Optimizing lipid management in a high-risk diabetes patient
History and presentation
A 76-year-old male with a history of diabetes for over 20 years and an MI treated by percutaneous coronary intervention (PCI) in 2014 was hospitalized in August 2018 for stroke and ventricular arrhythmia. CT scan revealed severe stenosis of the proximal left anterior descending (LAD) coronary artery. The arrhythmia resolved following stent implantation. His blood pressure, however, remained very low with deterioration of renal function and he complained of weight loss and muscle wasting. In April 2019, the patient was hospitalized with a second stroke due to significant carotid artery stenosis and was discharged after treatment without any permanent deficit.
Treatment and response
The patient was initially on atorvastatin 40 mg/day with low density lipoprotein-cholesterol (LDL-C) of 2.5 mmol/L. Diabetes treatment involved a combination of empagliflozin, dulaglutide and pioglitazone with HbA1C of 7.4 percent. To address issues of the low blood pressure and weight loss, empagliflozin and dulaglutide were withdrawn and replaced by glimepiride and basal insulin once daily, which led to minor weight gain and normalization of blood pressure, and improvement in HbA1C to 6.5 percent.
Following the second stroke, the patient's LDL-C was 2.36 mmol/L, high density lipoprotein-cholesterol (HDL-C) was 1.24 mmol/L, and triglyceride level was 1.2 mmol/L. Lipoprotein (a) [Lp(a)] level was within normal range, while C-reactive protein was elevated. In order to improve lipid control, alirocumab injection (75 mg, every 2 weeks) was added on top of atorvastatin 40 mg, resulting in an improvement of lipid profile with LDL-C reduced to 0.68 mmol/L. His weight loss had also stabilized.
Despite statin therapy, many patients with dyslipidaemia remain at high risk of cardiovascular (CV) events, suggesting that tighter lipid control is required to minimize their risk. The main CV risk factors include diabetes, dyslipidaemia, cigarette smoking, male gender and old age.1,2
According to 2019 European Society of Cardiology (ESC)/European Atherosclerotic Society (EAS) guidelines, the main goal of dyslipidaemia management is to reduce the risk of atherosclerotic CV disease (ASCVD). The intensity of lipid-lowering therapy should be tailored individually based on each patient's CV risk assessment. The 2019 ESC/EAS guidelines recommend that very-high-risk familial hypercholesterolaemia (FH) patients and those with acute coronary syndrome (ACS) receive a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to their treatment regimen if they do not achieve their LDL-C goals despite maximal tolerated statin therapy and ezetimibe.3 (Table)
PCSK9 inhibitors are an effective add-on therapy in selected high-risk patients whose LDL-C is inadequately controlled with maximum tolerated dose (MTD) of statins. Early studies have demonstrated a significant reduction in LDL-C levels by adding alirocumab to statin therapy.4 Alirocumab was subsequently evaluated in the ODYSSEY trial programme that included patients with high ASCVD risk or heterozygous FH (HeFH).5
In the head-to-head ODYSSEY COMBO II trial, 720 patients with high CV risk and elevated LDL-C on MTD of statin were randomized to receive add-on alirocumab or ezetimibe. The mean LDL-C reduction from baseline at 24 months was 50.6 percent for alirocumab vs 20.7 percent for ezetimibe, and the effect was maintained for 52 weeks.6
The ODYSSEY LONG TERM study, enrolling 2,341 high-risk patients, demonstrated the safety profile of alirocumab, with injection-site reaction being the most common adverse event (AE; 5.9 percent for alirocumab vs 4.2 percent for placebo). A post-hoc data analysis at 80 weeks also found that the rate of major adverse CV events (MACE) was nearly halved with alirocumab vs placebo (1.7 percent vs 3.3 percent).7 More recently, the ODDYSEY OUTCOMES placebo-controlled trial in 18,924 patients with prior ACS and high LDL-C levels despite MTD of statin therapy confirmed the benefits of add-on alirocumab. The incidence of AEs was similar in both study arms with the exception of local injection-site reactions.8
High-dose statin therapy can have negative effects on glucose metabolism and muscle function, and therefore may not be the optimal choice for all diabetes patients at high CV risk who require intensive lipid-lowering treatment. In our patient, adding alirocumab and switching to diabetes medications with CV benefits has improved his HbA1C and lipid profile, which may potentially minimize the risk of future CV events.
Our patient, who has a history of diabetes and multiple CV events, is considered to be at extremely high risk. The guidelines recommend a target LDL-C level of <1.4 mmol/L for this patient group, but an even lower target of <1.0 mmol/L would be advisable for this patient. Intensifying statin therapy was ruled out because of insulin resistance and muscle toxicity issues, while adding ezetimibe could only achieve modest reductions in LDL-C and CV risk. Therefore, we opted to add alirocumab on top of atorvastatin, which proved to be a particularly good choice for this patient. His lipid profile has normalized to optimal levels, which would reduce the chance of further CV events.
To achieve optimal CV risk reduction, clinical management of a complex case such as this requires a multidisciplinary team of specialists with good communication.