Use of an oral ACL inhibitor in two diabetic patients with hypercholesterolaemia and high/very high CV risk

Case 1: An older man with statin-associated muscle symptoms
A 62-year-old nonsmoking Chinese man with metabolic syndrome (MES; hypertension, obesity, hypercholesterolaemia) and mild hyperuricaemia presented with type 2 diabetes (T2D; HbA_1c, 8.4 percent) in October 2018. His only baseline medication was candesartan 8 mg QD.

To control MES, dapagliflozin/metformin 10/1,000 mg QD and atorvastatin 10 mg QD were added in November 2018 and amlodipine 2.5 mg QD was added in January 2020. Although his HbA_1c, blood pressure (BP) and LDL-cholesterol (LDL-C) were all on target after adding these medications to his regimen, the patient complained of proximal muscle weakness and myalgia in lower limbs, which were suspected to be statin-associated muscle symptoms (SAMS). Atorvastatin was therefore discontinued.

At a regular follow-up in March 2021, the patient’s body weight and BP were found to have increased. Bisoprolol 2.5 mg QD was added to enhance BP control. Although his LDL-C remained at 3.0 mmol/L, CT coronary angiography (CTCA) revealed left anterior descending coronary artery calcification and mild stenosis, leading to a diagnosis of coronary artery disease (CAD). Rosuvastatin 5 mg on alternate days was prescribed. Follow-up assessment in August 2021 revealed a marked reduction of LDL-C to 1.6 mmol/L. However, the patient complained of recurring myalgia and muscle weakness that affected daily activities, even though his creatine phosphokinase (CPK) level was within normal range.

In June 2024, rosuvastatin was switched to a fixed-dose combination (FDC) of bempedoic acid/ezetimibe 180/10 mg QD. As the patient reported oedema, candesartan was uptitrated to 16 mg QD while amlodipine was downtitrated to 2.5 mg QD. Within 2 months, muscle weakness and myalgia resolved, along with decreased CPK level (89 U/L), which confirmed the suspicion of SAMS when the patient first reported these symptoms in 2020. His LDL-C was 1.4 mmol/L and initial high-sensitivity C-reactive protein (hsCRP) level was 4.3 mg/L. Serum uric acid was elevated to 0.52 mmol/L, but the patient did not report any gout flares. Colchicine 0.5 mg and losartan 100 mg were prescribed to control uric acid and BP, respectively.

Last seen in October 2024, the patient remained free of myalgia and muscle weakness, and reported increased activity levels. His LDL-C level was 1.89 mmol/L and hsCRP level declined to <0.5 mg/L, without experiencing any cardiovascular (CV) events. His serum uric acid level also normalized. (Table)

Case 2: An elderly woman with suboptimal LDL-C control
A 72-year-old nonsmoking, nondrinking Chinese woman with a history of T2D, hypertension, obesity, dyslipidaemia, and CAD previously treated with percutaneous transluminal coronary angioplasty (PTCA) presented in November 2022. Her LDL-C level was 1.89 mmol/L while on ezetimibe/atorvastatin 10/20 mg QD and her fasting blood glucose (FBG) was 7.2 mmol/L.

Assessment in February 2023 showed LDL-C level of 1.98 mmol/L and HbA_1c of 7.4 percent. However, the patient refused uptitration to high-intensity statin therapy or the use of injectable lipid-lowering drugs. She continued with the daily dose of ezetimibe/atorvastatin 10/20 mg QD and commenced sitagliptin/metformin 100/1,000 mg QD, dapagliflozin/ metformin 10/1,000 mg QD, candesartan 8 mg QD, nebivolol 5 mg QD, and dual antiplatelet therapy.

In December 2023, the patient’s lipoprotein(a) level was found to be high at 398 nmol/L, and LDL-C was 1.80 mmol/L. Ezetimibe/atorvastatin was switched to triple therapy with atorvastatin 20 mg QD and bempedoic acid/ezetimibe FDC 180/10 mg QD to control LDL-C level.

