Summary
Background
Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial.
Methods
CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406).
Findings
Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72–0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83–1·09). HbA1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001).
Interpretation
Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes.
Funding
Esperion Therapeutics.
Introduction
The prevalence of diabetes is increasing globally, with the estimated number of individuals living with diabetes increasing from 529 million in 2021 to approximately 1·3 billion by 2050.
Diabetes doubles the risk of cardiovascular disease and results in half a decade of life-years lost, half of which are due to cardiovascular deaths.
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Lowering LDL cholesterol has been shown to reduce the risk of cardiovascular disease in patients with diabetes in primary prevention, with statins being used as the first-line pharmacological treatment.
Although beneficial, statins increase HbA1c in a dose-dependent manner and increase the risk of new-onset diabetes.
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Mendelian randomisation studies of common DNA variants near the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) gene, a target for statins, showed a lifelong reduced LDL cholesterol and reduced atherosclerotic cardiovascular disease risk but was also associated with increases in weight, insulin, HbA1c, and diabetes risk
Discussion
This prespecified analysis of the CLEAR Outcomes trial in patients with diabetes who were unwilling or unable to take guideline-recommended doses of statins showed that these individuals comprise a particularly high-risk group with an excess risk of cardiovascular events, ranging from 25% for MACE-4 events to 58% for MACE-3 events compared with individuals who were normoglycaemic. Treatment with bempedoic acid as monotherapy resulted in a placebo-corrected mean change in LDL cholesterol of approximately –21·2% in patients with diabetes,
and reduced MACE-4 events by 17% and MACE-3 events by 20% Although there was no statistically significant effect modification observed among those with versus without diabetes, the higher baseline risk of cardiovascular events resulted in greater absolute benefits in the diabetes population, which were almost double that observed in those without diabetes. These benefits were generally consistent in patients with diabetes, irrespective of whether there was a previous history of cardiovascular disease or not. Furthermore, among patients who were free from diabetes at baseline, treatment with bempedoic acid over an average follow-up of 3·4 years did not result in an increase in HbA1c or glucose concentrations, nor in the incidence of new-onset diabetes, and was associated with modest weight loss.
Statins are the recommended first line pharmacological treatment for lowering LDL cholesterol in patients with diabetes.
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Evidence for their use in primary prevention settings is largely derived from the Collaborative Atorvastatin Diabetes Study, where 10 mg atorvastatin reduced LDL cholesterol by 40% (the absolute difference vs placebo was 1·2 mmol/L) from a starting concentration of 3·04 mmol/L, and reduced the risk of major cardiovascular events by 37%.
Furthermore, a meta-analysis of statin trials shows that patients with diabetes derive similar relative benefits for each 1 mmol/L lowering of LDL cholesterol, but greater absolute benefits than those without diabetes.
Because patients with diabetes are at a greater absolute risk of cardiovascular events, they derive greater absolute benefits from further LDL cholesterol lowering using non-statin therapies such as ezetimibe or PCSK9 inhibitors compared with those without diabetes in large clinical outcome trials.
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However, all these trials were conducted on a background of maximally tolerated statin therapy in patients with stable atherosclerotic cardiovascular disease or recent acute coronary syndrome, and none of these non-statin approaches have been assessed as monotherapy in patients with diabetes. Therefore, the present study provides findings supporting the benefit of LDL cholesterol lowering per se, rather than the method of how this reduction is achieved, in patients with diabetes. Moreover, this is the first study since the Collaborative Atorvastatin Diabetes Study
to show cardiovascular benefits from LDL cholesterol lowering in a diabetes population without a previous history of cardiovascular disease. Finally, short interfering RNA-based therapies, such as inclisiran, have shown sustained meaningful reductions in LDL cholesterol in those with diabetes.
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Although cardiovascular outcome trials of inclisiran continue, the pooled safety data from three phase 3 studies suggest a lower risk of cardiovascular events with LDL cholesterol lowering achieved with inclisiran compared with placebo.
Guidelines have progressively lowered risk-based LDL cholesterol goals, including for the primary prevention of individuals with diabetes, when additional features associated with higher event rates, such as a long duration of diabetes or microvascular disease, are present.
This change inevitably means that a greater use of a combination of lipid-lowering therapies will be needed.
However, among patients who are statin intolerant, this presents a particular challenge, because even patients eligible for treatments such as PCSK9 monoclonal antibodies or inclisiran might not reach LDL cholesterol goals as recommended by regional practice guidelines with monotherapy.
