Comment

30 years ago, a patient with diabetes admitted to hospital with an acute myocardial infarction had a greater than one in four chance of dying in the next year.1 The only available outpatient treatment for glucose management was insulin, sulfonylureas, and metformin. Findings from the Diabetes Control and Complications Trial (DCCT)2 showed a convincing reduction in microvascular complications with intense insulin treatment, but it included only patients who were insulin dependent. No evidence was available to support intense pharmacological treatment of patients with non-insulin dependent diabetes.3 The University Group Diabetes Project, which did focus on patients with noninsulin dependent diabetes, had reported a confusing outcome, with no improvement reported in patients given insulin, and potentially adverse outcomes noted in those given tolbutamide.4 On the basis of these findings, the Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial was started. The DIGAMI 1 investigators postulated that improvement of glucose control while patients were in hospital for acute myocardial infarction, followed by continuation of this intensive treatment through the acute post-admission period, would improve mortality— the primary endpoint.5 The findings, published in The Lancet Diabetes & Endocrinology, confirm a survival advantage for participants in the intensively treated group during 20 year follow-up: median survival was 7·0 years (IQR 1·8–12·4) compared with patients in the control group (4·7 years, 1·0–11·4).6 Initially, this finding seems somewhat at odds with the recent results of ACCORD,7 ADVANCE,8 and VADT,9 which all reported no improvement or a higher mortality rate in individuals randomised to intensive treatment. Additional discrepancies lie in the negative results of DIGAMI 210 and Hi 511—two later studies of intense treatment of patients with diabetes admitted to hospital for cardiovascular disease—that also showed null results. Do the DIGAMI 1 findings represent an outlier, or do they portend what might be shown with long term follow-up of the aforementioned studies? The truth is likely neither. The difference in mortality was noted early in the DIGAMI 1 study, emerging as early as 3 months after hospital admission and significantly in favour of intensive insulin treatment at the study’s

specified end of 1 year,12 different from the null results or harm reported early on in more contemporary studies.8,9 Available treatments and treatment goals were substantially different in DIGAMI 1 than in the other studies. Patients in the DIGAMI 1 study entered the hospital with an average HbA1C of 8·2%, higher than the average baseline HbA1C in either of the subsequent studies10,11 of hospital treatment of patients with diabetes. Only a third of the DIGAMI 1 participants were receiving angiotensin-converting-enzyme inhibitors at the time of discharge from the hospital and none were receiving treatment with statins. Blood pressure values were not reported. By contrast, patients in DIAGMI 2 had an HbA1C of 7·0%, a systolic blood pressure of 135 mmHg, and 70% were receiving lipid-lowering treatment, at the time of discharge from the hospital. 10 Should a clinician treat their patients any differently on the basis of the results reported in the DIGAMI 1 study’s 20 year follow-up? I would argue no—new therapies to treat blood glucose and reduce the risks of increased lipids and blood pressure are available, and good clinicians already work with patients to achieve blood glucose targets in the DIGAMI 1 study. Instead, the value of this paper lies in its history. First, it points to the benefit of good glucose control even when other risk factors such as lipids or blood pressure cannot be or are not modified. Participants in the intensively treated group had a reduction in HbA1c of about 0·6%, an important and sizable reduction. Second, and perhaps most importantly, it provides an important reminder of how quickly medicine is advancing, something that is often forgotten in the busy day-to-day practice of medicine. In 20 years, we have gone from few glucoselowering-therapies to over half a dozen oral therapy drugs, plus insulin, plus effective treatments to reduce the risk of elevated lipids and blood pressure. Now, the challenge is choosing the best treatment option for our patients. We’ve come a long way.

John Thys/Reporters/Science Photo Library

DIGAMI 1: 20 years later

Lancet Diabetes Endocrinol 2014 Published Online May 13, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70106-8 See Online/Comment http://dx.doi.org/10.1016/ S2213-8587(14)70088-9

Denise E Bonds National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-7936, USA [email protected] I declare that I have no competing interests. This work in my own and does not represent the views of the US Government, National Institutes of Health, or the National Heart, Lung, and Blood Institute.

www.thelancet.com/diabetes-endocrinology Published online May 13, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70106-8

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Smith JW, Marcus FI, Serokman R. Prognosis of patients with diabetes mellitus after acute myocardial infarction. Am J Cardiol 1984; 54: 718–21. Holman RR, Dornan TL, Mayon-White V, et al. Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study. Lancet 1983; 1: 204–8. Weir GC, Nathan DM, Singer DE. Standards of care for diabetes. Diabetes Care 1994; 17: 1514–22. Knatterud GL, Klimt CR, Levin ME, Jacobson ME, Goldner MG. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment. JAMA 1978; 240: 37–42. Malmberg KA, Efendic S, Ryden LE. Feasibility of insulin-glucose infusion in diabetic patients with acute myocardial infarction. A report from the multicenter trial: DIGAMI. Diabetes Care 1994; 17: 1007–14. Ritsinger V, Malmnerg K, Mårtensson A, Rydén L, Wedel H, Norhammer A. Intensified insulin-based gylcaemic control after myocardial infarction: mortality during 20 year follow-up of the randomised Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial. Lancet Diabetes Endocrinol 2014; published online May 13. http://dx.doi. org/10.1016/S2213-8587(14)70088-9.

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Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545–59. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560–72. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129–39. Malmberg K, Ryden L, Wedel Het al. 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. Cheung NW, Wong VW, McLean M. The hyperglycemia: intensive insulin infusion in infarction (hi-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care 2006; 29: 765–70. Malmberg K, Ryden L, Efendic S, et al. 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.

www.thelancet.com/diabetes-endocrinology Published online May 13, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70106-8

DIGAMI 1: 20 years later.

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