Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death
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Abstract
Background—
Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus.
Methods and Results—
The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19–1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26–1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30–1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18–1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17–2.77; P<0.001) and hospitalization for heart failure (adjusted odds ratio, 4.72; 95% CI, 4.22–5.29; P<0.001).
Conclusions—
Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.
Introduction
Diabetes mellitus is a significant, well-established risk factor for multiple clinical outcomes, including macrovascular events (stroke, myocardial infarction [MI]) and microvascular complications (neuropathy, nephropathy).1 As treatment strategies for cardiovascular disease have been refined, the overall morbidity and mortality associated with cardiovascular events have declined.2 Patients with diabetes mellitus who have acute cardiovascular events continue to have worse outcomes compared with patients without diabetes mellitus.3,4 This disparity is of particular importance given the high prevalence of diabetes mellitus. Epidemiological studies from the United States have shown that clinical outcomes in patients with diabetes mellitus have improved over time, but the increased prevalence of diabetes mellitus has resulted in an increase in the absolute rate of complications from diabetes mellitus.5,6 Similar increases in incidence have also been seen across the world. As a result, the international prevalence of diabetes mellitus is expected to continue to rise as risk factors for diabetes mellitus become more common.7,8
Clinical Perspective on p 931
Despite the high prevalence and clear association of diabetes mellitus with adverse events, there are few contemporary data on the long-term outcomes from an international cohort of patients with diabetes mellitus. Prior studies have suggested that diabetes mellitus is associated with an increase in risk that is of a magnitude similar to that of the presence of known atherothrombosis.9 Uncertainty about the current long-term outcomes of stable patients with diabetes mellitus has led to significant debate over whether diabetes mellitus is truly a risk equivalent to coronary artery disease in this population.10,11 Furthermore, prior studies have suggested that diabetes mellitus may be associated with an increased risk of heart failure.12 However, it remains unclear whether this association is attributable to causal effects of diabetes mellitus or to other coexisting medical conditions (eg, hypertension, coronary artery disease, renal dysfunction).13,14 Thus, we sought to use the Reduction of Atherothrombosis for Continued Health (REACH) registry to describe current long-term cardiovascular outcomes, including hospitalization for heart failure, and to identify predictors of these cardiovascular events in an international cohort of patients with diabetes mellitus.
Methods
Study Design and Population
The REACH registry is a prospective cohort of patients with either established atherosclerosis or significant risk factors for atherosclerosis that has been described previously in detail.15–17 To be included in the registry, patients had to be ≥45 years old and had to have established atherosclerosis (coronary artery disease, peripheral artery disease, or cerebrovascular disease) or ≥3 risk factors for atherosclerosis. Subjects were considered to have coronary artery disease if they had ≥1 of the following: prior MI, history of coronary revascularization with percutaneous coronary intervention/coronary artery bypass graft surgery, stable angina, or history of unstable angina. Subjects were considered to have cerebrovascular disease if they had been diagnosed previously with either an ischemic stroke or transient ischemic attack by a neurologist or at the time of hospital discharge. Subjects with peripheral artery disease had either current intermittent claudication and an ankle-brachial index <0.9 or a history of intermittent claudication together with a prior intervention (angioplasty, stenting, atherectomy, peripheral arterial bypass grafting, amputation, or other vascular intervention).
Risk factors for atherosclerosis included age (≥65 years for men, ≥70 years for women), hypertension (patients receiving treatment for hypertension and patients with systolic blood pressure ≥150 mm Hg despite therapy), current therapy for hypercholesterolemia, ongoing tobacco use of ≥15 cigarettes a day, diabetes mellitus, diabetic nephropathy, ankle-brachial index <0.9, asymptomatic carotid stenosis ≥70%, and carotid intima media thickness ≥2 times that of adjacent sites. Patients were considered to have diabetes mellitus if they were being treated for diabetes mellitus with either medications or lifestyle modifications at baseline or if they had at least 2 fasting blood glucose measures >126 mg/dL and were not being treated with either medications or lifestyle modifications.
Patients were enrolled in the REACH registry between 2003 and 2004 and were followed up until 2008. Detailed personal and medical history was collected at baseline and then annually. The initial follow-up was planned for up to 2 years, but the registry was extended for an additional 2 years. Although the majority of sites participated for the entire 4 years of follow-up, countries and sites that did not participate in the 4-year follow-up were excluded from these analyses (n=45 227 subjects were eligible and 23 009 excluded).
