 2003; 31:359–66.[CrossRef][Web of Science][Medline]
16. Opie L. The glucose hypothesis: relation to acute myocardial ischaemia. J Mol Cell Cardiol 1970; 1:107–14.[Medline]
17. Hansen T, Thiel S, Wouters P, Christiansen J, Van den Berghe B. Intensive insulin therapy exerts anti-inflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-gind lectin levels. J Clin Endocrinol Metab 2003; 88:1082–8.
18. Messoten D, Swinnen J, Vanderhoydonc F, Wouters PJ, Van den Berghe G. Contribution of circulating lipids to the improved outcome of critical illness by glycaemic control with intensive insulin therapy. J Clin Endocrinol Metab 2004; 89:219–26.
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