Previous diabetes 3400 New diabetes 580 Non diabetes 10719
FIGURE 3 Kaplan-Meier curves for composite outcome of cardiovascular mortality/morbidity at 1 year by diabetic status. p=0.005 for previous versus new diabetes diagnosis; p< 0.001 for previous versus no diabetes diagnosis; p< 0.001 for new versus no diabetes diagnosis.
Significant increases in post-MI mortality have been described in diabetic patients treated with thrombolysis compared to those without diabetes (40). This increase in mortality is largely the result of reinfarction and heart failure (40-42). In GUSTO-I, the 30-day mortality was 6.2% in nondiabetics compared to 9.7 and 12.5% in non-insulin-treated and insulin-treated diabetics (40). Diabetes remained an independent predictor of mortality at one year (14.5 vs. 8.9% in non diabetics). The incidence of nonfatal cardiac events is also increased in patients with diabetes after an MI (43,44). This was recently shown in an analysis from the VALIANT trial of 14,703 patients with an acute MI complicated by left ventricular dysfunction (43). At one year, the rate of composite cardiovascular endpoints was higher for those with previously known or newly diagnosed diabetes than for those without (36 and 29 vs. 23%) (Fig. 3).
The long-term outcome in diabetics who present with a NSTEMI or unstable angina is worse than for non diabetics (42,45,46). This was evaluated in the OASIS registry of 8013 patients, 21% of whom had diabetes (46). After a two year follow-up, diabetes was an independent predictor of mortality (18 vs. 10% for non diabetics, relative risk 1.57, 95% CI 1.38 1.81).
The Framingham study established the epidemiologic link between diabetes and HF (47) showing that the relative risk of HF remained elevated at 3.8-fold in diabetic men and 5.5-fold in diabetic women even after exclusion of patients with coronary artery disease. Current studies show similar data. In a report of 9591 subjects with type 2 diabetes and matched controls, HF was more frequent at baseline in diabetics (11.8 vs. 4.5%) (48). Among those free of HF at baseline, HF developed more often in diabetics during a 30-month follow-up (7.7 vs. 3.4%). In elderly diabetic patients the incidence is even higher as shown in a national sample of Medicare claims from 1994 to 1999; this population included over 150,000 registered Medicare patients with diabetes who were > 65 years of age (49). The prevalence of HF was 22.3% in 1994, with a subsequent incidence of newly diagnosed HF of 12.6% per year. Factors associated with HF in adult diabetic patients are age, duration of diabetes, insulin use, peripheral arterial disease, ischemic heart disease, and poor glycemic control. The importance of glycemic control was shown in an analysis from Kaiser Permanente health maintenance organization. They evaluated almost 50,000 adult patients with type 2 diabetes and no HF at the beginning who were followed for a mean of 2.2 years (50). Each 1% increase in hemoglobin (Hb) A1c was associated with an 8% increased risk of heart failure.
The etiology of heart failure in patients with diabetes is diverse and involves systolic heart failure due to coronary artery disease, diastolic heart failure due to hypertension, and left ventricular hypertrophy and the diabetic cardiomyopathy, which may contribute to other etiologies. The ventricular dysfunction due to diabetic cardiomyopathy is manifested by systolic and/or diastolic dysfunction. Several pathologic changes have been described in the myocardium in diabetics including fibrosis, infiltration of the interstitium with periodic acid-Schiff-positive material, and alterations in the myocardial capillary basement membrane. Several clinical features were found in diabetic patients who may be interpreted as early signs of developing heart failure: Diabetic patients had higher left ventricular mass, wall thickness, and arterial stiffness and reduced systolic function compared to normals in the Strong Heart study. Abnormal diastolic function has been noted in 27 to 70% of asymptomatic diabetic patients, which may be due in part to increased left ventricular mass. Diastolic dysfunction is more abnormal in those with worse glycemic control and in those who are also hypertensive. Autonomic neuropathy may play a role in the development of left ventricular dysfunction. Microcirculatory dysfunction in diabetics may be due to downregulation of the expression of vascular endothelial growth factor (VEGF). Local replenishment of VEGF via DNA gene therapy was associated with increased capillary density and a significant improvement in cardiac function in an animal model (51).