In this context, the findings from the present study offer clinicians and patients with diabetes an additional option for those unable to tolerate statins, which could be used in combination with other non-statin LDL cholesterol lowering therapies, to help reach current guideline-recommended LDL cholesterol goals.
The observation that statins increase the risk of diabetes in a dose-dependent manner inevitably raises concerns among patients and clinicians about their use.
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Related to the inhibition of HMG-CoA reductase, individuals carrying HMGCR alleles associated with lifelong reductions in LDL cholesterol have higher serum HbA1c, glucose, and insulin concentrations, as well as a greater weight, BMI, and waist-to-hip ratio.
There have been concerns about LDL cholesterol lowering with non-statins, such as ezetimibe and PCSK9 inhibitors, since common genetic variants in NPC1L1 and PCSK9 genes associated with lifelong LDL cholesterol reductions are also associated with a higher risk of diabetes.
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However, clinical trials that showed significant reductions in LDL cholesterol via these pathways showed no increased risk of new-onset diabetes.
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The target for bempedoic acid, ACLY, is two steps proximal to HMG-CoA in the intrinsic cholesterol biosynthesis pathway. In Mendelian randomisation studies, individuals carrying ACLY alleles associated with lifelong reductions in LDL cholesterol and reduced atherosclerotic cardiovascular disease risk had, in comparison with the HMGCR association studies, a lower weight, no increase in waist-to-hip ratio, and no excess risk of diabetes.
Consistent with these genetic data, we observed no adverse signal for harm, with respect to measures of glycaemia or risk of new-onset diabetes, with bempedoic acid treatment. Furthermore, weight was modestly lower over a median follow-up of 3·4 years among patients treated with bempedoic acid. By contrast, statins modestly increase weight.
The present study cannot offer mechanistic insights into this observation, but the concordance between genetic and pharmacological studies of statins and genetic and pharmacological studies of bempedoic acid should provide clinicians and patients with further assurance about glycaemic safety from the pharmacological inhibition of ACLY with bempedoic acid (appendix p 7).
The Global Burden of Disease projects that by 2050 there will be approximately 1·3 billion individuals living with diabetes globally.
This, in turn, will result in a considerable increase in the absolute numbers of adverse health outcomes resulting from diabetes and thus a considerable burden on health-care systems globally. A substantial proportion of those adverse health outcomes will result from atherosclerotic cardiovascular disease, which occurs twice as commonly in those with diabetes compared with those without. Hence, although there is a clear need for health policies to focus on diabetes prevention, in parallel there is also a pressing need to better prevent adverse health outcomes in individuals with diabetes. A multi-factorial approach is needed, with the control of multiple risk factors. At any given age, the lowest risk is observed in those with the greatest number of controlled risk factors.
Moreover, newer glucose-lowering therapies such as SGLT2 inhibitors and GLP-1 receptor agonists have emerged, which reduce the risk of cardiovascular events, but these therapies are underused.
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In the present trial, the use of these therapies among patients with diabetes was low, at 2·9% for GLP-1 agonists and 5·2% (appendix p 2) for SGLT2 inhibitors, but their use in this trial was consistent with their current use in real-world settings.
The limitations of this study merit consideration. Although the analyses were prespecified, the inclusion criteria inevitably mean that the CLEAR Outcomes trial enrolled a population with higher risk features, such as individuals with diabetes or prediabetes, with a much smaller cohort in the normoglycaemia category. Hence, this might limit the potential extrapolation of findings to a broader cohort. Although the sample size for the CLEAR Outcomes trial was large, it was not formally powered to assess interactions between diabetes status and allocated treatment. Although the present study provides the largest size and duration of study to date on exposure to bempedoic acid and the effect on measures of glycaemia and new-onset diabetes, the median follow-up was only 3·4 years, and as such the present observations cannot necessarily be extrapolated to a longer timeframe. It is uncertain what effect the greater use of GLP-1 receptor agonists and or SGLT2 inhibitors could have had on the observations in patients with diabetes. Finally, it should be noted that the study enrolled patients unwilling or unable to tolerate statins. Many of these patients might reflect a so-called nocebo effect, whereby negative expectations lead to greater negative outcomes. Many of these patients might be able to tolerate statins as suggested by the N=1 trials.
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In conclusion, among patients with diabetes unable or unwilling to take guideline-recommended doses of statins, bempedoic acid used as monotherapy provided significant, clinically meaningful reductions in cardiovascular events. Furthermore, consistent with genetic studies, bempedoic acid did not increase the risk of new-onset diabetes nor worsen measures of glycaemia among those without diabetes. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for patients with and without diabetes who are unwilling or unable to take guideline recommended doses of statins.
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