Diabetes Is an Important Risk Factor for CVD Mortality in the Elderly

October 18, 2006 — The negative impact of diabetes on cardiovascular disease (CVD) mortality persists into old age, with elderly people who have diabetes being twice as likely to die as their peers without diabetes, an observational study has found.

Richard A. Kronmal, MD, from the University of Washington in Seattle, and colleagues report their findings in the October 17 online issue of PLoS Medicine. "The relative risk [of CVD mortality] reported herein is far more noteworthy and of greater public health impact than a similar relative risk in a middle aged population," the authors note. "Elderly people often receive less intensive management of CVD risk factors than younger individuals. Our findings strengthen the rationale for the opposite approach."

In an accompanying editorial, Andre Pascal Kengne, MD, and Anushka Patel, MD, from the University of Sydney in Sydney, Australia, say the new data "make an important contribution to our knowledge of morbidity and mortality associated with diabetes mellitus in older adults."

Diabetes Is Important in Old Age

Kronmal and colleagues note that most studies on the burden of diabetes mellitus have been conducted in middle-aged populations and have often been adjusted only for traditional risk factors. Using the Cardiovascular Health Study, a longitudinal observational study of adults aged 65 years or older, they assessed mortality in older people with diabetes treated with oral hypoglycemic agents (OHGAs) and insulin, and adjusted for nontraditional (eg, inflammation, subclinical vascular disease, and psychosocial factors) as well as traditional covariates.

A total of 5372 participants were followed up for 11 years (1989-2001), 322 of whom (5.5%) were treated with OHGAs and 194 of whom (3.3%) were treated with insulin. Total, CVD, coronary heart disease (CHD), and non-CVD/noncancer mortality were recorded.

Table. Incidence Rates and HRs for Total, CVD, and Non-CVD Endpoints in CHS Participants Categorized by Baseline Glycemia Status and Type of Antihyperglycemic Treatment*

* HR, indicates hazard ratio; CVD, cardiovascular disease; CHS, Cardiovascular Health Study; DM, diabetes mellitus; OHGA, oral hypoglycemic agents; and CHD, coronary heart disease. Specific figures for stroke, non-CVD, and cancer deaths are not reported in this table.
† Adjusted for age, sex, and other covariates.
‡ Includes atherosclerotic CHD, cerebrovascular disease, other atherosclerotic heart disease, and other cardiovascular events.
Source: PloS Med. Published online October 17, 2006.

Second author Joshua I. Barzilay, MD, from Emory University School of Medicine in Atlanta, Georgia, told heartwire that a recent Scandinavian study "had suggested that diabetes in the over 75s was not a big risk."

"[But] we found that diabetes mellitus continues to be associated with a deleterious effect on mortality in older adults."

For combined CVD and CHD deaths, adjusted mortality risks were around 2 and 2.5 times higher, respectively, than in participants without diabetes, the authors note, stating that these estimates are similar to those from studies of older individuals with diabetes from prior decades, which adjusted only for traditional CVD risk factors.

Diabetic Patients Have Also Experienced Declines in CVD and CHD Mortality

Thus, 2 conclusions can be drawn, the authors note. First, "given the decreasing rate of CVD and CHD mortality in the general population, but the unvarying relative risk of mortality associated with diabetes, it follows that older adults with diabetes are experiencing the same rate of decline in CVD and CHD mortality as people without diabetes."

This is important as there has been conflicting data as to whether diabetic patients were or were not experiencing the same decline in CVD and CHD mortality as nondiabetic patients, Dr. Barzilay explained.

Second, the additional adjustment for nontraditional risk factors "did not have much of an impact on mortality" Dr. Barzilay notes, a somewhat puzzling finding given that subclinical CVD is known to be a strong predictor of clinical disease.

In their editorial, Drs. Kengne and Patel say, "These data provide reliable evidence that diabetes is an important adverse risk factor among older adults, with estimates of the strength of the associations comparable to published data for younger cohorts."

"These data confirm that older adults with diabetes are at very high absolute risk of death from cardiovascular causes (4-5% per year). Thus strategies aimed at reducing these risks should be aggressively pursued among such individuals, wherever possible."

Effects on Women Receiving Insulin

Dr. Kronmal and colleagues also found that women with diabetes vs women without had a greater relative total mortality risk vs men (2.28 vs 1.80). When this risk was categorized by treatment type, it appeared that women who took OHGAs had a mortality risk similar to men, whereas those treated with insulin had a much higher relative mortality than men, particularly in terms of deaths from renal and infectious causes.

"Thus the overall increased mortality of women than men with diabetes appears to be accounted for by insulin therapy. This finding has not, to our knowledge, yet been reported," the authors state.