Among patients with HF, those with diabetes have higher mortality rates (Fig. 4). This relationship was demonstrated in a report from studies of left ventricular dysfunction (SOLVD) which enrolled 6791 patients, including 1310 with diabetes (52). Compared to nondiabetics, diabetic patients were significantly more likely to be admitted for heart failure (risk ratio 1.6) and had higher rates at one year of all-cause mortality (32 vs. 22%). The increase in all-cause mortality associated with diabetes in SOLVD was limited to patients with an ischemic cardiomyopathy (adjusted relative risk 1.37 compared to 0.98 in patients with non-ischemic cardiomyopathy) (53). In the presence of coronary disease, diabetes was independent of other risk factors for predicting worsening of heart failure. Among patients with diabetes, those who develop HF have poorer prognosis than those who do not develop heart failure. In an analysis of Medicare patients, the mortality rates were 32.7 and 3.7% per year, respectively (hazard ratio [HR] 10.6) (49). The five-year survival rate for diabetics with HF was 12.5%.
Diabetic patients with systolic heart failure are treated in the same way as nondiabetics, with ACE inhibitors and beta-blockers. A meta-analysis of beta blocker trials in HF (including 1883 diabetics) showed a relative risk reduction in mortality of 23% with beta-blocker treatment (54). Both the SOLVD and SAVE trials also showed that diabetics benefit from angiotensin-converting enzyme (ACE) inhibitors (52,55). In a meta-analysis of ACE inhibitor trials in HF that included 2398 diabetics, the survival benefit with ACE inhibitor therapy was the same for those with diabetes as for those without (relative risk 0.84) (54). The optimal therapy for diabetic patients with diastolic heart failure is not known, as no prospective randomized
studies exist. Considering hypertension and diabetic cardiomyopathy as the principal cause for diastolic heart failure in diabetics, an optimized treatment for these risk factors seems to be a reasonable recommendation.
The optimum choice of glucose lowering drugs in diabetic patients with symptomatic heart failure is not known, as no prospective randomized studies exist that have included exclusively this important patient population. Neither insulin nor sulfonyureas have been shown to be safe in diabetic patients with heart failure. There are mixed data for thiazolidinediones and metformin.
Thiazolidinediones (TZDs) increase insulin sensitivity. In both randomized and observational studies, TZD use has been associated with worsening HF and pulmonary edema (56,57). Weight gain and fluid retention are more common with concomitant insulin therapy. The PROactive trial randomly assigned 5238 patients with type 2 diabetes and either coronary artery disease, stroke, or peripheral arterial disease to pioglitazone or placebo (58). The primary endpoint was a composite of all-cause mortality, nonfatal MI (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. At a mean follow-up of almost three years, there was a 10% non-significant difference between the two groups in this endpoint (hazard ratio [HR] 0.90,95% CI 0.80-1.02). There was a significant improvement with pioglitazone in a principal secondary endpoint of all-cause mortality, nonfatal MI, and stroke that were components of the primary endpoint (HR 0.84, 95% CI 0.72-0.98). Pioglitazone use was also associated with improved glycemic control and a significant increase in hospital admissions for HF (6 vs. 4%) but no increase in mortality due to HF. Despite these concerns, TZDs are being used with increasing frequency in diabetic patients with HF and may be associated with improved outcomes (46,47). This was documented in a retrospective study of 16,417 Medicare members with diabetes who were discharged from the hospital with a primary discharge diagnosis of HF; 2226 patients (13.6%) were treated with a TZD (59). At one year, the crude one-year mortality rate was significantly lower in these patients than in the 12,069 treated with neither a TZD nor metformin (30.1 vs. 36.0%, multivariable adjusted hazard ratio 0.87, 95% CI 0.80-0.94) (Fig. 5). Based upon all of these findings, TZDs should be
avoided in patients with symptomatic congestive HF unless prospective studies will have shown treatment benefits. Possibly the often occurring sodium and water retention increases preload and aggravates underlying left ventricular dysfunction.
According to the U.S. Food and Drug Administration, metformin is contraindicated in patients with HF treated with drugs (60). However, as metformin is an effective and useful agent in the management of diabetes mellitus it is prescribed in many patients with heart failure. The safety of metformin and its possible prognostic benefit was shown in the Medicare study described above; 1861 (11.3%) were treated with metformin (59). At one year, the crude one-year mortality rate was significantly lower in these patients than in the 12,069 treated with neither metformin nor a TZD (24.7 vs. 36.0%, hazard ratio 0.87, 95% CI 0.78-0.97).
In summary, patients with type 2 diabetes and HF have a poor prognosis. Optimal treatment for these patients is not known. Therefore they should be treated as non diabetics with ACE inhibitors, beta blockers, and diuretics. Certainly, tight glucose control does not harm these patients.
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All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.