Institutional review boards in each country reviewed and approved the protocol according to the local requirements. Signed informed consent was required for all patients.
End Points
Patients in the REACH registry were followed up for end points including cardiovascular death, MI, stroke, hospitalization for ischemia, and hospitalization for heart failure. The end points in the registry were investigator reported and were not adjudicated. Cardiovascular death was defined as any death resulting from stroke, MI, or other cardiovascular causes (eg, deaths caused by pulmonary embolism; any sudden death, including unobserved and unexpected deaths, unless proven to have a noncardiovascular cause by autopsy; death after a vascular operation, procedure, or amputation; death caused by heart failure; death after a visceral or limb infarction; and any other death that could not be definitely attributed to a nonvascular cause or hemorrhage). Any MI or stroke followed by a death in the next 28 days (regardless of the cause) was considered to be a fatal MI or fatal stroke.
Statistical Analysis
Categorical variables were calculated as frequencies and percentages, and continuous variables were calculated as mean and standard deviations. Missing data at baseline were infrequent (<1% or 2% for most variables; diabetes status was missing for 3 patients). Imputations were performed with the multiple imputation approach for baseline characteristics that were missing.18 The cohort of patients with diabetes mellitus was further classified by baseline characteristics into patients with risk factors only (no established atherothrombotic disease) or known atherothrombosis (patients with established coronary, peripheral, or cerebral artery disease). Patients with diabetes mellitus and known atherothrombosis were further stratified into those with known atherothrombosis and no prior ischemic event (established atherothrombosis but no prior MI or stroke, eg, patients with a history of revascularization) or with atherothrombosis with prior ischemic events (MI or stroke).
Four-year event rates in these patients were generated with the corrected group prognosis method, which is an alternative approach to estimate 4-year cumulative incidence rates (and 95% confidence intervals [CIs]) as a function of different baseline risk factors.19 Models that controlled for sex and age were developed separately and evaluated the primary outcome (composite of cardiovascular death, nonfatal MI, or nonfatal stroke), secondary outcome (composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for ischemia), all-cause mortality, noncardiovascular death, hospitalization for heart failure, and the individual components of the primary composite end point. Hospitalization for ischemia was defined as hospitalization for unstable angina, transient ischemic attack, worsening of claudication related to peripheral artery disease, other ischemic arterial event, coronary artery bypass grafting, coronary angioplasty/stenting, carotid surgery, carotid angioplasty/stenting, amputation affecting lower limbs, peripheral bypass graft, or angioplasty/stenting for peripheral artery disease.
A Cox proportional hazard survival model was developed to identify the predictors of cardiovascular death, MI, or stroke. Candidate variables were selected from previously described risk factors in patients with atherothrombosis or diabetes mellitus.11 Variables included in the final model were sex, age, geographic region (Latin America, Middle East, Eastern Europe, Western Europe, Asia, Japan), cardiovascular risk factors (current smoker, body mass index, ischemic event [none, ≤1 year since event, >1 year since event], hypercholesterolemia, hypertension, renal dysfunction, vascular disease status [polyvascular disease, known atherosclerosis in only one vascular territory, or risk factors only], congestive heart failure, atrial fibrillation), and medications (statins, aspirin, blood pressure treatment, antihyperglycemic agent). The proportional hazard assumption was tested by visual inspection of the Schoenfeld residuals.
The association between diabetes mellitus and hospitalization for heart failure was assessed via a logistic regression model owing to limited data on the timing of this event. Variables included in the heart failure model were selected from the same candidate variables and with the same methods as used for the prior model.
Statistical significance was considered to be a 2-sided value of P<0.05. Statistical analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC).
Results
A total of 45 227 of the patients who were enrolled in the REACH registry had follow-up at 4 years. Of those, 19 699 patients (43.6%) had diabetes mellitus. The mean age of patients in the subgroup with diabetes mellitus was 68.4 years, which was similar to that of patients without diabetes mellitus (P=0.40). The overall proportion of patients from North America or Western Europe included in the analysis was 66.9%.
