The global number of deaths from cardiovascular disease (CVD) increased by 14.5% between 2006 and 2016, and by 53.7% among people over 70 years.1 Coronary heart disease (CHD) and stroke caused a third of all deaths worldwide in 2016.

Decreased renal function (estimated glomerular filtration rate [eGFR]<60 mL/min/1.73 m2) has been associated with an increased risk of all-cause and cardiovascular mortality, with risk rising progressively with decreasing eGFR.2 In fact, individuals with eGFR<60 are more likely to die from cardiovascular causes than from kidney failure.2,3 At the population level, deaths due to reduced eGFR accounted for 3.9% of the total global number of deaths in 2013, and more than half were estimated to occur secondary to CVD.4

In individuals with moderately decreased eGFR (eGFR=30-59), the risk of total and cardiovascular mortality is up to 3 times greater than in individuals with normal eGFR.2 Current international guidelines consider that all individuals with eGFR=30-59 have a high5 or very high6–8 risk of CVD, and recommend aggressive management, in some cases similar to that for established CHD. This increased risk has also been attributed to people with diabetes mellitus (DM).5,8

Nevertheless, only a few studies have analyzed the risk of CHD or CVD or mortality in people with decreased eGFR compared with people with prior CVD or DM, and have shown conflicting results.9-12 Moreover, the results have given rise to concerns that the combination of decreased eGFR and DM could have the highest risk.

In north-east Spain, an area with a low incidence of CHD,5 individuals with type 2 diabetes were reported to have lower cardiovascular risk than coronary patients.13 However, no studies have compared this risk in individuals with decreased eGFR, DM, or CHD. The objective of this study was to compare the added risk of CHD, CVD and total mortality in a population-based cohort of 60- to 84-year-olds with eGFR=30-59, DM, or previous CHD in a region with a low incidence of CHD.5

Of the initial cohort (130 233 individuals),14 we excluded 14 individuals with eGFR ≥ 120 resulting in 130 219 individuals (122 443 aged <85 years and 7776 aged ≥ 85 years; Table 1 of the supplementary data).

The median age of 60- to 84-year-olds was 69 [IQR 64-75] years. This age group had a lower percentage of women than the older group (55.3% vs 68.8%, respectively), and a lower prevalence of eGFR <60 (11.4% vs 47.1%, respectively) and cardiovascular risk factors, except DM, and CVD, and drug treatment. Individuals were stratified to baseline groups according to eGFR (30-59), DM or CHD, and combinations (Table 1). Individuals with none of these diseases were younger and had fewer comorbidities and drug treatments than patients with any of these diseases. Those with eGFR=30-59 were older than DM or CHD patients and had a higher percentage of women.

During a median follow-up of 38.3 [IQR, 33.8-42.7] months, 1276 individuals developed a CHD event, 1533 a CVD event, and 3976 individuals died. Crude incidence rates of CHD and CVD events, and death per 1000 person-years are shown in Table 2. The incidence of CHD and CVD was similarly higher in eGFR=30-59 and DM compared with individuals without the diseases, and lower than in individuals with previous CHD, even for the group with both eGFR=30-59 and DM. In contrast, individuals with eGFR=30-59 showed similar crude mortality rates to those with established CHD, and even higher rates when combined with DM. Among patients with established CHD, the incidence of all events increased in the presence of decreased eGFR or DM, with the highest rates observed in individuals with CHD plus eGFR=30-59 and DM.

We analyzed the cumulative incidence of admission per 1000 person-years (Figure 1 and Figure 1 of the supplementary data) and multivariate adjusted hazard ratios for hospital admission due to CHD events, CVD and all-cause mortality in individuals with eGFR=30-59, DM or CHD, and combinations, compared with individuals without these diseases (Table 3). eGFR=30-59 and DM carried a similarly increased risk of CHD and CVD and both, individually or combined, were lower than established CHD. However, risk of all-cause mortality was similar for eGFR=30-59, DM and CHD, and significantly higher for the combination of eGFR=30-59 plus DM. In individuals with established CHD, the risk of all events increased significantly in the presence of DM, and even more in individuals with eGFR=30-59 plus DM.

Figure 1.

Cumulative incidence function of admission per 1000 person-years due to CHD (A) and CVD (B) in individuals aged 60-84 years with moderately decreased eGFR (30-59 mL/min/1.73 m2), CHD, and DM, and combinations, compared with individuals without these diseases, considering death as a competing risk for CHD and any CVD. CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate.

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We performed a subanalysis to assess the risk of all events in the more common category of mildly decreased eGFR (eGFR=45-59). In these individuals, the adjusted multivariate subdistribution HR was 1.28 (95%CI, 0.96-1.70) for CHD events, 1.22 (1.03-1.46) for any CVD, and the HR for mortality was 1.27 (1.12-1.45); for individuals with eGFR=45-59 plus DM, the corresponding HRs were 1.29 (0.83-2.01), 1.56 (1.22-1.99) and 1.97 (1.67-2.32), respectively.

The sensitivity analysis including all individuals with CVD (Table 2 of the supplementary data), and individuals aged ≥ 85 years yielded similar results (Table 3 of the supplementary data).

In this population-based cohort of 60- to 84-year-olds in a region with a low incidence of CHD, crude rates and the adjusted risk of hospital admission for CHD and CVD events in individuals with eGFR=30-59 were similarly high to those in individuals with DM. Both, alone or combined, were lower than those in individuals with previous CHD. The incidence and adjusted risk were closer to that of established CHD for CVD when eGFR=30-59 plus DM was considered. There were no differences in all-cause mortality between individuals with eGFR=30-59, DM or established CHD. Moreover, in patients with established CHD, DM substantially increased the risk of CHD events, which was highest in individuals with CHD plus DM and eGFR=30-59.

