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ORIGINAL ARTICLE

How to Improve the Cardiac Prognosis for Diabetes

Johan Herlitz, MD, PHD
Klas Malmberg, MD, PHD

Cardiovascular disease is a leading cause of death in diabetic patients. It has been reported to count for almost 80% of all deaths. About three-fourths of these deaths result from coronary artery disease. Studies have shown that diabetic patients who have had an acute myocardial infarction (AMI) have a mortality of about twice that of nondiabetic patients. Various medications have been shown to improve the prognosis among diabetic patients suffering from ischemic heart disease. They include -blockers, thrombolytic agents, aspirin, ACE inhibitors, and lipid-lowering drugs. Experiences indicate that treatment with -blockers, thrombolytic agents, and ACE inhibitors is particularly advantageous in diabetic patients who have suffered AMI. Metabolic control also may be of major importance during the acute cardiac event because it is assumed that fatty acid metabolism is increased with a compromised glycolysis not only in ischemic but also in the nonischemic areas. One way to suppress free fatty acid oxidation is by the infusion of insulin-glucose. In the Swedish Diabetes Mellitus and Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study, patients with diabetes and AMI were randomized to receive insulin-glucose infusion followed by intensive subcutaneous insulin treatment or to be control subjects. The 1-year mortality was reduced 30% by insulin treatment. Diabetic patients who suffer from coronary artery disease have a particularly adverse prognosis. Previous experiences indicate that treatment with -blockers, thrombolytic agents, and ACE inhibitors is particularly advantageous in diabetic patients who have suffered AMI. Aspirin and lipid-lowering drugs should be offered to these patients on traditional indications as well. Metabolic control seems to be of major importance for the outcome.

Diabetes Care 22 (Suppl. 2):B89–B96, 1999

Cardiovascular disease is a leading cause of death in diabetic patients. It has been reported to count for almost 80% of all deaths. About three-fourths of these deaths result from coronary artery disease. In this article, we describe the possibilities to improve the cardiac prognosis in patients with coronary artery disease and diabetes based on experiences in the last two decades.

OCCURRENCE OF DIABETES AMONG PATIENTS WITH CORONARY ARTERY DISEASE

Myocardial infarction
The prevalence of diabetes among patients with acute myocardial infarction (AMI) varies in different reports between 6 and 22% (1–7). The discrepancies are probably explained by different diagnostic criteria for diabetes. Based on determinations of HbA_1c at hospital admission, an overall prevalence of undiagnosed diabetes of 5% has been suggested (8).

Other manifestations of coronary artery disease
Among patients admitted to the emergency department because of acute chest pain or other symptoms raising suspicion of AMI, 8% had a history of diabetes (9). Among patients being hospitalized because of suspected AMI but in whom the diagnosis was not confirmed, 14% had a history of diabetes (10). An overrepresentation of diabetes has also been shown among patients who suffer a sudden death (11).

Type 1 versus type 2 diabetes
It has been a consistent finding that the majority of diabetic patients with AMI have type 2 (7,12–14). This might be explained by the fact that 80–90% of diabetic patients overall have type 2. Whether the risk of developing AMI at equivalent age and duration of diabetes is the same for type 1 and type 2 diabetes has not been satisfactorily evaluated.

PROGNOSIS OF PATIENTS WITH DIABETES AND CORONARY ARTERY DISEASE

Early mortality
AMI. Studies before as well as after the introduction of fibrinolytic therapy have consistently shown that diabetic patients who have had an AMI have an early mortality rate of about twice that of nondiabetic patients (4–7,12,15–23).

Other manifestations of ischemic heart disease. Among patients with unstable angina pectoris (24) and patients hospitalized with suspected AMI but in whom the diagnosis was not confirmed (10), the mortality was about twice as high among diabetic patients as compared with nondiabetic patients. Among all diabetic patients admitted to the emergency department with acute chest pain or other symptoms raising suspicion of AMI, those with a history of diabetes had a 1-year mortality rate of 25% as compared with 10% among those without such a history (9).

