The Worst Combination for Coronary Artery Disease Under Strong-Statin Therapy Is Chronic Kidney Disease and Diabetes ― Non-Lipid Residual Risk Assessment From the REAL-CAD Study ―
論文ID: CJ-23-0694
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論文ID: CJ-23-0694
Low-density lipoprotein cholesterol (LDL-C) lowering therapies, especially strong statins, have been reproducibly certified for controlling coronary artery disease (CAD). However, even under strong-statin treatment, many patients still develop CAD through the so-called “residual risk”.
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Residual Lipid Risk FactorsMany residual lipid risks have been considered. Beyond strong statins, PCSK9 inhibitors have made possible “further LDL-C” lowering, and they have shown CAD risk reduction up to LDL-C 20 mg/dL in a high-risk group with no significant safety concerns.1 Beyond LDL, other residual lipid risk factors have been verified. “Triglyceride-rich lipoproteins” are a promising target, but the results with fibrates and SPPARM-alpha are not as clear as with statins.2,3 Lipoprotein (a) “Lp(a)” is also a promising target, and a new class of Lp(a)-lowering drugs is being tested. High-density lipoprotein (HDL) has been considered as a good target, but HDL-C raising effects with CETP inhibitors have been disappointing, even though their LDL-C lowering effects seem quite promising.
Residual Non-Lipid Risk FactorsClassical risk factors are also considered as residual risks, especially “diabetes mellitus” and “hypertension”. In each case, the appropriate treatment intensity is debated, as lowering it too much can cause adverse events, and inadequate treatment is a problem in a considerable number of cases.
Chronic kidney disease (CKD) is an established major CAD risk factor. CKD stages G3a–G4 have approximately double and triple the cardiovascular mortality risk relative to patients without CKD. Statins are beneficial in early CKD, but show less clear benefit in advanced CKD and/or endstage kidney disease. Treatment with the SGLT2 inhibitor, empagliflozin, in CKD has led to a lower risk of progression of CKD or death from cardiovascular causes.4
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition and a risk factor for CAD, which is the principal cause of death in patients with NAFLD. NAFLD has a complex association with both lipid and non-lipid residual risks. Lipid-lowering lowering therapies (e.g., statins, ezetimibe, fibrates, omega-3 fatty acids) have generally been negative or yielded inconsistent results on NASH itself.5 NAFLD should be a condition that requires strategic treatment in the post-statin era.
“Inflammation” may also be listed as a residual risk. High-sensitivity C-reactive protein (hsCRP) is often high in NAFLD or metabolic syndrome, and it has been debated whether inflammation itself should be the therapeutic target in CAD. In the CANTOS study, for those treated with canakinumab (anti-interleukin-1β antibody) who achieved on-treatment hsCRP concentrations <2 mg/L, cardiovascular mortality and all-cause mortality rates were both reduced by 31% with no effect on lipid concentrations.6
Awaited Strategy for Residual Risk AssessmentMany residual risks have been identified, but what is really needed is a strategy to clarify which risks should be dealt with first. It is necessary to quantitatively understand the magnitude of the influence of each residual risk and to clarify which treatments should be prioritized. This strategy will vary according to the patient’s situation, country of residence, or sex.
So, under what conditions should we first consider the residual risks that should be treated preferentially? At present, secondary prevention of CAD, which is treated with strong statins, should be prioritized, because of the high residual risk.
Non-Lipid Residual Risk Assessment From the REAL-CAD StudyREAL-CAD is a large-scale clinical trial that evaluated the effect of high-dose statin administration on secondary prevention of cardiovascular events in Japan. A total of 13,054 Japanese patients with a history of CAD (chronic coronary syndrome: CCS) were randomly assigned to a standard-dose group of pitavastatin 1 mg/day or a high-dose group of 4 mg/day for 3.9 years (median) tracked.
To date, several residual risk assessments have been reported as subanalyses of the REAL-CAD study, assessing the effects of 3 representative risk factors (blood pressure, glucose level, and renal function) alone or in combination. Wakabayashi et al reported a significantly worse prognosis in the group with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 with primary endpoints among 5,540 patients with CCS receiving 4 mg/day pitavastatin.7 Kamiya et al reported an eGFR ≤60 mL/min/1.73 m2 showed the highest risk of the primary outcome, and the combination of eGFR ≤60 and hemoglobin A1c (HbA1c) ≥6.0% showed the highest risk of all-cause death among 8,743 patients.8
In this issue of the Journal, Higuma et al9 use classification and regression tree analysis for combined risk factors to determine which comorbidities, or combination of comorbidities, best predicted cardiovascular events in 11,141 patients after excluding 1,272 patients because of missing data. They found a significantly worse prognosis at the primary endpoint in the eGFR ≤60 group, and the combination of eGFR ≤60 and HbA1c ≥6.0 was the worst. However, even in the eGFR >60 group, systolic blood pressure (SBP) ≥140 mmHg met the secondary endpoint, and the combination of eGFR ≤60 and HbA1c ≥6.0 was also the worst at the secondary endpoint. This study appears to be the first to demonstrate the importance of combined risk stratification in CAD patients treated with statin as the authors described.
The Next Target in CCS Under Strong-Statin Therapy RevealedFrom subanalyses of the REAL-CAD study among CCS subject under strong-statin therapy, Higuma et al9 conclude that prognostic factor contributing most to non-lipid residual risk was CKD (eGFR ≤60), and CKD with poor glucose control (HbA1c ≥6.0%) was the worst combination. Next worst prognostic factors were poor glucose control and high SBP (≥140 mmHg). Regarding the secondary endpoint, high SBP was worse even without CKD (Figure).
The next therapeutic target revealed from the REAL-CAD study. CKD was the sole worst contributing prognostic factor in patients with CCS under pitavastatin therapy. As a combination, CKD and poor glucose control was the worst. CCS, chronic coronary syndrome; CKD, chronic kidney disease; Diabetes, diabetes mellitus; HT, hypertension.
Once the high-impact residual risks and their worst-case combinations have been identified, the next step is to treat them and verify efficacy. Needless to say, if possible, a class of drug that can treat both of the combinations is preferable. Recent therapeutic advances in CKD provided concreate options. The SGLT2 inhibitors were developed as antidiabetic agents, have been established as CKD therapeutics, and have been shown to reduce cardiovascular mortality rates, making them one of the most important drug candidates for this purpose.
Now that the therapeutic targets that should be used on top of strong-statin therapy have been identified, the next step is to put them into practice.
The author reports no conflicts of interest to disclose.
