Statin therapy is the first line of defense against high low-density lipoprotein-cholesterol (LDL-C) and the risk for atherosclerotic cardiovascular disease (ASCVD), the leading cause of morbidity and mortality in people with diabetes.1 For individuals who cannot tolerate statins, alternatives like niacin, ezetimibe, bile acid sequestrants, and fibrates can decrease lipid levels and thus ASCVD risk.1 In patients with diabetes, even high-dose statins may not sufficiently lower LDL-C, so proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be used as adjunctive therapy.
Endocrinologist Yehuda Handelsman, MD, medical director of the Metabolic Institute of America in Tarzana, California, advised clinicians to “recognize that these patients need intensive therapy both because they have a higher risk and because they seem to respond the best compared to other groups of patients. Traditionally many clinicians did not recognize the high risk of patients with diabetes and thus did not treat them as intensively as they should.”
How PCSK9 Inhibitors Reduce LDL-C
The PCSK9 inhibitors alirocumab and evolocumab offer a different mechanism of action to control dyslipidemia than statins.1 The monoclonal antibodies, injected monthly or twice monthly, target the PCSK9 protein in the liver to reduce circulating LDL-C in the bloodstream — in some cases, by up to 60%.1
In patients with diabetes who are at a greater risk for ASCVD, the American Diabetes Association recommends lowering LDL-C to < 70 mg/dL with statins and PCSK9 inhibitors.2 The organization urges clinicians to follow the recommendations rather than rely on the American College of Cardiology/American Heart Association online ASCVD risk calculator because it does not factor in patients’ duration of diabetes or comorbidities.2 Even in patients with diabetes without ASCVD risk, the groups recommend moderate-intensity lipid therapy (30% to 50% reduction in LDL-C), as well as lifestyle interventions.2
The American Association of Clinical Endocrinologists and the American College of Endocrinology recommend even more aggressive lipid therapy in patients with ASCVD, diabetes, unstable angina, and chronic kidney disease: <55 mg/dL for LDL-C and <80 mg/dL for non-high-density lipoprotein cholesterol (HDL-C).3
ASCVD Outcomes in Patients With Diabetes
While there is no disputing the effectiveness of the lipid-lowering properties of evolocumab and alirocumab in patients with diabetes, only recently have there been ASCVD outcomes data in patients with diabetes taking PCSK9 inhibitors.1
A subanalysis of the FOURIER trial (N=27,564) examined the cardiovascular efficacy and safety of evolocumab for a median 2.2 years in patients with ASCVD, 40% of whom had diabetes.4 The composite primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.4
Compared with placebo, evolocumab showed a statistically significant reduction in ASCVD events in patients with and without diabetes (hazard ratio [HR] 0.83; 95% CI, 0.75-0.93 and HR 0.87; 95% CI, 0.79-0.96, respectively). In patients with diabetes, adverse events with evolocumab (78.5%) compared with placebo (78.3%) were similar in patients without diabetes (76.8%). Only injection site reactions occurred more frequently in patients administered evolocumab.4
Preliminary data from the ODYSSEY OUTCOMES trial showed similar robust ASCVD outcomes for alirocumab in 18,924 patients, 28.5% of whom had diabetes.5 Median follow-up for the study was 2.8 years and the composite primary end point was coronary heart disease (CHD) death, non-fatal MI, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Overall, alirocumab reduced the risk for major adverse cardiovascular events by 9.5% compared with placebo (HR 0.85; 95% CI, 0.78-0.93; P =.0003).5
Patients who had an LDL-C >100 mg/dL at baseline benefited most from alirocumab treatment, with a 24% reduction in major adverse cardiac events (CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization) and all-cause death by 29%. The treatment-emergent adverse events were similar in the alirocumab and placebo groups (75.8% vs 77.1%, respectively).5
The Paradox of Increased Blood Glucose
Despite the need and recommendations to lower lipid levels in patients with diabetes, the ADA acknowledges that statin and PCKS9 inhibitor therapy can cause a modest increase in incident diabetes.2 Nevertheless, the group states that the benefits of moderate to intensive lipid therapy outweigh the risks associated with ASCVD risk.2
In a 20-study meta-analysis, de Carvalho and colleagues reported a slight increase in fasting blood glucose and glycated hemoglobin (HbA1c) levels in 68,123 patients who were taking concomitant statins and PCSK9 inhibitors.6 Compared with patients taking placebo, patients administered statins and PCSK9 inhibitors had an absolute glycemic increase (weighted mean difference) of 1.88 mg/dL (95% CI, 0.91-2.68; P <.001).6 HbA1c levels also rose with dual lipid therapy compared with placebo: the weighted mean difference was 0.032% (95% CI, 0.011-0.050; P <.001). Long-term trials in the meta-analysis, however, did not show an increase in incident diabetes.
“The meta-analysis did not show an increase in the incidence of type 2 diabetes mellitus, but a small increase in blood glucose, by about 5 mg/dL,” said co-investigator Andrei C. Sposito, MD, PhD, professor of cardiology at the State University of Campinas, in Campinas, Brazil. “The analysis had only short-term studies and this needs to be taken into account in assessing the magnitude of glycemic change.”
“In clinical practice we have not seen increases in glucose nor conversion to diabetes,” noted Dr Handelsman. “In the registration trials of both PCSK9 inhibitors on the market there was no impact on glucose. In the FOURIER study, there seemed to have been a 0.4%-compared-to-placebo increase in conversion to diabetes. In the ODYSSEY trial it was not observed. I personally do not see it as an issue.”
Summary and Clinical Applicability
Diabetes adds an extra risk in individuals with high LDL-C. Aggressive lipid-lowering to reduce ASCVD risk includes statins and other boosters such as niacin, ezetimibe, and PCSK-9 inhibitors.
Limitations and Disclosures
1. 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;7(13):1-25.
2. Chamberlain JJ, Johnson EL, Leal S, Rhinehart AS, Shubrook JH, Peterson L. Cardiovascular disease and risk management: review of the American Diabetes Association standards of medical care in diabetes 2018. Ann Intern Med. 2018;168(9):640-650.
3. Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314-329.
4. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in diabetes and the risk of development of diabetes: a prespecified analysis from the randomized controlled FOURIER trial. Lancet Diabetes Endocrinol. 2017;5(12):941-950.
5. Steg PG, Schwartz GG, Szarek M, et al. The ODYSSEY OUTCOMES trial: topline results alirocumab in patients after acute coronary syndrome. Presented at: American College of Cardiology Annual Scientific Session 2018; March 10-12, 2018; Orlando, Florida. ClinicalTrials.gov: NCT01663402.
6. de Carvalho LSF, Campos AM, Sposito AC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incident type 2 diabetes: a systematic review and meta-analysis with over 96,000 patient-years. Diabetes Care. 2018;41(2):364-367.