Long-term mortality
Even the long-term prognosis after development of AMI is unfavorably affected by a history of diabetes (25–27). In a representative population of patients hospitalized with AMI, 75% of those with a history of diabetes were dead after 5 years (27).

MECHANISMS BEHIND THE UNFAVORABLE PROGNOSIS OF PATIENTS WITH DIABETES AND CORONARY ARTERY DISEASE— Many conditions contribute to an adverse prognosis for diabetic patients suffering from ischemic heart disease. They include a more severe and diffuse coronary artery disease (28–31); microvascular dysfunction (32–34); decreased vasodilatory reserve (35–37); decreased fibrinolytic activity, mainly due to increased levels of plasminogen activator inhibitor-1 (38,39); elevated spontaneous and induced platelet aggregation (40,41); and elevated levels of the coagulation factors VIIIc, fibrinopeptide A, fibrinogen, and the von Willebrand factor (40–43). Many of these conditions might contribute to the high incidence of pump failure in diabetic patients. Patients with diabetes do not develop larger infarcts. Still, they have a high incidence of clinical pump failure, probably caused by a smaller reserve capacity of both systolic and diastolic function due to many of the reasons listed (44). The diabetic cardiomyopathic process initially manifests as diminished left ventricular compliance in the presence of normal systolic function (45–47), whereas frank systolic dysfunction usually appears in patients with long-standing disease who have advanced microvascular complications or coexistent hypertension (48–50).

It is possible that the autonomic dysfunction that is common in both type 1 and type 2 diabetes (51–53) increases the risk of cardiac death. Suggested mechanisms are an increased heart rate (54) and a decreased heart-rate variability (55). Intact vagal responsiveness is an important protective factor for the ischemic myocardium (56). Many diabetic patients, a priori (57) have impaired vagal function as evaluated by heart-rate variability, which may make them more susceptible to the possible adverse effects of elevated adrenergic activity, as they lack the pre- and postsynaptic buffer function.

MEDICATION

-Blockers
AMI. The use of -blockers in the post-myocardial infarction period is well documented (58–60). Institution of this treatment in the early phase of AMI reduces infarct size and decreases acute complications (61–63). Traditionally, diabetes has been considered less suitable for -blockers because of fears of worsening metabolic control with diminished hypoglycemic warning signs and more severe hypoglycemic attacks (64–69). These drawbacks have not been confirmed, however, with ₁-selective blocking agents (67–70).

The first study to draw attention to the impact of the use of -blockers on mortality in diabetic patients with AMI was the Norwegian Timolol Trial (71). Among the diabetic patients (5% of the study population), a marked relative reduction in total mortality (63%) was observed as compared with a 33% reduction among nondiabetic patients. Similarly, the rate of reinfarction was reduced by 83% in the diabetic patients and by 34% in the nondiabetic patients. The mean follow-up was 17 months. Similarly, the Göteborg Metoprolol Trial, in which 8% of the study population had a history of diabetes (72), showed a much more marked relative reduction in mortality and in reinfarction rate with metoprolol in the diabetic patients than in the nondiabetic patients. Also, early mortality has been reported to be more favorably affected by -blockers in diabetic patients than in nondiabetic patients (72). Table 1 shows the various -blocker trials in which results on diabetic patients were reported. Included on the table is an observation study (73) in which patients discharged from the hospital after development of AMI were evaluated in relation to whether they had diabetes and whether they were prescribed a -blocker (propranolol). When simultaneously considering other risk indicators for death, prescription of a -blocker was an independent predictor for increased survival among diabetic patients but not among nondiabetic patients.

Other manifestations of a coronary artery disease
Among 14,417 patients with chronic coronary artery disease who had been screened for participation in a study with the lipid-lowering drug bezafibrate, 19% had type 2 diabetes (74). Among these patients, 33% were receiving a -blocker. The total mortality during the 3-year follow-up was 7.8% in those receiving -blockers compared with 14.0% in those who were not (a 44% reduction). After multiple adjustment, multivariate analysis identified -blocker therapy as a significant independent contributor to improved survival (relative risk 0.58; 90% CI 0.46–0.74). Thus, therapy with -blockers appears to be associated with improved long-term survival in other patients with coronary artery disease as well as in those who developed AMI.

