LISBON -- Presence of diabetes had no bearing on cardiovascular risk reduction with the PCSK9 inhibitor evolocumab (Repatha) in the FOURIER trial, researchers said here.
The 40% of patients in the trial who had diabetes saw at least as good a reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization, with a hazard ratio of 0.83 (95% CI 0.75-0.93) compared with 0.87 (95% CI 0.79-0.96) among participants without diabetes (P for interaction=0.60).
New-onset diabetes and glycemia weren't worsened by the drug, including in patients with prediabetes at baseline, Marc Sabatine, MD, of Brigham and Women's Hospital and Harvard in Boston, and colleagues reported here at the European Association for the Study of Diabetes meeting and simultaneously online in the Lancet Diabetes and Endocrinology.
"Recent guidelines have recommended identifying patients with diabetes and established atherosclerotic cardiovascular disease as having an extreme risk and requiring more intensive treatment to achieve lower LDL cholesterol goals. With similar relative and greater absolute risk reduction in patients with diabetes, and no discernible effect on glycemia, PCSK9 inhibition might be a particularly attractive therapy in this population," the group wrote.
But there's one catch, cautioned Luca Lotta, MD, PhD, and Simon Griffin, DM, both of the University of Cambridge School of Clinical Medicine in England, in an accompanying editorial.
They wrote that "in view of their high costs, access to PCSK9 inhibitors is likely to remain limited for the vast majority of the half a billion people with type 2 diabetes worldwide for the foreseeable future."
Increased risk of type 2 diabetes has been a concern with statins, albeit the net effect on risk of cardiovascular disease still "strongly justifies their use irrespective of this concern." The FOURIER findings in that regard were reassuring on face, but they weren't sufficient to exclude a small to moderate effect of evolocumab on diabetes risk. That would require pooling of data from several trials, Lotta and Griffin wrote.
The prespecified secondary analysis of FOURIER included the 27,564 statin-treated patients with atherosclerotic disease in the trial, who were randomized to evolocumab (140 mg every 2 weeks or 420 mg once a month) versus placebo for a median of 2.2 years. Diabetes status at baseline was defined by patient history, clinical events committee review of medical records, or baseline HbA1c of 6.5% or greater or fasting plasma glucose of 7.0 mmol/L or greater.
The study was funded by Amgen
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PCSK9 inhibition and type 2 diabetes
The focus of cardiovascular disease prevention has shifted from normalisation of risk factors to absolute risk reduction. Reducing LDL cholesterol concentration by 1 mmol/L for about 5 years is consistently associated with a 23–25% lowered risk of major cardiovascular events, with statin and non-statin therapies alike, irrespective of baseline LDL cholesterol concentration.1 In high-income and middle-income countries, statins are now routinely recommended as first-line LDL cholesterol-lowering therapy for people with 10-year modelled risk above, somewhat arbitrary, country-specific thresholds defined by economic and clinical considerations. This high-risk category includes most patients with type 2 diabetes. Statins achieve similar reductions in relative risk among people with and without diabetes.2 However, even among patients on maximum doses, with LDL cholesterol concentrations in the normal range, further reductions in LDL cholesterol and modelled risk are possible.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that catalyses the degradation of the LDL receptor, thereby reducing LDL cholesterol uptake by cells and increasing circulating concentrations. In The Lancet Diabetes & Endocrinology, Marc Sabatine and colleagues report on the efficacy and safety of PCSK9 inhibition in people with and without diabetes.3 The investigators undertook a prespecified secondary analysis of data from FOURIER,4 a randomised, placebo-controlled trial of subcutaneous injections of the anti-PCSK9 monoclonal antibody evolocumab given every 2 or 4 weeks, in 27 564 patients with atherosclerotic disease who were on statin therapy.