To our knowledge, ours is the first study to compare cardiovascular risk between individuals with eGFR=30-59, DM and CHD in a region with a low incidence of CHD. Our results confirm the higher cardiovascular risk associated with eGFR=30-59 compared with a normal eGFR level, similar to individuals with DM. However, this increased risk is lower than that in patients with established CHD. Previously, another study in the same area found that individuals with DM had a lower CHD incidence and 10-year cardiovascular mortality than patients with a first acute myocardial infarction (MI) without diabetes.13

Our results are comparable to those of similar study in Canada, which also reported higher adjusted relative rates of myocardial infarction in individuals with decreased eGFR (1.4; 95%CI, 1.3-1.5), DM (2.0; 95%CI, 1.9-2.1), and decreased eGFR plus DM (2.7; 95%CI, 2.5-2.9), and lower than in individuals with established CHD (3.8; 95%CI, 3.5-4.1).10 However, these authors also reported no differences in all-cause mortality.

Some studies have compared rates of cardiovascular death in these groups. One study in individuals aged 45-64 years old observed a 60% lower risk of cardiovascular death in individuals with eGFR=30-59 (0.39; 95%CI, 0.24-0.62) compared with those with prior MI.12 More recently, the risk of cardiovascular death was found to be increased more than 2-fold in individuals aged 40-65 years old with eGFR <60 (2.31; 95%CI, 1.91-2.71), more than 4-fold in participants with diabetes mellitus (4.62; 95%CI, 4.13-5.11), and more than 6-fold in participants with CVD (6.78; 95%CI, 6.16-7.4) compared with individuals without these diseases.11 There were no differences in risk in individuals with eGFR <60 and DM without CVD (10.03; 95%CI, 6.47–13.6) and those with CVD,11 which we did not find in eGFR=30-59. However, in individuals aged> 65 years, no differences in risk of cardiovascular death were observed between individuals with eGFR <60 and those with previous MI, even though the former group had a lower risk of CVD, suggesting that case-fatality rates may be higher in individuals with decreased eGFR.9 Inequalities in cardiovascular treatment could also explain the worse prognosis, and mask differences in mortality risk. The broad implementation of interventional cardiology and preventive secondary measures has improved prognosis in patients with established CHD.16 However, while the post-MI prognosis in patients with renal dysfunction has also significantly improved in the last decade,17 there have been reports of a lower frequency of referral for coronary angiography and treatment with guideline-based cardiovascular medications.18–20 Interestingly, some authors have reported that, after adjusting for eGFR, they observed a reduced difference between sexes in in-hospital and long-term mortality following ST-segment elevation MI.21

In patients with established CHD, we observed a further increase in crude incidence rates and risk of all outcomes with DM, especially with DM plus eGFR=30-59, which has been reported previously in eGFR <60 for cardiovascular death.11 Most cardiovascular events occur in patients with established CVD,22,23 but not all patients have the same risk of new events.22–24 Moreover, in clinical practice, many CHD patients do not achieve the guideline standards for secondary prevention.25,26 It is therefore important to identify the highest-risk patients, who are most likely to benefit from a more intensive approach. DM is a known risk factor for short and long-term prognosis after CV events.5,23,24,27 Similarly, renal insufficiency has also been found to be a a predictor of MI, stroke or cardiovascular death, and all-cause-mortality at 1 and 2 years and in the long-term following acute coronary syndrome.21,23,28 The presence of diabetes and chronic kidney disease have been found to increase the risk of all-cause mortality and nonfatal myocardional or coronary death at 5 years in different subtypes of stable CHD.24 Our study confirms that, in a southern European population, CHD patients with DM or decreased eGFR and DM are at higher risk of CHD and CVD events than CHD patients without these diseases, and may therefore benefit from more intensive treatment.

In our study of a population-based cohort of 60- to 84-year-olds in a region with a low incidence of CHD, the adjusted higher risk of hospital admission for CHD and CVD in individuals with eGFR=30-59 was comparable to that in individuals with DM, and ∼50% lower than that in those with established CHD.

Our results have important implications for clinical practice in the region. According to these results, individuals aged 60-79 years with eGFR=30-59, and especially the more common and mildest eGFR decrease (= 45-59), should probably not be considered as coronary-risk equivalent based solely on eGFR. Moreover, individuals with established CHD and either DM or eGFR=30-59, or both, had a further increased risk of new events and should be prioritized for more intensive risk management.

Further research is needed to better understand how to manage risk in individuals with eGFR=30-59, especially in combination with DM, and to evaluate the prognosis and use of interventional and other acute cardiovascular treatments in individuals with decreased eGFR and CHD.

This project was supported by a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded under the 2011 call of the Health Strategy Action, within the National Research Program oriented to Societal Challenges. This program forms part of the Technical, Scientific and Innovation Research National Plan 2008-2011, co-funded by European Union ERDF funds (European Regional Development Fund) (PI11/02220).

Ministry of Economy and Competitiveness through the Carlos III Institute of Health (Red RedIAPP RD12/0007) and European Regional Development Funds (ERDF-FEDER) Generalitat de Catalunya through the Agency for Management of Universities and Research Grants (AGAUR) [2014 SGR 1225] [2014 SGR 902].

None declared.