Mechanisms
There are several possible explanations for a particularly favorable effect of -blockers after development of AMI in diabetic patients. One is a change in myocardial metabolism in the direction of glucose from free fatty acid utilization. This shift reduces myocardial oxygen consumption and results in smaller infarcts (75). -blockers may also improve the autonomic dysbalance that is characteristic of many diabetic patients (54). On hospital admission, patients with diabetes have significantly higher heart rates than do nondiabetic patients (72). This is explained by the parasympathetic damage that precedes a subsequent sympathetic disturbance (54), as has been previously discussed. According to Kjekshus (76), the -blocker–induced reduction in postinfarction mortality relates to the magnitude of the heart-rate reduction. This reduction is more pronounced in patients with an initially high heart rate (77). Lipid-soluble ₁-selective blockers (e.g., metoprolol) have in the experimental setting improved vagal tone and prevented ventricular fibrillation initiated by acute coronary occlusion. Based on these experiments, it was postulated that the protective effect is medicated via influences on the central nervous system (78). This may be of special relevance for people with diabetes.

Thrombolytic agents
In deciding whether to use this treatment, the benefits must be weighed against any potential adverse side effects. In a meta-analysis including all large thrombolytic trials, information on a history of diabetes was available in 43,343 patients, of which 10% had a history of diabetes. The relative reduction in mortality after treatment with thrombolytic agents was similar in diabetic and nondiabetic patients (79). However, the number of lives saved per 1,000 treated patients was 37 among the diabetic patients versus 17 among the nondiabetic patients. This is explained by the higher mortality in the diabetic patients. It has also been shown that mortality in AMI is markedly reduced after the introduction of thrombolysis in diabetic patients as well as in nondiabetic patients (80). Angiographic data indicate a similar patency rate in diabetic and nondiabetic patients 90 min after thrombolytic therapy (14,81). Thus, data so far indicate a similar effect and an improved cost benefit in diabetic patients given thrombolytic agents as compared with nondiabetic patients. Thus, some suggestions that reperfusion after thrombolytic treatment is impaired in diabetic patients (14,82) do not get support from either angiographic or survival data. Previously, diabetic retinopathy was a contraindication to thrombolytic treatment (83). However, so far, bleeding from retinopathy in a diabetic patient has only been reported once (84). One small study suggested an excess risk of hemorrhagic complications in diabetic patients >75 years of age (85), but in an analysis of >9,000 patients treated with thrombolysis, of whom 1/10 had diabetes, complication rates were similar in diabetic and nondiabetic patients (7). Thus, available information suggests that indications and contraindications for thrombolysis should be similar in diabetic and nondiabetic patients—i.e., all patients with suspected AMI and having either ST-segment elevation or new developed left bundle branch block should be considered for such treatment.

Aspirin
Aspirin has been shown to reduce mortality after development of AMI (86) and to reduce the development of cardiovascular events among patients with stable angina pectoris (87). In the Second International Study of Infarct Survival (ISIS-2), the mortality did not differ between diabetic patients randomized to aspirin and those randomized to placebo. This should be compared with an aspirin-induced mortality reduction of 23% among nondiabetic patients (86). Aspirin reduces platelet aggregation to collagen less efficiently in diabetic subjects than in nondiabetic subjects (88). Other data suggest that diabetic patients may require larger doses of aspirin to suppress the synthesis of thromboxane A2 (89,90). On the other hand, 160 mg of aspirin was shown to protect against cardiovascular events in the Swedish Aspirin Angina Pectoris Trial (SAPAT) (91). Other data have also supported aspirin as effective secondary preventive therapy in diabetic patients (92). Further research must clarify what the optimal aspirin dose is in diabetic patients suffering from ischemic heart disease.

ACE inhibitors
ACE inhibitors have been shown to reduce mortality after development of AMI in the early phase (93) and in a prolonged postinfarction perspective (94,95). The impact of ACE inhibitors on the prognosis in diabetic patients was not published in the postinfarction trials (94,95).

