Pcsk9 inhibition benefits outweigh risks in patients with diabetes georgia state university address atlanta

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.”

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 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

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. What are the requirements for georgia state university 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.”

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.

4. Georgia state university professors 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. What is georgia state university known for 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.