Compared with those without diabetes mellitus, patients with diabetes mellitus were less frequently male or white and had lower rates of coronary artery disease (50.4% versus 64.5%; P<0.001) and cerebrovascular disease (24.0% versus 31.7%; P<0.001) at baseline. There were no differences between the groups in the proportion of patients with peripheral vascular disease at baseline (P=0.20). A history of heart failure was more common in patients with diabetes mellitus (16.1% versus 11.8%; P<0.001). Cardiovascular risk factors such as hypertension, hypercholesterolemia, obesity, and renal dysfunction were more common in patients with diabetes compared with patients without diabetes (Table 1).
| Diabetes Mellitus(n=19 699) | No Diabetes Mellitus(n=25 525) | P Value | |
|---|---|---|---|
| Age, mean (SD), y | 68.4 (9.5) | 68.4 (10.3) | 0.40 |
| Men, n (%) | 12 154 (61.8) | 17 090 (67.0) | <0.001 |
| Location, n (%) | |||
| North America | 7942 (40.3) | 7700 (30.2) | <0.001 |
| Latin America | 627 (3.2) | 749 (2.9) | 0.13 |
| Western Europe | 5810 (29.5) | 8811 (34.5) | <0.001 |
| Eastern Europe | 1238 (6.3) | 3288 (12.9) | <0.001 |
| Middle East | 218 (1.1) | 246 (1.9) | 0.13 |
| Asia | 1542 (7.8) | 1980 (7.8) | 0.78 |
| Japan | 2322 (11.8) | 2751 (10.8) | 0.001 |
| Ethnicity, n (%) | |||
| White | 10 799 (60.1) | 15 513 (67.8) | <0.001 |
| Hispanic | 1099 (6.1) | 916 (4.0) | <0.001 |
| East Asian | 3103 (17.3) | 3882 (17.0) | 0.42 |
| South Asian | 221 (1.2) | 149 (0.7) | <0.001 |
| Other Asian | 1116 (6.2) | 1091 (4.8) | <0.001 |
| Black | 983 (5.5) | 506 (2.2) | <0.001 |
| Other | 655 (3.6) | 832 (3.6) | 0.96 |
| CV risk factors, n (%) | |||
| Hypertension | 17 167 (87.2) | 19 582 (76.7) | <0.001 |
| Hypercholesterolemia | 14451 (73.4) | 17 335 (68.0) | <0.001 |
| Obesity (BMI ≥30 kg/m2) | 7377 (37.9) | 5326 (21.1) | <0.001 |
| Current smoker | 2672 (14.0) | 4167 (16.8) | <0.001 |
| Heart failure | 3118 (16.1) | 2967 (11.8) | <0.001 |
| Renal dysfunction | 4704 (32.4) | 101 (0.5) | <0.001 |
| Vascular disease, n (%) | |||
| CAD at baseline | 9935 (50.4) | 16 454 (64.5) | <0.001 |
| CVD at baseline | 4725 (24.0) | 8079 (31.7) | <0.001 |
| PAD at baseline | 2511 (12.8) | 3358 (13.2) | 0.20 |
| Medication use at 4 y, n (%) | |||
| ≥1 Antithrombotic agent | 10 185 (83.7) | 15 498 (91.0) | <0.001 |
| Statin | 9007 (74.1) | 12 147 (71.5) | <0.001 |
| ACE inhibitor or ARB | 9376 (77.1) | 10 876 (63.9) | <0.001 |
| Aspirin only | 6482 (53.3) | 9860 (57.9) | <0.001 |
| Other antiplatelet only | 1409 (11.6) | 2434 (14.3) | <0.001 |
| Aspirin+other antiplatelet | 1425 (11.7) | 1855 (10.9) | 0.03 |
| β-Blocker | 5882 (48.5) | 9091 (53.5) | <0.001 |
| Diuretic | 6175 (50.9) | 6596 (38.9) | <0.001 |
| Insulin | 3789 (31.2) | 90 (0.5) | <0.001 |
| Biguanides | 5137 (42.4) | 484 (2.9) | <0.001 |
| Sulfonylureas | 4862 (40.2) | 293 (1.7) | <0.001 |
| Thiazolidinedione | 1953 (16.2) | 98 (0.6) | <0.001 |
| ≥1 Antihyperglycemic agent | 10 599 (87.0) | 877 (5.2) | <0.001 |
The use of at least 1 antithrombotic drug at 4 years was lower in the patients with diabetes mellitus than in those without diabetes mellitus (83.7% versus 91.0%; P<0.001). Aspirin was used in slightly more than half the overall cohort with diabetes mellitus (53.3%) and without diabetes mellitus (57.9%). In the patients with diabetes mellitus, the use of aspirin was similar among those with known atherothrombosis and risk factors only (53.8% versus 52.1%; P=0.08). Statin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and diuretics were used more commonly in patients with diabetes mellitus, whereas β-blockers were used more frequently in patients without diabetes mellitus (48.5% versus 53.5%; P<0.001).