However, in GISSI-3, the impact of lisinopril on mortality in diabetic patients with suspected AMI was published (96). Of the 18,131 patients, 15% were defined as diabetic patients. Treatment with lisinopril was associated with a decreased 6-week mortality (8.7 vs. 12.4%; OR 0.68; 95% CI 0.53–0.86). This difference was significantly greater than that observed in nondiabetic patients.

Thus, available information indicates that ACE inhibitors should be used on broad indications in diabetic patients with ischemic heart disease. Patients with heart failure in particular should receive such treatment, but ACE inhibitors possibly should be given more generally to patients with AMI.

A broader use of ACE inhibitors could also be supported by the evidence that it preserves kidney function even in patients without overt hypertension and with signs of microvascular disease.

Lipid-lowering drugs
In the Scandinavian Simvastatin Survival Study (97) 4,444 patients with either previous myocardial infarction or angina pectoris and a serum total cholesterol of 5.5–8.0 mmol/l and serum triglycerides <2.5 mmol/l were randomized to receive either simvastatin or placebo. Patients were followed for a median of 5.4 years. Only 202 patients (5%) had a history of diabetes. Among these patients, the relative risks of main endpoints in simvastatin-treated patients were as follows: total mortality 0.57 (95% CI 0.30–1.08), major coronary heart disease events 0.45 (95% CI 0.27–0.74), and any atherosclerotic event 0.63 (95% CI 0.43–0.92). Risk reductions were, in general, similar in diabetic and nondiabetic patients. Thus, the absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with coronary artery disease because diabetic patients have a higher absolute risk of recurrent coronary heart disease events and other atherosclerotic events (97).

Glycemic control and metabolic intervention
Several recent studies have reported that glucose level, measured as fasting blood glucose or HbA_1c, is a major determinant of future development of coronary heart disease among patients with type 2 diabetes (98–101). Metabolic control may also be of major importance during the acute cardiac event, as it is assumed that fatty acid metabolism is increased with a compromised glycolysis, not only in ischemic but also in the nonischemic areas (102). One way to suppress free fatty acid oxidation is by the infusion of insulin-glucose (103). Furthermore, intense insulin treatment may also restore impaired platelet function, correct the disturbed lipoprotein pattern, and decrease plasma plasminogen activator inhibitor-1 activity (104–106). It is notable that these perturbations are closely interrelated and may be of importance for the increased mortality and morbidity after an AMI among patients with diabetes.

Based on the assumption that an optimal glucose metabolism would be of particular value in diabetic patients with AMI, Gwilt et al. (107) described a protocol for insulin infusion and stated that the administration was safe and simple. This regimen was then implemented in a small study, without any beneficial effects on morbidity or mortality when compared with historical control subjects (16). In contrast, Clark et al. (108) noted a reduction in morbidity and mortality by insulin infusions in a study that, however, was nonrandomized. A few years ago, Davies et al. (109) reported on a small randomized study, which was terminated prematurely due to difficulties in obtaining adequate levels of blood glucose in the insulin-infusion group. In fact, the levels did not differ from those in the control group. However, cardiovascular events decreased by 40% after intense treatment of type 1 diabetic patients in the Diabetes Control and Complications Trial (DCCT) (110).

In the Swedish Diabetes Mellitus and Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study, 620 patients with diabetes and AMI were randomized to a control group or to a group receiving insulin-glucose infusion followed by intensive subcutaneous insulin treatment for at least 3 months. During follow-up, the 1-year mortality rate was reduced by 30% by the institution of intensive insulin treatment, and this therapy tended to favorably influence all cardiovascular causes of death (111,112). In a recent long-term follow-up, the favorable effect was sustained with an absolute mortality difference of 11% between the groups, implying one saved life for every nine patients treated according to the DIGAMI protocol. Of special interest is that patients without previous insulin treatment and with a relatively low-risk profile benefited the most (113).

