Letters

Intensive insulin treatment after acute myocardial infarction in diabetes mellitus

Evidence exists from study of non-insulin dependent diabetes in Japan

Editor–In his editorial prompted by the publication of the DIGAMI (diabetes mellitus, insulin glucose infusion in acute myocardial infarction) trial,¹ Malcolm Nattrass states that (in non-insulin dependent diabetes) "evidence [is] still awaited for a relation between diabetic control and microvascular complications."² It is true that we all await with interest the results of the United Kingdom prospective diabetes study, but some evidence does already exist. Although it is not directly relevant to Nattrass's editorial, in other contexts I have been surprised that it is rarely discussed and is almost never referenced in publications written by authors working on diabetes outside Asia and Australasia.

The study to which I refer is the Kumamoto study.³ This randomised 110 patients with non-insulin dependent diabetes (half with existing microvascular complications and half without) into a group treated with multiple injections and a group given normal care. After six years of follow up, both retinopathy and nephropathy were convincingly less common in the group treated with multiple injections—both the primary prevention cohort and the secondary prevention cohort.

While I do not necessarily advocate this trial as definitive evidence of the same effect as that in the diabetes control and complications trial in non-insulin dependent diabetes, it seems a pity that it is discussed so rarely outside Asia and Australasia. This may be due to failure on our part to take note of studies published in journals from other continents. It may also be due to reservations, on the part of those who do know about the study, about whether results obtained in Japanese patients (who were, for example, not obese) also apply to populations of patients that might have different characteristics and different therapeutic responses.

Rhys Williams, Professor of epidemiology and public health ^a

^a Nuffield Institute for Health, Leeds LS2 9PL

1. 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. BMJ 1997;314:1512-5. (24 May.)
2. Nattrass M. Managing diabetes after myocardial infarction. BMJ 1997;314:1497. (24 May.) [Free Full Text]
3. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.

Factors other than continued use of subcutaneous insulin may be important

Editor–The long term follow up data from the DIGAMI (diabetes mellitus, insulin glucose infusion in acute myocardial infarction) study confirm the data at one year follow up.¹ These data showed that diabetic patients who received an insulin-glucose infusion followed by intensive subcutaneous insulin after myocardial infarction had a lower mortality than a control group who received standard treatment. Unfortunately, this new publication adds little to previous publications of data from the same study.^{2 3 4} In particular, the authors are unable to identify whether the improved mortality is due to the intravenous insulin given in hospital, the subcutaneous insulin given after discharge, or improvements in patients' general care. As in previous publications, the authors assert that there were no other differences between the two groups in the treatment given in hospital, but they provide no supporting data. In particular, there are no data on the use of thrombolytic treatment, ß blockers, or angiotensin converting enzyme inhibitors during the acute event.

In the accompanying editorial Malcolm Nattrass emphasises the importance of these other treatments, which remain the most important factors along with cholesterol reduction in improving mortality in diabetic patients after myocardial infarction.⁵ He hopes that, after the publication of the data from the DIGAMI study, clinicians will not be reluctant to introduce insulin treatment; on the basis of the results of this single study, however, this approach would be premature.

In particular, it should be recalled that half of patients could not be randomised to the study, and in most cases this was because the patient was either unwilling or unable to comply with the treatment regimen. Furthermore, the high use of insulin in the control group (49% at one year) suggests that factors other than the continued use of subcutaneous insulin may be important.

Before this intervention package can be applied in routine clinical care, further studies are necessary to identify the effective component and to determine which patients might benefit.

B Miles Fisher, Consultant physician ^b

^b Royal Alexander Hospital, Paisley, Renfrewshire PA2 9PN

1. 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. BMJ 197;314:1512-5. (24 May.)
2. Malmberg K, Efendic S, Ryden L. Feasibility of insulin-glucose infusion in diabetic patients with acute myocardial infarction. Diabetes Care 1994;17:1007-14. [Abstract]
3. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, 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.
4. Malmberg K, Ryden L, Hamsten A, Herlitz J, Walenstrom A, Wedel H on behalf of the DIGAMI Study Group. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J 1996;17:1337-44.
5. Nattrass M. Managing diabetes after myocardial infarction. BMJ 1997;314:1497. (24 May.)

Intensive insulin regimens in primary prevention should be assessed

Editor–The DIGAMI (diabetes mellitus, insulin glucose infusion in acute myocardial infarction) trial confirms the role of intensive control of diabetes (with insulin) as secondary prevention after myocardial infarction.¹ The results of this trial may have far reaching implications. The fact that the beneficial effects of strict glycaemic control (or the beneficial effects of insulin, or both) were greatest in patients who had not previously been treated with insulin and were considered to be at low risk requires further explanation. This group was by far the biggest, and the numbers in other groups (as low as 100) may have been too small for a treatment difference to be detected. The duration of diabetes was not given for each group, but the low risk group had probably had it for a shorter period and probably had fewer macrovascular complications at the time of entry into the study. The benefits of treatment may be related not only to the effect on glycaemic control but also to the point in the development of macrovascular disease at which insulin treatment is started. Two questions arise from this: how long should treatment continue, and when should insulin treatment begin?

From the DIGAMI trial it seems that patients with non-insulin dependent diabetes who are not already taking insulin should receive intensive insulin treatment for at least three months after infarction. It has been shown, however, that (compared with non-diabetic survivors) diabetic survivors of myocardial infarction remain at increased risk of subsequent cardiovascular events far beyond this period.² It could be argued, therefore, that secondary prevention with such dramatic benefits should not be stopped unless the risks or cost of treatment outweigh those of macrovascular disease. Studies comparing different durations of insulin treatment are needed.

Studies evaluating other treatments, such as antiplatelet and lipid lowering treatment, in secondary prevention have followed a logical progression to evaluation in primary prevention. Although the cost:benefit ratio of primary prevention is not as persuasive as that of secondary prevention, it is difficult to cost the personal gain of prevention of first events. Given the risk of macrovascular disease in patients with non-insulin dependent diabetes and evidence that glycaemic control affects this risk,³ a strong argument could be made for studies to explore the role of improved glycaemic control through intensive insulin regimens in primary prevention. Despite the financial (and other) implications of treating all patients with non-insulin dependent diabetes with insulin, the potential gain in this population is difficult to ignore.

Kevin McLaughlin, Senior registrar in medicine ^c

^c Glasgow Royal Infirmary, Glasgow G4 0SF

1. 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. BMJ 1997;314:1512-5. (24 May.)
2. Ulvenstam G, Aberg A, Bergstrand R, Johannson S, Pennert K, Vedin A, et al. Long-term prognosis after myocardial infarction in men with diabetes mellitus. Diabetes 1985;34:787-92. [Abstract]
3. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 1994;43:960-7. [Abstract]