Search Menu Aims Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin—glucose infusion followed by insulin-based long-term glucose control; group 2, insulin—glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2. At randomization, HbA1c was 7.
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When viewed with other browsers, some characters or attributes may not be rendered correctly. From Research to Practice and Coronary Heart Disease In Brief People with diabetes who suffer an acute myocardial infarction MI are at markedly increased risk of future cardiovascular morbidity and mortality.
The DIGAMI study compared "conventional" anti-diabetic therapy to intensive insulin therapy consisting of acute insulin infusion during the early hours of MI and thrice-daily subcutaneous insulin injection for the remainder of the hospital stay and a minimum of 3 months thereafter. Although there was an overall reduction in adverse outcomes in patients receiving the intensive insulin regimen, it is unclear which component the IV insulin infusion or the intensive chronic therapy was responsible.
Josephson, MS, MD Despite many advances in modern medicine, diabetes mellitus continues to be associated with increased morbidity and mortality.
The leading cause of death in people with diabetes continues to be myocardial infarction MI. Although improvements have been made in the treatment of cardiac disease, diabetic patients with acute MI continue to have a poor prognosis.
This increase in mortality is shown during both initial hospitalization and long-term follow up. Diabetes may be associated with severe coronary artery disease, systolic left ventricular dysfunction, autonomic neuropathy, and larger infarct size. These processes not only leave these diabetic patients at higher risk of death when having an acute MI, but also increase their risk of recurrent cardiac events and other long-term complications.
Plasma catecholamines, glucagon, and cortisol increase, resulting in insulin resistance. Decreased insulin sensitivity causes impaired glucose utilization and increased free fatty acid turnover in cardiac muscle. People with diabetes are more sensitive to catacholamine stimulation, and thus they have a dramatic increase in plasma free fatty acids and a decrease in glucose utilization. Glucose does not require oxygen when metabolized glycolysis , but this process, as described above, is impaired by the hormonal changes that take place during MI.
This shift from glucose use to free fatty acid use increases the oxygen demand of the heart muscle. Insulin, either endogenous or exogenous, favors the use of glucose rather than free fatty acids as an energy source. By preferentially using glucose, myocardial oxygen demand decreases, and the supply-demand imbalance may be reduced. Studies have shown that insulin may have a role in restoring other cardiac and metabolic dysfunctions common in diabetic patients. One such dysfunction is the increased platelet aggregation, which can be reduced with insulin administration.
This impairment may potentiate ischemic heart disease by facilitating coronary artery occlusion and reocclusion. Insulin therapy has been shown to decrease tPAi-1 levels and possibly normalize the fibrinolytic process. These actions of insulin appear to reduce many of the biochemical obstacles diabetic patients face during and after MI. Intensive insulin therapy included an insulin-glucose infusion during the initial 24 hours of hospitalization, followed by subcutaneous insulin four times daily for a minimum of 3 months.
Morbidity and mortality were assessed in the acute, sub-acute, and chronic phases. The diagnosis of MI was divided into probable or possible using conventional criteria Table 1. The remaining patients were then randomized to either a control group patients or an insulin infusion group patients.
Figure 1. Adapted from reference 1. The infusion was continued for a minimum of 24 hours, at which point the patients were changed to subcutaneous insulin injections 4 times daily. Table 1. Development of new Q waves in 2 of the 12 standard electrocardiogram leads. Possible Myocardial Infarction Chest pain combined with at least one of the following: 1. One serum creatine kinase or serum lactate dehydrogenase above the 2. New Q waves in 1 of the 12 standard electrocardiogram leads.
Patients who were randomized to the control group were managed according to standard coronary care practice without insulin-glucose infusion. Subcutaneous insulin was used only if determined to be necessary by a CCU physician, particularly if the patient was on insulin before admission. In addition to the diabetes treatment, all patients received thrombolytic therapy streptokinase , beta-blockers, aspirin, heparin, nitroglycerin, percutaneous transluminal coronary angioplasty PTCA , and coronary artery bypass graft CABG surgery acutely and chronically as deemed appropriate by their physicians.
All patients in the study were classified into four pre-stratified groups according to their previous anti-diabetic management and initial cardiac risk classification. The pre-stratified risk groups were 1 no previous insulin; low cardiac risk, 2 previous insulin; low cardiac risk, 3 no previous insulin; high cardiac risk, and 4 previous insulin; high cardiac risk. Overall, concomitant therapy was similar between both groups of the study. Thus, regardless of the treatment protocol received, the in-hospital courses were similar.
Hospital stay was slightly different in that the average length of stay was Overall, patients had a mortality of Though the infusion group had a slightly lower mortality than the control group in the hospital 9. When examining mortality in the pre-stratified risk groups, the greatest mortality reduction is noted for patients who had never been on insulin before and were classified as low cardiac risk.