The patient remained well as of February 2024, with LDL-C at 1.5 mmol/L and no further CV events reported. (Table)

Discussion
Diabetes is an independent major risk factor of CV disease (CVD), and comorbidities such as CAD, hypertension and dyslipidaemia further elevate CV risk.^1-3 Although statins remain the guideline-recommended first-line LDL-C lowering treatment, observational study data show that across Asia, many high-risk patients fail to reach guideline-recommended LDL-C goals with statins either as monotherapy or in combination with ezetimibe.^4,5

There are multiple challenges with statin therapy. Often, patients do not achieve LDL-C targets because of inability to tolerate statins at any dose or a dose necessary to achieve their therapeutic goals. Statin intolerance has been reported in 5–30 percent of patients and is largely defined by myalgias that include muscle aches, fatigue and weakness.⁶ As seen in our first case, these muscle symptoms can impact quality of life and day-to-day functioning.

Uptitration to high-intensity statins has been found to reduce the risk of subsequent CV events. However, real-world evidence indicates that very few patients at very high CV risk (<20 percent) were titrated to high-intensity statins after nearly 10 years of follow-up, as observed in our second case.⁷ For patients with high or very high CV risk, failure to attain LDL-C goals puts them at greater risk of subsequent CV events.¹

Our patients were switched to bempedoic acid/ezetimibe FDC for better tolerability and LDL-C control. In the phase III CLEAR Tranquility trial, bempedoic acid added to ezetimibe led to a mean change in LDL-C of -28.5 percent at 12 weeks in 269 patients with a history of intolerance to ≥1 statin, with similar efficacy observed amongst patients with diabetes (-25.5 percent).⁸ Another phase III trial explored the effects of bempedoic acid/ezetimibe FDC in 301 high-risk patients with hypercholesterolaemia receiving maximally tolerated statins. At week 12, bempedoic acid/ezetimibe FDC led to a greater reduction of LDL-C vs placebo (36.2 vs 1.8 percent; p<0.001), and this significant benefit was consistently observed in patients with diabetes (p<0.001).⁹ No fatal adverse events (AEs) occurred in both studies.^8,9

The pivotal phase III CLEAR Outcomes trial aimed to assess the CV benefits of bempedoic acid vs placebo in 13,970 patients with CVD or high CV risk who were unable or unwilling to take statin therapy. At a median follow-up of 40.6 months, bempedoic acid significantly reduced the risk of four-component major adverse CV events (MACE-4) comprising death from CV causes, nonfatal MI, nonfatal stroke, or coronary revascularization (hazard ratio [HR], 0.87; 95 percent confidence interval [CI], 0.79–0.96; p=0.004). At 6 months, the between-group difference in mean reduction in LDL-C was -20.3 percent and that in median reduction in hsCRP was -21.6 percent, both in favour of bempedoic acid. Overall incidences of AEs, serious AEs, and AEs leading to discontinuation were comparable between groups.¹⁰

Dyslipidaemia is one of the major risk factors for CVD in patients with diabetes.¹¹ A prespecified analysis of CLEAR Outcomes investigated the efficacy of bempedoic acid in patients with diabetes (n=6,373), as well as its safety in terms of new-onset diabetes among patients without diabetes at baseline. Over a median of 3.4 years of follow-up, bempedoic acid reduced the risk of MACE-4 in patients with diabetes, prediabetes and normoglycaemia, with no significant interaction by baseline glycaemic status (pinteraction =0.42). However, the difference in absolute risk with bempedoic acid was greatest among patients with diabetes (p_interaction=0.0063).¹² (Figure 1)

At 6 months, bempedoic acid led to 24–26 percent reductions of LDL-C, and 19–26 percent reductions of hsCRP, irrespective of glycaemic status (all p<0.001). The proportions of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups irrespective of baseline glycaemic status, indicating that bempedoic acid did not increase the risk of new-onset diabetes.¹² (Figure 2)

Overall, AEs, serious AEs, and AEs leading to discontinuation were similar between groups and were consistent with the overall population of CLEAR Outcomes. Amongst patients with diabetes, the incidence of hyperuricaemia was higher in the bempedoic acid vs placebo group (12.4 vs 6.4 percent), as was the incidence of gout (3.0 vs 2.1 percent).¹² Therefore, it is important to monitor uric acid levels. These AEs can be managed by using documented agents that lower uric acid levels, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors or losartan, along with dietary advice to avoid high-purine foods.

The convenient single-pill approach with bempedoic acid/ezetimibe FDC offers remarkable efficacy and cardiometabolic safety and is thus a favourable option for patients with diabetes who are statin-intolerant or who require additional LDL-C reduction despite maximally tolerated statins, as demonstrated by the positive outcomes of our two patients.