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Further options for treating lipids in people with diabetes: targeting LDL-cholesterol and beyond
1Department of Metabolic Medicine/Chemical Pathology, Guy's & St Thomas' Hospitals, London, UK.
Abstract:
Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL-cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off-patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD.
Insights
Diabetes increases cardiovascular disease (CVD) risk. Novel therapies like PCSK-9 inhibitors significantly lower LDL-cholesterol, reducing CVD events in diabetic patients, though cost may limit use to high-risk individuals.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Diabetes mellitus is a significant risk factor for cardiovascular disease (CVD).
- Statins and ezetimibe have demonstrated efficacy in reducing CVD events in diabetic populations.
- Emerging lipid-lowering therapies offer new strategies for managing CVD risk in diabetes.
Purpose of the Study:
- To review the efficacy of novel lipid-lowering therapies in reducing cardiovascular disease (CVD) events in patients with diabetes.
- To compare the outcomes of proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors and cholesterol ester transfer protein (CETP) inhibitors.
- To evaluate the potential of inflammation-targeting therapies for CVD risk reduction in diabetes.
Main Methods:
- Review of clinical trial data for lipid-lowering agents, including statins, ezetimibe, PCSK-9 inhibitors, CETP inhibitors, and anti-inflammatory drugs.
- Analysis of cardiovascular outcome data, particularly in patient subgroups with diabetes.
- Assessment of LDL-cholesterol reduction and its correlation with CVD event reduction.
Main Results:
- PCSK-9 inhibitors (e.g., evolocumab) achieve substantial LDL-cholesterol reduction (50-55%) and significant CVD risk reduction (20% in 2 years) in diabetic patients.
- CETP inhibitors have shown limited success in improving broad CVD endpoints.
- Canakinumab demonstrated a reduction in acute coronary intervention but with increased infection risk.
Conclusions:
- Novel therapies, especially PCSK-9 inhibitors, offer potent LDL-cholesterol lowering and CVD risk reduction in diabetes.
- The high efficacy of existing therapies and the cost of novel agents may restrict their use to high-risk diabetic individuals.
- Targeting inflammation presents a potential, albeit complex, avenue for CVD prevention in diabetes.
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