In summary, recent reports suggest that hyperglycemia is a strong determinant for the development of macrovascular disease in patients with diabetes. Furthermore, data from both DCCT and the DIGAMI trials strongly indicate that tight glycemic control by means of strict insulin treatments is of importance for both primary and secondary prevention of cardiovascular disease in patients with diabetes.

Coronary artery bypass grafting
A meta-analysis of large randomized trials has shown that coronary artery bypass grafting (CABG) will reduce mortality during 10 years of follow-up in stable angina pectoris as compared with medical treatment (114). Information on the outcome among diabetic patients was not given. Thus, the true impact of CABG on survival among diabetic patients with symptomatic coronary artery disease is not known. In observational studies, diabetic patients have been reported during the subsequent years to have a mortality twice that of nondiabetic patients (115–117). Such data might indicate that the impact of CABG on survival in patients with symptomatic coronary artery disease is similar in diabetic and nondiabetic patients. In agreement with such a hypothesis are the observations that various aspects of quality of life, including symptoms of angina pectoris, are improved similarly in diabetic and in nondiabetic patients (118). Thus, in spite of the lack of firm evidence about the prognostic benefit of CABG among diabetic patients with ischemic heart disease, other data support its value.

Percutaneous transluminal coronary angioplasty
No randomized trials have ever been performed that prove percutaneous transluminal coronary angioplasty (PTCA) to improve the prognosis neither among diabetic nor among non-diabetic patients with ischemic heart disease. Thus, information on outcome after PTCA is based on observational studies. In the National Heart, Lung, and Blood Institute PTCA Registry, diabetic patients had a 9-year mortality rate of 36% as compared with 18% in nondiabetic patients (119). Thus, the doubling of mortality also appears to remain after PTCA. From an optimistic point of view, this might be interpreted as though, if similar risk indicators also operate after PTCA, such treatment has a similar impact on the prognosis (favorable, unfavorable, or no impact at all) in diabetic and nondiabetic patients. However, in the recently published Bypass Angioplasty Revascularization Investigation (120), diabetic patients with ischemic heart disease and two- or three-vessel disease had a 5-year mortality of 35% if randomized to PTCA and 19% if randomized to CABG (P = 0.003). These data strongly indicate that diabetic patients with multivessel disease should undergo CABG rather than PTCA. However, because this observation was based on a subgroup analysis and was not strictly prospectively defined, the authors recommend a prospective randomized trial to further explore the issue.

COMMENT— It is important to stress that much of our understanding of treatment effects in diabetic patients with ischemic heart disease is based on retrospective subgroup findings. Of necessity, such data must be interpreted with caution. However, if such subgroup analysis repeatedly gives similar information, then data become more solid.

Furthermore, the proportion of diabetic patients participating in the referenced trials has mostly been much lower than the prevalence of diabetes in nonselected AMI populations. This is best explained by the fact that the sickest patients do not participate in randomized trials and that diabetic patients are overrepresented among such high-risk patients. Such a fact might underestimate the true impact of treatment effects on diabetic patients with ischemic heart disease.

In the majority of studies, the majority of diabetic patients had type 2 diabetes. Therefore, most of the observations described and the recommendations given are particularly relevant for type 2 diabetes. It is not clearly shown that the prognostic factors are identical in type 1 and type 2 diabetes. However, at present and without sufficient data, we recommend that diabetic patients with ischemic heart disease be given the same treatment for their heart disease regardless of whether they have type 1 or type 2 diabetes.

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From the Division of Cardiology (J.H.), Sahlgrenska University Hospital, Göteborg; and the Department of Cardiology (K.M.), Karolinska Hospital, Stockholm, Sweden.

Address correspondence and reprint requests to Johan Herlitz, MD, PhD, Division of Cardiology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

Received for publication 27 May 1998 and accepted in revised form 6 October 1998.

Abbreviations: AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; DIGAMI, Swedish Diabetes Mellitus and Insulin Glucose Infusion in Acute Myocardial Infarction Study; DCCT, Diabetes Control and Complications Trial; ISIS, International Study of Infarct Survival; PTCA, percutaneous transluminal coronary angioplasty.

This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.

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