In the patients with diabetes mellitus, the most commonly prescribed treatments were biguanides (42.3%), followed by sulfonylureas (40.2%), insulin (31.2%), and thiazolidinediones (16.2%). In patients with diabetes mellitus, patients with known atherothrombosis were less frequently treated with antihyperglycemic drugs (84.8% versus 91.7%; P<0.001; Table I in the online-only Data Supplement).
The overall hazard rate of cardiovascular death, MI, or stroke (adjusted for age and sex) was greater in patients with diabetes mellitus than in patients without diabetes mellitus (16.5% versus 13.1%; P<0.001; Table 2). Similar relationships were seen for the individual components of cardiovascular death (8.9% versus 6.0%; P<0.001) and nonfatal MI (4.4% versus 3.2%; P<0.001), but there was no difference in nonfatal stroke (5.7% versus 5.3%; P=0.14). There was also a marked increase in all-cause mortality in patients with diabetes compared with those without diabetes (14.3% versus 9.9%; P<0.001). Similar results were seen in the cohort of patients on hypoglycemic agents at baseline (Table II in the online-only Data Supplement).
| No Diabetes MellitusOverall(n=25 525) | Diabetes MellitusOverall(n=19 699) | P Value (Diabetes Mellitus vs No Diabetes Mellitus) | Diabetes Mellitus, Known Atherothrombosis(n=13 673) | Diabetes Risk Factors Only(n=6026) | P Value (Known vs Risk Factors Only) | |
|---|---|---|---|---|---|---|
| CV death, nonfatal MI, or nonfatal stroke | 13.1 (12.6–13.5) | 16.5 (16.0–17.1) | <0.001 | 19.5 (18.7–20.2) | 9.5 (8.6–10.3) | <0.001 |
| CV death, nonfatal MI, nonfatal stroke, or hospitalization for ischemia* | 25.6 (25.1–26.2) | 27.0 (26.3–27.6) | 0.001 | 33.0 (32.1–33.8) | 13.8 (13.0–14.7) | <0.001 |
| All-cause mortality | 9.9 (9.5–10.3) | 14.3 (13.8–14.9) | <0.001 | 16.4 (15.7–17.1) | 8.7 (7.9–9.5) | <0.001 |
| CV death | 6.0 (5.7–6.3) | 8.9 (8.4–9.4) | <0.001 | 10.5 (10.0–11.1) | 4.5 (3.9–5.1) | <0.001 |
| Nonfatal MI | 3.2 (2.9–3.4) | 4.4 (4.0–4.7) | <0.001 | 5.2 (4.7–5.6) | 2.4 (2.0–2.9) | <0.001 |
| Nonfatal stroke | 5.3 (5.0–5.6) | 5.7 (5.3–6.0) | 0.14 | 6.7 (6.2–7.2) | 3.3 (2.8–3.8) | <0.001 |
| Non-CV death | 4.2 (4.0–4.5) | 6.2 (5.8–6.6) | <0.001 | 6.7 (6.2–7.2) | 4.6 (4.0–5.2) | <0.001 |
After adjustment for potential confounders, the presence of diabetes mellitus was associated with an increased risk of the primary composite end point of cardiovascular death, MI, or stroke; all-cause mortality; cardiovascular death; noncardiovascular death; nonfatal MI; nonfatal stroke; and the composite end point of cardiovascular death, MI, stroke, or cardiovascular hospitalization (Table III in the online-only Data Supplement).
