Ezetimibe in type 2 diabetes

• there is evidence that patients with type 2 diabetes and no coronary heart disease (CHD) have the same CHD risk as non-diabetic patients who have survived an acute myocardial infarction (1)
• individuals with T2DM have two-to four-fold increased risk of coronary artery disease (CHD), the leading cause of death among people with T2DM (2)
• cholesterol and LDL-cholesterol levels are not higher in diabetic than non-diabetic patients (although both may be higher than desirable); triglyceride levels are often elevated and there may be low levels of HDL- cholesterol; raised levels of triglycerides lead to smaller and denser LDL particles with greater atherogenic potential. Dyslipidaemia is common in patients with type 2 diabetes and raised cholesterol is a major risk factor for CHD in patients with type 2 diabetes
  • study evidence in people with T2DM have found an increased association between CHD and high triglycerides and low HDL-C combined, compared to the two lipid parameters assessed separately (3)
    
    
• evidence for the beneficial effect of choleserol-lowering treatment with statins in diabetic patients:
  • In patients with a history of CHD: the 4S trial lowering cholesterol with simvastatin decreased the incidence of recurrent major coronary events by 55% (p=0.002) in diabetic patients compared with 32% (p<0.001) among non-diabetic patients. Similar results were seen in the CARE trial where 14% (n=586) of the trial population had diabetes.
  • The Heart Protection study (HPS) included 6000 patients with diabetes and randomised patients to treatment with simvastatin 40mg or placebo. In patients with diabetes it was found that treatment with a statin for 5 years in 1000 patients would prevent major cardiovascular events in 70 cases. The HPS was the first trial with sufficient patients with diabetes to provide evidence for the benefits of cholesterol lowering in primary, as well as secondary, prevention of CHD. The results at 4.8 year follow up of simvastatin versus placebo

• the Cholesterol Treatment Trialists' Collaboration meta-analysis found that the cardiovascular benefits of LDL-C lowering with statin therapy were similar in those with and without diabetes mellitus (4)

• ezetimibe in T2DM:
  • in the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trial evaluating the addition of ezetimibe concomitant with statin therapy, which lowered LDL-C levels below previous targets to a median level of 53 mg/dL in 18144 patients with recent acute coronary syndromes (27% of whom had diabetes mellitus)
    • individuals with diabetes mellitus had significantly greater relative and absolute benefit in improved cardiovascular outcomes than those without diabetes mellitus (5)
      
      
• PCSK9 inhibitors in T2DM (6)
  
  • clinical evidence shows that PCSK9 inhibitors are well tolerated and provide significant LDL-C lowering in individuals with hyperlipidemia and diabetes mellitus on top of maximally tolerated statin therapy, without loss of glycemic control or increased risk of developing diabetes mellitus in those without pre-existing diabetes mellitus, and can prevent or reduce further cardiovascular events
• evidence for the role for other therapies in type 2 diabetes (6)
  • clinical outcomes studies for niacin and fenofibrate (ACCORD [Action to Control Cardiovascular Risk in Diabetes] and FIELD [Fenofibrate Intervention and Event Lowering in Diabetes]) did not demonstrate significant cardiovascular benefits in individuals with diabetes mellitus, although there was a suggestion of benefit in subgroups with very high triglyceride levels in the fenofibrate studies
    
    
• remnant cholesterol and cardiovascular risk in diabetes (7)
  • in a primary prevention trial with high prevalence of diabetes and obesity in high CV risk participants, triglycerides and remnant-C (total cholesterol - (LDL-c+HDL-c)), but not LDL-c and HDL-c, were associated with MACE. The authors concluded: "Remnant-c should be considered a preferential treatment target in this population"
    
    
• changes in levels of non-HDL-C in diabetes (8)
  • a network meta-analysis indicated that rosuvastatin, at moderate and high intensity doses, and simvastatin and atorvastatin, at high intensity doses, were most effective at moderately reducing levels of non-HDL-C in patients with diabetes

Reference:

1. Haffner SM et al (1998). Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. NEJM, 339, 229-34
2. Aronson D, Edelman ER. Coronary artery disease and diabetes mellitusCardiol Clin. 2014 Aug; 32(3):439-55
3. Lee JS et al. Triglyceride and HDL-C Dyslipidemia and Risks of Coronary Heart Disease and Ischemic Stroke by Glycemic Dysregulation Status: The Strong Heart Study. Diabetes Care. 2017;40:529-537. doi: 10.2337/dc16-1958.
4. Cholesterol Treatment Trialists Collaborators.Efficacy of cholesterol-lowering therapy in

18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125.

1. Giugliano RP et al; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators.Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs. without diabetes: results from IMPROVE-IT. Circulation. 2018;137:1571-1582.
2. Handelsman Y, Lepor NE.PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc. 2018 Jul 3; 7(13): e008953.
3. Castañer O, Pintó X, Subirana I, et al. Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease J Am Coll Cardiol. 2020, 76 (23) 2712–2724, doi.org/10.1016/j.jacc.2020.10.008
4. Hodkinson A, Tsimpida D, Kontopantelis E, Rutter M K, Mamas M A, Panagioti M et al. Comparative effectiveness of statins on non-high density lipoprotein cholesterol in people with diabetes and at risk of cardiovascular disease: systematic review and network meta-analysis BMJ 2022; 376 :e067731 doi:10.1136/bmj-2021-067731