Evolocumab lowered LDL cholesterol similarly in people with diabetes (57%, 95% CI 56–58; p<0·0001) and without diabetes (60%, 60–61; p<0·0001) at baseline, down to 0·8 mmol/L in both subgroups at 48 weeks. The primary efficacy endpoint of FOURIER—a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation—was similarly reduced in both subgroups after a median follow-up of 2·2 years, with hazard ratios of 0·83 (95% CI 0·75–0·93; p=0·0008) in patients with diabetes at baseline and 0·87 (0·79–0·96; p=0·0052) in those without. Consideration of adverse effects is particularly important in view of the historical controversy over statins. Evolocumab was well
tolerated, with similar proportions of patients having adverse events (eg, muscle-related and neurocognitive events) in the evolocumab and placebo groups, in both patients with and without diabetes at baseline. The frequency of drug discontinuation was similar in the evolocumab and placebo groups,4 occurring less often (5·7% per year) than in the IMPROVE-IT trial (7% per year),5 which assessed the addition of once-daily oral ezetimibe to statin therapy.
One concern related to statins is the increased risk of type 2 diabetes,6 albeit that the net effect on risk of cardiovascular disease, the most burdensome complication of diabetes, strongly justifies their use irrespective of this concern. Evidence from meta-analyses6 of statin trials including more than 90 000 patients followed up for 4·2 years, and mendelian randomisation studies6 of LDL cholesterol-lowering variants near the gene encoding the HMG-coenzyme A reductase protein (the target for statins), confirm an adverse effect of statins on bodyweight (0·24 kg higher) and incidence of diabetes (12% higher).6 Findings from genetic studies including data from more than half a million individuals have shown associations between PCSK9 variants and bodyweight (1·03 kg higher), fasting glucose (0·09 mmol/L higher), and odds of diabetes (19–29% higher).7,8 The FOURIER investigators report no evidence of an association between evolocumab and bodyweight, or incidence of new-onset diabetes (HR 1·05, 95% CI 0·94–1·17), including (in a post-hoc analysis) in patients who had prediabetes at baseline (1·00, 0·89–1·13). They also identified no effect of evolocumab on glycaemia (as measured by HbA1c and fasting plasma glucose concentrations) in patients with diabetes, prediabetes, or normoglycaemia. These results reassure us that PCSK9 inhibition is unlikely to have a major effect on diabetes risk.
Notably, FOURIER was adequately powered to detect the effect sizes for diabetes risk identified in genetic studies of PCSK9.7,8 However, estimates from genetic studies are scaled to a 1 mmol/L lower LDL cholesterol concentration and reflect a lifelong exposure to differences in PCSK9 function in the general population. By contrast, FOURIER investigated pharmacological
PCSK9 inhibition reducing LDL cholesterol by about
2 www.thelancet.com/diabetes-endocrinology Published online September 15, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30321-2
1·5 mmol/L over 2·2 years of follow-up, in the setting of a high-risk population previously exposed to statin treatment. Hence, a small to moderate effect of evolocumab on diabetes risk will only be excluded by the pooling of data from several trials, as was undertaken for statins. The consistent direction of effect of results of genetic studies and trials of lipid-lowering drugs highlights as yet unexplained mechanisms in the aetiology of diabetes that merit further investigation. The discrepancy in effect sizes between genetic studies and trials raises the possibility that cardiovascular risk reductions of greater than 25% could be achieved through longer-term treatment from an earlier age. As the rationale for basing prescribing decisions on absolute risk assumes a consistent effect size, perhaps we should consider incorporating risk estimates standardised by age and sex, rather than absolute risk, into guidelines and shared decision making with patients.
Ezetimibe is the recommended additional LDL cholesterol-lowering drug for patients prescribed a maximum tolerated dose of statin. Although ezetimibe is considerably cheaper than evolocumab, it has a smaller effect on LDL cholesterol. In IMPROVE-IT,5 adding ezetimibe to statins achieved a reduction of 0·43 mmol/L in LDL cholesterol compared with placebo, and was associated with a greater reduction in relative risk of cardiovascular events among people with diabetes than those without. These data from FOURIER suggest that evolocumab is an effective and safe option for patients with diabetes and atherosclerotic disease. If PCSK9 inhibitors, or other emerging therapies, have few adverse effects, including a minimal effect on diabetes risk, such findings might influence prescribing decisions. However, in view of their high costs,9 access to PCSK9 inhibitors is likely to remain limited for the vast majority of the half a billion people with type 2 diabetes worldwide for the foreseeable future.9
Luca A Lotta, *Simon J Griffin
MRC Epidemiology Unit (LAL, SJG), and Primary Care Unit,
Institute of Public Health (SJG), University of Cambridge School of
Clinical Medicine, Cambridge Biomedical Campus, Cambridge
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