Among patients with diabetes mellitus, those with known atherothrombosis had significantly higher rates of cardiovascular death, MI, or stroke (19.5% versus 9.5%; P<0.001; Figure 1). All-cause mortality and noncardiovascular death were also higher in patients with known atherothrombosis compared with patients with risk factors only. In patients with diabetes mellitus and prior coronary revascularization but no prior MI, the hazard rate of cardiovascular death, nonfatal MI, or stroke was 14.8% (95% CI, 13.31–16.21). At 4 years, the hazard rate for cardiovascular death was 7.7% (95% CI, 6.6–8.81), whereas the hazard rate for noncardiovascular death was 5.8% (95% CI, 4.82–6.81). The hazard rate for nonfatal MI was 4.1% (95% CI, 3.24–4.89), and the hazard rate for nonfatal stroke was 4.6% (95% CI, 3.73–5.48).
Figure 1. Adjusted cumulative incidence curves in patients included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. Cumulative incidence curves were adjusted for age and sex. MI indicates myocardial infarction.
Compared with those patients in REACH without diabetes mellitus, the presence of diabetes mellitus was associated with a 33% increase in the odds of hospitalization for heart failure that was present even after adjustment for potential confounders (9.4% versus 5.9%; adjusted odds ratio [OR], 1.33; 95% CI, 1.18–1.50; Figure 2). The association between diabetes mellitus and hospitalization for heart failure was seen in the patients with known atherothrombosis (adjusted OR, 1.30; 95% CI, 1.14–1.48) and risk factors only for atherothrombosis (adjusted OR, 1.56; 95% CI, 1.06–2.29). Patients with diabetes mellitus and known atherothrombosis had a higher absolute risk of hospitalization for heart failure compared with patients with diabetes mellitus and risk factors only (11.4% versus 4.8%; P≤0.001). Furthermore, 3.3% of patients with diabetes mellitus both had an ischemic event and were hospitalized for heart failure during the 4 years of follow-up (Figure I in the online-only Data Supplement). Patients with a history of heart failure at baseline had higher rates of cardiovascular events than patients with no heart failure at baseline (Table IV in the online-only Data Supplement). A history of heart failure at baseline in patients with diabetes mellitus was independently associated with both cardiovascular death (adjusted hazard ratio [HR], 2.45; 95% CI, 2.17–2.77; P<0.001) and hospitalization for heart failure (adjusted OR, 4.72; 95% CI, 4.22–5.29; P<0.001).
Figure 2. Incidence of hospitalization for heart failure by 4 years in patients with diabetes mellitus. The bar graph represents the incidence of hospitalization for heart failure in the overall cohort and selected subgroups and is stratified on the basis of the presence or absence of diabetes mellitus. The odds ratio (OR) reflects the odds of heart failure in patients with diabetes mellitus at baseline compared with patients without diabetes mellitus at baseline. The OR is adjusted for the following characteristics: sex, age, geographic region (Latin America, Middle East, Eastern Europe, Western Europe, Asia, Japan), cardiovascular risk factors (current smoker, body mass index, ischemic event [none, ≤1 year since event, >1 year since event], hypercholesterolemia, hypertension, renal dysfunction, vascular disease status [polyvascular disease, known atherosclerosis in only one vascular territory, or risk factors only], congestive heart failure, atrial fibrillation), and medications (statins, aspirin, blood pressure treatment, antihyperglycemic agent). CI indicates confidence interval.
Given that patients with diabetes mellitus were found to be at increased risk of cardiovascular events, we sought to identify the predictors of cardiovascular death, nonfatal MI, or nonfatal stroke specifically in the population with diabetes mellitus. When we restricted the populations to include only patients with diabetes mellitus, a multivariate analysis found that the greatest predictors for cardiovascular death, nonfatal MI, and nonfatal stroke were the presence of polyvascular disease and congestive heart failure at baseline (Table 3). Other notable predictors of cardiovascular death, MI, or stroke in this population of patients with diabetes mellitus included recent ischemic events, age, and insulin use at baseline. Men were also at increased risk of these events compared with women (HR, 1.19; 95% CI, 1.09–1.29; P<0.001). In terms of geography, compared with North American patients, patients from Eastern Europe were at higher risk of cardiovascular death, MI, or stroke (HR, 1.20; 95% CI, 1.03–1.39; P=0.02), whereas patients from Japan were at lower risk of these events (HR, 0.61; 95% CI, 0.52–0.71; P<0.001).
