This is the first study describing incident hHF and associated mortality in a large Asian population with CHD and IGT. In Chinese patients with CHD and IGT, we show that higher age, higher plasma creatinine, lower haemoglobin, prior HF, prior MI and prior AF were all predictive of incident hHF, and that higher age, higher plasma creatinine, prior HF, prior MI, prior AF and prior stroke were predictive of hHF/CV death. Death following hHF was predicted by older age and higher plasma creatinine. Allocation to acarbose 50 mg TID, compared with placebo, in the ACE trial,(4, 6) showed no risk reductions for incident hHF, recurrent hHF or for hHF/CV death despite an 18% reduction in the risk of T2D.(5)
Our within trial observations are in accord with those seen in the NAVIGATOR trial, which also showed no reduction in hHF in patients with IGT and CHD despite the improved glycaemic control achieved with nateglinide, a short-acting insulin secretagogue.(10, 11) Lowering post-prandial glycemia has been suggested as a way to reduce HF risk,(12, 13) but neither increasing post prandial insulin concentrations with nateglinide, nor using the insulin-sparing mode of action of acarbose to do so, reduced the risk of hHF in populations with IGT and CHD (Figure 2).
Similar findings have been reported consistently with other glucose-lowering therapies (DPP-4 inhibitors and insulin) in patients with established T2D (10, 14-16) suggesting that therapeutic strategies focused on glycaemic control in T2D have a neutral effect on incident hHF or hHF-related death. Additionally, despite the reduced risk for new-onset diabetes seen with acarbose in the ACE trial, the within-trial risk of incident and recurrent hHF was unchanged. IGT is a precursor to T2D and has been shown to be a risk factor for cardiovascular morbidity. Thus, it is plausible that metabolic alterations leading to myocardial damage may start at an earlier stage, even before the formal diagnosis of T2D. In the ACE trial, 2.1% of participants experienced ≥1 episode of hHF, equating to 0.46 cases per 100 person-years of follow-up.(5) The hHF rate was similar in the NAVIGATOR trial (0.36 cases per 100 person-years of follow-up). For comparison, in the EXAMINE and the ELIXA trials, 3.6% and 8.3% of patients with acute coronary syndrome and established T2D experienced ≥1 episode of hHF respectively, equating to 1.09 and 1.94 cases per 100 person-years of follow-up.(17, 18) The higher hHF rates observed in T2D patients, compared with IGT subjects, likely reflects their more advanced CHD and myocardial damage, which could be secondary to longer duration of abnormal glycaemic exposure.
MI is a major predictor of HF, as confirmed in our study, but given no CV benefit was evident in the three ~5-year duration randomized controlled trials that have compared intensive with conventional glycaemic control in T2D patients (19-21), it may not be surprising that improving glycaemic control over a similar timescale in ACE subjects with CHF and IGT had little impact on incident hHF. In the longer term, the UKPDS has demonstrated a legacy effect of the benefits of earlier improved glycaemic control with sulfonylurea or insulin in people with newly-diagnosed T2D. The UKPDS showed a 15% lower risk of MI (P = 0.01) over a median follow-up of 16.8 years, but did not report HF rates. (22)
Considering the increasing burden of HF events observed in people with IGT or T2D, early screening for those factors contributing to an individual’s heightened risk needs careful consideration. Several studies have shown that prior HF is a powerful independent predictor of readmission (23, 24). Our study is in accord with these observations, confirming that in a Chinese population with CHD and IGT a prior history of HF was the most significant predictor of hHF.
In our multivariable model, older age and increased plasma creatinine were also major predictors for incident hHF and subsequent case fatality. Kidney dysfunction is common in elderly populations and strongly associated with short-term and long-term outcomes in patients with HF (25).
In the high-risk ACE trial population with CHD and IGT, previous MI but not angina was independently associated with hHF. Of note, measures of glycaemic control, weight and blood pressure showed no association with hHF. This may reflect the fact that ACE trial participants were exceptionally well-managed with respect to administration of evidence-based secondary CV prevention therapies, as there was a protocol-mandated 4-week CV risk factor optimisation run-in period preceding randomisation.(4) Hence, additional HF risk factors such as age and plasma creatinine may become more prominent with good control of traditional CV risk factors such as hypertension, dyslipidaemia and smoking. However, an alternative interpretation of the ACE and the NAVIGATOR trial findings might be that in populations with CHD and IGT already established on maximum CV secondary prevention, those with kidney disease have a poorer prognosis with a higher risk of hHF and CV death. In this context it is important to note novel glucose-lowering treatments with SGLT-2 inhibitors with their promising beneficial renal profile have been shown to be of particular value in reducing the risk of HF in people with or without T2D. (26-30)
Of note, there were some differences between the major predictors for hHF reported by the NAVIGATOR and the ACE trials. NAVIGATOR, which included 9,306 participants with IGT and either CV disease or CV risk, confirmed waist circumference among three major predictors of hHF (11). In the ACE trial by contrast, neither waist circumference nor BMI were independently associated with an increased hHF rates, possibly due to phenotypic differences in those recruited. Whilst NAVIGATOR recruited subjects with a mean BMI≥30 kg/m2, the mean BMI of the ACE Chinese participants was 25.4 kg/m2. This could suggest that the mechanisms leading to the development of HF in an Asian ‘lean’ cardiometabolic phenotype are distinct from those in Western patients whose IGT is closely linked to obesity.
Epidemiological data strongly support the role of AF in the development of HF in people with diabetes. The pathophysiology and risk factors for AF and HF are closely aligned, with affected patients usually being elderly with multiple comorbidities (31, 32). In our study, we found prior AF to be an independent predictor of incident hHF, as did NAVIGATOR. (11)
These analyses have several limitations. Firstly, of the entire spectrum of heart failure events the ACE trial only examined hHF events. Restricting HF outcomes to hospitalised cases does not reflect contemporary management of HF, with an on-going shift towards community and ambulatory care. Secondly, left ventricular ejection fraction data was not collected so we do not know whether participants with incident hHF had a reduced or preserved ejection fraction. While T2D and IGT are associated with both types of HF, it is likely that adjudicated hHF events represent ischemic cardiomyopathy as the more predominant phenotype. Hence, more subtle changes expected in HF with a preserved ejection fraction, which are frequently observed in the setting of IGT and insulin resistance(33), have not been detected in this trial. Thirdly, any conclusions regarding the predictive role of AF for HF in the ACE and NAVIGATOR populations need to circumspect given the low number of hHF events recorded in both trials.
In conclusion, in Chinese patients with CHD and IGT established on optimal secondary CV risk prevention, we identified higher age, increased plasma creatinine, lower haemoglobin, prior MI and prior AF as independent predictors of hHF. Higher age and increased creatinine predicted case fatality. Allocation to acarbose 50mg TID was not associated with reductions in hHF, hHF/CV death, recurrent hHF or death following hHF. These findings will assist health care professionals to risk stratify patients with CHD and IGT and help identify those that might benefit from early screening for signs of HF. As this study focused on a Chinese population with a lower BMI compared with similar Western cohorts studied to date, any extrapolation of our results should consider the potential influence of phenotypic differences on HF risk.