Discussion Patients with diabetes not only are at increased risk of having an MI, but also are more likely to have complications, increased mortality, and recurrent infarctions. Though other studies have evaluated the relationship between improved diabetic control and post-MI morbidity and mortality, the DIGAMI study is the first to show such a large reduction in mortality for diabetic patients with MIs at 1 year.
To place the DIGAMI results in perspective, it is important to note the decrease in overall mortality in diabetic patients with MI in all treatment groups. Some credit the overall improvement to widespread use of medications, such as beta-blockers, aspirin, and thrombolytics.
There are indications in experimental settings that propranolol may shift myocardial metabolism from free fatty acid utilization to glucose utilization. This change in metabolism would decrease myocardial muscle oxygen requirements, shifting the supply-demand imbalance and possibly reducing infarction size. Thus, some researchers believe diabetic patients may show a greater benefit when heart rate, and thus myocardial oxygen demand, is decreased.
Other cardiac medications now widely used that may have had an effect on overall diabetic MI mortality are aspirin and thrombolytics. Thromboxane A production and platelet aggregability have been shown to be increased in diabetic patients, fostering a hypercoagulable state.
It is reasonable to propose that increased anti-platelet and fibrinolytic therapy may have aided in the overall decreased mortality in the diabetic patients with cardiac events included in this study.
The change in mortality during hospitalization and at 3 months post-MI was not significant. In this group, insulin was given in both the acute setting insulin-glucose infusion as well as throughout the year following the MI subcutaneous insulin. This makes determining which intervention was responsible for the decrease in mortality impossible: the acute intervention insulin-glucose infusions or the long-term intervention subcutaneous insulin.
This is an important consideration especially when contemplating implementing this protocol. This study did not provide data showing a direct relationship between insulin-glucose infusion and the decreased mortality at 1 year. Instead, it showed a decreased mortality in diabetic patients admitted with MIs when given an intensive insulin regimen extending from admission up to 1 year.
When considering treating diabetic patients in such an aggressive manner using insulin, other social needs should be considered. In implementing this protocol, a patient should be willing to commit to both an acute and a long-term intervention program to fully improve their mortality. This type of commitment may not be possible in a portion of the population due to either inability or unwillingness to administer insulin.
This in itself may have created a bias because the patients studied were required to agree to aggressive insulin therapy for an extended period of time. Though unavoidable, this bias should be taken into consideration before making insulin therapy the standard of care. There is also a possibility that in the course of implementing prolonged intensive insulin therapy, patients had increased follow-up appointments and continuing care visits with their outpatient physicians.
The authors of the DIGAMI study addressed this possible discrepancy, stating that any increased follow-up should be considered part of comprehensive aggressive diabetic management.
Though insulin may help reduce mortality in theory, a treatment plan that patients are willing and able to perform may achieve more long-term success. A final point to emphasize in reviewing the DIGAMI results is the significant mortality reduction noted in patients who were never previously on insulin and who had low cardiac risk factors.
Interestingly, the patients who appeared to have the least baseline disease benefited most from aggressive therapy. This is consistent with other studies that found early aggressive management may protect patients from diabetic complications. The Diabetes Control and Complications Trial DCCT revealed that intensive insulin therapy delayed the onset and slowed the progression of microangiopathies nephropathy, neuropathy, and retinopathy.
These benefits of intensive treatment were greater in the primary prevention group, whose subjects had no symptoms at baseline. Conclusion Diabetes continues to adversely affect the prognosis in individuals presenting with MI.
Though the DIGAMI study showed decreased mortality in diabetic patients 1 year after MI, the modest sample size and lack of positive findings in other endpoints make this finding less robust. Overall, this study was successful in showing the feasibility and potential advantage of aggressive long-term insulin management in diabetic patients with MIs.
This advantage likely cannot be accounted for by the insulin-glucose infusion protocol alone. The researchers acknowledged this and emphasized that it was the comprehensive care, including insulin and frequent physician visits both acutely and chronically, that might have benefited these patients most. This is in accord with the DCCT, which recommended treating diabetic patients aggressively early in their disease process to provide the greatest benefit and possibly prevent long-term complications.
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This is precisely what Mellbin and associates have done. Finally, use of secondary end points in post hoc analyses, especially when they were negative in the original report, is especially prone to overinterpretation. All of the differences in the current report are related to the secondary end points, even though the authors of the original DIGAMI 2 study did not report any differences in these secondary end points. Why does this approach raise such a serious concern? Finally, statistical adjustment for multiple variables is markedly limited with a small number of events. Our findings have important implications for the analysis and interpretation of clinical studies. The study used 3 treatment strategies: 1 acute insulin-glucose infusion followed by insulin-based long-term glucose control; 2 insulin-glucose infusion followed by standard glucose control; and 3 routine metabolic management according to local practice.
DIGAMI 2 trial post hoc analysis: Lessons in overinterpretation