| HR (95% CI) | P Value | |
|---|---|---|
| Polyvascular disease vs risk factors only | 1.92 (1.66–2.22) | <0.001 |
| Congestive heart failure, yes vs no | 1.70 (1.55–1.87) | <0.001 |
| ≤1 y since ischemic event vs no ischemic event | 1.64 (1.45–1.85) | <0.001 |
| Single vascular territory disease vs risk factors only | 1.45 (1.28–1.64) | <0.001 |
| Renal dysfunction, yes vs no | 1.39 (1.28–1.51) | <0.001 |
| >1 y since ischemic event vs no ischemic event | 1.36 (1.23–1.50) | <0.001 |
| Age, per 10-y increase | 1.34 (1.28–1.41) | <0.001 |
| Insulin use at baseline, yes vs no | 1.33 (1.21–1.46) | <0.001 |
| Smoker, current vs former or never | 1.25 (1.11–1.40) | <0.001 |
| Atrial fibrillation, yes vs no | 1.24 (1.11–1.39) | <0.001 |
| Eastern Europe (vs North America) | 1.20 (1.03,1.39) | 0.02 |
| Sex, male vs female | 1.19 (1.09–1.29) | <0.001 |
| Statins, yes vs no | 0.82 (0.72–0.94) | 0.003 |
| Japan (vs North America) | 0.61 (0.52–0.71) | <0.001 |
Similarly, patients with diabetes mellitus were at increased risk of hospitalization for heart failure. Thus, we sought to identify the predictors of hospitalization for heart failure in the population with diabetes mellitus. In patients with diabetes mellitus, the presence of baseline congestive heart failure had the largest association with hospitalization for heart failure (Table 4). Geographic region was also a significant predictor of hospitalization for hospitalization for heart failure. Compared with North America, the risk of hospitalization for heart failure was higher in Eastern Europe (OR, 1.38; 95% CI, 1.12–1.70; P=0.002) and Western Europe (OR, 1.24; 95% CI, 1.09–1.40; P=0.001) but was lower in Japan (OR, 0.44; 95% CI, 0.34–0.58; P<0.001; Table V in the online-only Data Supplement).
| OR (95% CI) | P Value | |
|---|---|---|
| Congestive heart failure (baseline), yes vs no | 4.72 (4.22–5.29) | <0.001 |
| Polyvascular disease vs risk factors | 1.98 (1.64–2.39) | <0.001 |
| Middle East vs North America | 1.86 (1.22–2.85) | 0.004 |
| Atrial fibrillation, yes vs no | 1.68 (1.47–1.93) | <0.001 |
| Renal dysfunction, yes vs no | 1.58 (1.39–1.80) | <0.001 |
| Medications for CHF at baseline, yes vs no | 1.58 (1.21–2.08) | 0.001 |
| Single vascular territory disease vs risk factors | 1.46 (1.24–1.71) | <0.001 |
| Eastern Europe vs North America | 1.38 (1.12–1.70) | 0.002 |
| Age, per 10-y increase | 1.30 (1.22–1.39) | <0.001 |
| Western Europe vs North America | 1.24 (1.09–1.40) | 0.001 |
| Insulin use at baseline, yes vs no | 1.23 (1.08–1.40) | 0.002 |
| Smoker, current vs former or never | 1.20 (1.01–1.44) | 0.04 |
| Ischemic event >1 y vs no ischemic event | 1.19 (1.04–1.35) | 0.01 |
| Obese BMI (>30 kg/m2) vs normal BMI (20–25 kg/m2) | 1.18 (1.01–1.38) | 0.04 |
| Japan vs North America | 0.44 (0.34–0.58) | <0.001 |
Discussion
Our data show that 1 of 6 patients in an international cohort with diabetes mellitus and either established atherothrombosis or additional risk factors for atherothrombosis experienced cardiovascular death, MI, or stroke during 4 years of follow-up. Rates of cardiovascular events, including cardiovascular mortality, were significantly higher in patients with diabetes mellitus compared with patients without diabetes mellitus. Although significant progress has been made in the management and treatment of patients with cardiovascular disease,20–22 these data provide evidence that rates of cardiovascular events remain elevated in patients with diabetes mellitus. Thus, the presence of diabetes mellitus continues to be a significant risk factor for ischemic events despite the use of evidence-based therapies in a contemporary, international cohort of patients.