Dr. Barzilay says this is an interesting finding and that he has also observed a 3- to 4-fold increased risk for CHD in people with diabetes and high morning insulin levels in another study. "We plan to look at this in more detail in larger studies with greater numbers."

Ongoing Trials Will Help Answer the Question

Drs. Kengne and Patel say the observation that the relative risk for mortality, particularly that due to infectious or renal causes, associated with diabetes was significantly greater among individuals treated with insulin compared with those receiving OHGAs and that women with diabetes receiving insulin had a particularly high risk for death compared with women without diabetes, are "interesting.... [but] can only be considered hypothesis generating."

Ongoing clinical trials, such as ADVANCE and ACCORD, should help shed further light on these questions, the authors note.

ACCORD is testing 3 complementary medical strategies for type 2 diabetes in just more than 10,000 patients. The 3 specific hypotheses are as follows:

• Does a strategy targeting hemoglobin A1c of less than 6.0% reduce the rate of CVD events more than 1, which targets a hemoglobin A1c of 7.0% to 7.9%?
• In the context of good glycemic control, does using a fibrate to raise high-density lipoprotein cholesterol and/or lower triglyceride levels in addition to a statin for treatment of low-density lipoprotein cholesterol levels reduce the rate of CVD events compared with just using a statin alone?
• In the context of good glycemic control, does targeting a systolic blood pressure of less than 120 mm Hg reduce the rate of CVD events more than 1, which targets systolic blood pressure of less than 140 mm Hg?

The primary endpoint of ACCORD will be the first occurrence of a major CVD event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

The ADVANCE trial is to determine the effects of blood pressure lowering and intensive glucose lowering on macrovascular and microvascular disease in 11,140 individuals with early type 2 diabetes.

PLoS Med. Published online October 17, 2006.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Identify the effects of concomitant depression among older patients with diabetes.
• Specify the group at highest cardiovascular risk among older patients with diabetes.

Clinical Context

Depression has multiple negative health effects beyond its impact on mood, and a study by Black and colleagues, published in the October 2003 issue of Diabetes Care, suggests that depression may worsen outcomes among older patients with diabetes. The authors followed up 2830 Mexican Americans and found that subjects with depression in addition to diabetes experienced higher rates of mortality, microvascular and macrovascular complications, and disability when compared with patients with diabetes alone. These associations remained true on multivariable analysis, and complications of diabetes occurred not only more frequently but also earlier among subjects with diabetes and depression.

The authors of the current study examined a cohort of older adults to determine the effects of age, diabetes treatment, and sex on mortality outcomes in this specific patient population.

Study Highlights

• Study participants included community-dwelling adults at age 65 years or older. Patients with illnesses that would lead to early death were excluded from study participation. The patient cohort was followed up between 1989 and 2001.
• The main study outcome was the relationship between diabetes and mortality. Diabetes was defined for this study as disease requiring treatment with oral medications or insulin.
• Participants included 5372 patients without diabetes, 322 patients with diabetes treated with OHGAs, and 194 patients with diabetes treated with insulin. Patients without diabetes were more likely to be healthy and have no significant CVD at baseline. Patients without diabetes also experienced fewer difficulties with activities of daily living.
• The median follow-up period was 11.1 years. Median rates of survival for subjects without diabetes, with diabetes treated with oral medications, and with diabetes treated with insulin were older than 12 years, slightly younger than 10 years, and 7.5 years, respectively.
• Compared with subjects without diabetes, those treated with oral medications and insulin experienced adjusted hazard ratios for total mortality of 1.33 and 2.04, respectively. The respective adjusted hazard ratios for mortality due to CHD were 2.47 and 2.75. The presence of diabetes did not significantly increase the risk for cerebrovascular mortality.
• Mortality due to infection or renal disease was not significantly different between the cohort without diabetes and subjects using OHGAs. However, participants using insulin had an adjusted hazard ratio of 6.55 for mortality due to infection or renal disease compared with subjects without diabetes.
• Noncardiovascular causes of death, particularly cancer, were more common among subjects without diabetes.
• Adjustment for baseline age, sex, smoking, and psychosocial factors diminished most of the study's significant results, but the increased risk for death associated with diabetes remained significant.
• There was no difference in mortality data between patients between the ages of 65 and 74 years and those older than age 74 years. However, women were noted to have a higher risk for mortality associated with diabetes compared with men, particularly among women who used insulin.

Pearls for Practice

• Previous research has demonstrated that concomitant depression in addition to diabetes can increase the risk for mortality, microvascular and macrovascular complications, and disability.
• In the current study, diabetes increased the risk for mortality among patients older than 65 years. The greatest impact of diabetes on mortality was noted among women receiving insulin.