By Salynn Boyles, Contributing Writer
Worsening heart failure severity -- indicated by increasing doses of loop diuretics -- was associated in a dose-dependent manner with rising risks of developing diabetes, a Danish study showed.
The risk of developing diabetes was about three times as high in patients taking the highest doses as in those who weren't taking any loop diuretics (HR 3.02, 95% CI 2.66-3.43), according to Malene N. Demant of Copenhagen University Hospital Gentofte, and colleagues.
The use of renin-angiotensin system inhibitors (RASis), however, appeared to mitigate that risk, they reported in Diabetologia.
"From an epidemiological perspective, the poor prognosis associated with diabetes in patients with heart failure has confused researchers for 35 years," the authors wrote. "Our data add important insights to the understanding of the mechanisms underlying this poor prognosis, because it might be that the sickest patients are those who develop diabetes. Thus, diabetes may, in part, be a marker of heart failure severity in addition to being a causal risk factor for mortality in heart failure cohorts."
More than 3 decades ago, findings from the Framingham Heart Study linked diabetes with a worse prognosis in patients with heart failure. Significant advances in diabetes treatments since then have not improved outcomes in patients with diabetes complicated by heart failure.
"This has led to the hypothesis that diabetes may in some cases be a marker of heart failure severity rather than a causal risk factor for adverse outcomes as such," Demant and colleagues wrote. "In this context, chronic heart failure has been shown to be associated with hyperinsulinemia and increased insulin resistance in a severity-dependent manner."
The impact of heart failure severity on the risk of developing diabetes has not been well studied, the researchers noted. In an 2010 investigation, which had a design similar to the current study, the researchers reported that heart failure increased diabetes risk in a severity-dependent manner in newly discharged myocardial infarction (MI) patients.
Demant's group followed patients discharged after hospitalization for heart failure from 1997 to 2010 and who had not previously been treated with hypoglycemic agents or loop diuretics. Data on these patients came from four nationwide administrative registries.
The patients were divided into five groups according to the dosage of prescribed loop diuretics based on arbitrary values:
• Group 1: no loop diuretics (31% of patients)
• Group 2: >0-40 mg/day (25%)
• Group 3: >40-80 mg/day (17%)
• Group 4: >80-159 mg/day (12%)
• Group 5: ≥160 mg/day (15%)
Mean patient age at hospitalization ranged from 72.1 in group 1 to 76.5 in group 5. About half of the patients in all groups were women. Concomitant disease included ischemic heart disease, acute MI, and atrial flutter/fibrillation.
In all, 8% developed diabetes, and the mean time to the first claimed prescription of a hypoglycemic agent was 1,080 days (interquartile range 475 to 2,037).
The higher the loop-diuretic dosage, the higher the proportion of patients who developed diabetes. Among those taking the highest dosage, the 10-year cumulative risk of developing diabetes exceeded 25%. Crude incidence rates for developing diabetes were 1.6 (95% CI 1.5- 1.7), 1.9 (95% CI 1.5- 2.0), 2.3 (95% CI 2.2-2.4), 2.6 (95% CI 2.5- 2.8) and 3.0 (95% CI 2.9-3.2) per 100 person-years in groups 1 to 5.
In comparison with group 1 patients with and without ischemic heart disease, the hazard ratios associated with loop-diuretic dosage were found to be slightly lower for patients with ischemic heart disease than for those without in groups 2 to 5 (P<0.0001 for interactions):
• HR 1.22 (95% CI 1.10-1.34) versus 1.29 (95% CI 1.19-1.41)
• HR 1.38 (95% CI 1.24- 1.54) versus 1.50 (95% CI 1.38-1.64)
• HR 1.55 (95% CI 1.38-1.75) versus 1.81 (95% CI 1.64-1.99)
• HR 1.86 (95% CI 1.68-2.07) versus 2.00 (95% CI 1.83-2.20)
Just as with RASis, the use of beta blockers appeared to lower risk versus nonusage for groups 2 to 5 compared with group 1 (P<0.0001 for interactions):
• HR 0.86 (95% CI 0.79-0.94) versus 1.60 (95% CI 1.46-1.75)
• HR 0.97 (95% CI 0.88-1.07) versus 1.66 (95% CI 1.51-1.83)
• HR 0.91 (95% CI 0.81-1.02) versus 2.03 (95% CI 1.82-2.26)
• HR 1.03 (95% CI 0.93-1.14) and 2.17 (95% CI 1.96-2.40)
A total of 62,565 (63%) patients died during the study period, and the adjusted HR for death among those who developed diabetes was 1.16 (95% CI 1.12-1.19) compared with those who did not develop diabetes. Increasing loop-diuretic dosage was associated with increased risk for death: HRs 1.14 (95% CI 1.12-1.17), 1.17 (95% CI 1.14-1.20), 1.29 (95%CI 1.26-1.33) and 1.45 (95% CI 1.41-1.48) for groups 2 to 5 compared with group 1.
The researchers noted that the results should be considered "hypothesis generating," but the finding that RASis seemed to attenuate diabetes risk may be worthy of further study.
They noted that large-scale clinical studies have found that treatment with RASis or angiotensin II receptor antagonists reduced the relative risk of the development of diabetes by 14% to 34%, although newer studies have found less or no risk reduction. Other medications such as beta-blockers have also been linked to increased risks of diabetes in some previous studies.
"We found the opposite in the present study, i.e., a lowered risk of diabetes associated with [beta-blockers], which, as for RASis, may have been due to blockage of a high sympathetic tone and/or improved cardiac function," they said, adding that a selection bias for prescribing beta-blockers to generally healthier patients couldn't be ruled out.
Diabetes Awareness in HF Management
Study limitations included the lack of data on possibly relevant variables such as body mass index, smoking status, blood glucose values, New York Heart Association class, hypertension, and left ventricular ejection fraction. In addition, both heart failure severity and diabetes were defined from prescription claims, which were characterized by the authors as "rough phenotypic markers" of true severity.
The authors also did not explore the mechanisms for these effects in this study, but they did suggest several possibilities, such as patients with heart failure having decreased cardiac output and diminished oxygen; glucose and insulin distribution to peripheral muscular tissue which may lead to increased insulin resistance and decreased insulin release; lack of physical activity in those with the most severe heart failure; and potential side effects of loop-diuretic drugs.
Nevertheless, the findings emphasize the need to closely monitor and treat patients with heart failure if necessary with the goal of preventing diabetes, the researchers concluded.
"Future strategies for heart failure management should include increased awareness of risk of diabetes in patients with severe heart failure," they wrote.
The study was funded by the Copenhagen University Hospital Gentofte.
Demant reported no relevant relationships with industry.
Two co-authors reported support from the Danish Agency for Science, Technology and Innovation and Novo Nordisk Foundation.
One co-author reported equity ownership in Novo Nordisk A/S and receiving honoraria from the company.
One co-author reported holding stock in Novo Nordisk A/S.