In addition to the increased risk of ischemic events, we found an independent association between diabetes mellitus and the risk of hospitalization for heart failure. The predictors associated with hospitalization for heart failure were similar to the factors associated with future ischemic events; however, a history of heart failure was the strongest predictor of future heart failure hospitalizations. The risk of hospitalization for heart failure also varied by region. These findings are consistent with prior studies that have found geographic differences in both the incidence of heart failure and the effectiveness of therapies for heart failure. For example, the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial, which evaluated the effectiveness of spironolactone in patients with heart failure and preserved ejection fraction, found an ≈3-fold difference in the rate of hospitalization for heart failure in patients in the United States, Canada, Brazil, or Argentina compared with those treated in either Russia or Georgia.23
Our data support prior studies that have also found an association between diabetes mellitus and increased risk of hospitalization for heart failure.24 Despite these data, the association between diabetes mellitus and heart failure remains underrecognized by clinicians.25 Nonetheless, in an era in which there is increasing emphasis on chronic disease management as a strategy to contain healthcare costs, these findings highlight the significance of diabetes mellitus and the need for therapies that improve outcomes in this population.
Multiple hypotheses have been proposed for the mechanism behind the association of diabetes mellitus and heart failure, including an increased burden of ischemic heart disease, other medical comorbidities associated with diabetes mellitus, medications used in the treatment of diabetes mellitus, and a direct metabolic effect of altered glucose regulation, but the exact mechanism remains poorly defined.26 In the REACH registry, we found a 33% increase in the risk of hospitalization for heart failure in patients with diabetes mellitus. Similar associations were seen in patients with diabetes mellitus and prior ischemic events (MI, stroke), diabetes mellitus and known atherothrombosis but no prior ischemic events, and diabetes mellitus with risk factors only for atherothrombosis. Although these findings can be viewed only as hypothesis generating, they suggest that the mechanism of the association between diabetes mellitus and heart failure could be related to a process specific to patients with diabetes mellitus rather than an increased burden of atherothrombosis.27,28
We did find, however, that the risk of future ischemic events in patients with diabetes mellitus was associated with the extent and severity of atherothrombosis (number of vascular beds affected by atherothrombosis, the presence of recent ischemic events) and with other risk factors for cardiovascular events such as increasing age, history of heart failure, and renal dysfunction. These risk factors have previously been shown to affect outcomes in a general population of patients at high risk for ischemic events.17 Our findings extend these observations and show that the extent of vascular disease remains a powerful predictor of ischemic events specifically in patients with diabetes mellitus.
As shown from these data, the presence of diabetes mellitus significantly increases the risk of ischemic events. However, prior studies have not found the use of antihyperglycemic therapies to clearly reduce the risk of macrovascular events (eg, MI) in patients with type II diabetes mellitus despite improving glycemic control.28–32 Although the lack of cardiovascular benefit from glycemic control does not negate the importance of glycemic control, it suggests that attempts to improve cardiovascular outcomes in patients with diabetes mellitus should be broad and should focus on pathways other than those that affect only glycemic control. For example, prior studies of antiplatelet therapies in stable patients with established atherothrombosis have found that enhanced platelet inhibition with clopidogrel 75 mg daily and aspirin 81 mg daily reduced the incidence of cardiovascular death, MI, or stroke compared with patients treated with aspirin only.33 Ongoing trials of dual antiplatelet therapy in patients with diabetes mellitus and established atherosclerosis but no prior ischemic events will test the hypothesis that enhanced antiplatelet therapy can reduce cardiovascular events in patients with diabetes mellitus and atherosclerosis (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus; http://www.clinicaltrials.gov; identifier, NCT01991795).34
Our findings should be considered in light of some limitations. This analysis was not a population-based observational study, and the prevalence of some risk factors was influenced by the inclusion criteria for the registry. This registry captured significant clinical data, including medication use, that were used in the adjusted analyses, but the duration of diabetes mellitus and the degree of glycemic control in patients with diabetes mellitus as measured by hemoglobin A1c or fasting plasma glucose were not available. The end points in this observational registry were reported by investigators and were not adjudicated by an independent clinical events committee, as is common in many randomized, clinical trials. Although the relationship between diabetes mellitus and heart failure was present even after controlling for geography, it is possible that the geographic variation seen in the association with hospitalization for heart failure reflects differences in the frequency with which hospital-based treatment strategies were used in these particular areas. Finally, 4-year follow-up was not obtained from all patients. This was related to whether the research site that initially enrolled the patient participated in the follow-up and was not attributable to patient-specific factors and thus would not be expected to bias the results.
These data show that the presence of diabetes mellitus significantly increases the risk of cardiovascular events. This risk is present both in patients with diabetes mellitus and established atherosclerosis and in those with diabetes mellitus who have only risk factors for atherosclerosis. In patients with diabetes mellitus, the presence of heart failure in particular is also a significant risk marker associated with increased risk of cardiovascular events. Although current therapies have improved overall outcomes for patients with cardiovascular disease, the high incidence of events in patients with diabetes mellitus and risk factors for cardiovascular disease highlights the need for further therapies that can improve outcomes in this particularly high-risk patient population.
Sources of Funding
The REACH registry was sponsored by
Disclosures
Dr Cavender reports consulting fees from AstraZeneca and Merck-Sharpe Dohme. Dr Steg discloses the following relationships: research grants (to INSERM U1148) from Servier and Sanofi; speaker or consultant fees (including steering committee, data monitoring committee, and critical events committee memberships) from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, BristolMyersSquibb, Daiichi-Sankyo-Lilly, GlaxoSmithKline, Medtronic, Merck-Sharpe Dohme, Novartis, Otsuka, Pfizer, Sanofi, Servier, The Medicines Company, and Vivus; and stockholder in Aterovax. Dr Ohman discloses the following relationships: research grants (to the Duke Clinical Research Institute) from Daiichi Sankyo, Eli Lilly and Company and Gilead Sciences; and consulting fees from Abiomed, AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceuticals, Pozen, Inc, sanofi-aventis, The Medicines Company, and WebMD. Dr Goto discloses the following relationships: research grants from sanofi-aventis, Boehringer-Ingelheim, Otsuka, and Daiichi-Sankyo; and lecture fees from sanofi-aventis, Bayer, AstraZeneca, Eisai, Otsuka, Novartis, Asteras, Pfizer, Medtronic-Japan, Tanabe-Mitsubishi, Takeda, Daiichi-Sankyo, Mochida, and MSD. Dr Bhatt discloses the following relationships: advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; chair of the American Heart Association Get With The Guidelines Steering Committee; data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and WebMD (continuing medical education steering committees); other: Clinical Cardiology (deputy editor); research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, St. Jude Medical, and The Medicines Company; trustee of the American College of Cardiology; and unfunded research for FlowCo, PLx Pharma, and Takeda. The other authors report no conflicts.
Footnotes
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CLINICAL PERSPECTIVE
This analysis of patients with diabetes mellitus from the Reduction of Atherothrombosis for Continued Health (REACH) registry, an international study of patients at high risk of atherothrombosis or established atherothrombosis, found that cardiovascular events were more frequent in patients with diabetes mellitus. In the current era, 1 of 6 patients with diabetes mellitus in the REACH registry experienced a cardiovascular death, myocardial infarction, or stroke during 4 years of follow-up. Thus, the presence of diabetes mellitus continues to be a significant risk factor for ischemic events despite the use of evidence-based therapies in a contemporary, international cohort of patients. In addition, the presence of diabetes mellitus was associated with a 33% greater odds of hospitalization for heart failure. This risk was present both in patients with diabetes mellitus and established atherosclerosis and in those with diabetes mellitus and only risk factors for atherosclerosis. The association between diabetes mellitus and heart failure was seen in patients with prior ischemic events (myocardial infarction, stroke), diabetes mellitus and known atherothrombosis but no prior ischemic events, and those with diabetes mellitus with risk factors only for atherothrombosis. These findings suggest that it is possible that the mechanism of the association between diabetes mellitus and heart failure could be related to a process specific to patients with diabetes mellitus rather than an increased burden of atherothrombosis. In an era in which there is increasing emphasis on chronic disease management, these findings highlight the significance of diabetes mellitus and the continued need for therapies that improve outcomes in this high-risk population.
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