PCSK9 Inhibitors: No Short-term Diabetes Risk in Meta-analysis

Marlene Busko

September 29, 2017

BARCELONA, SPAIN — Taking proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to reduce LDL cholesterol is associated with a small increase in HbA1c levels, but this does not translate into increased risk of new or worsening diabetes, at least with 42 weeks of treatment, suggests a large meta-analysis[1].

"In the short term, there is an increase in glycemia and HbA1c , but at this point, with 1.5 years of follow-up, we did not show a clear increase in the risk of incident type 2 diabetes," Dr Luiz Sérgio Carvalho (University of Campinas, São Paulo, Brazil) said at a press briefing prior to his presentation of the study here at the European Society of Cardiology (ESC) 2017 Congress.

"The effect on type 2 diabetes was apparent only in individuals who achieved very low levels of LDL cholesterol after treatment," he said, referring to a related exploratory analysis that suggested more intense LDL-C lowering with PCSK9 inhibitors and treatment longer than 1 year were associated with new or worsening type 2 diabetes.

"The small but probably significant risk is probably a smaller effect than the cardiovascular benefit [of] the medications," Carvalho told theheart.org | Medscape Cardiology.

"The increases in the glycemic indexes were very small, and we just have to [watch] for the future analyses of the trials, with longer follow-up, and see if there will be an increased risk of type 2 diabetes, Carvalho said.

"It's sounding rather familiar like the statin story—a minor effect on glycemia but clearly overwhelmingly positive effects of these agents" on cardiovascular risk, commented Dr Louise Bowman (University of Oxford, UK), who cochaired the session where Carvalho's formal presentation was made.

Session cochair Dr Robert G Xuereb (The Heart Clinic, Ta' Xbiex, Malta) noted study limitations include that "it was a short-term follow-up and a nonhomogenous study group, so obviously we need to have more data, and this study has served to draw awareness to this issue."

Importantly, the PCSK9 inhibitor evolocumab (Repatha, Amgen) was not associated with worsened or incident diabetes over 2 years in a prespecified analysis of the FOURIER trial, which was presented this month at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting and simultaneously published in Lancet Diabetes and Endocrinology[2].

Lower Cholesterol, but With Risk of Diabetes?

In the SPIRE and FOURIER trials, a 60-mg/dL reduction in LDL cholesterol on PCSK9 inhibitors was associated with 20% reduction in cardiovascular events, Carvalho said. But a PCSK9 loss-of-function genetic variant is associated with prediabetes and diabetes, so the researchers aimed to determine the effect of PCSK9 inhibitors on glucose levels and potential new or worsening diabetes.

The team conducted a meta-analysis of phase 2 and phase 3 randomized controlled trials of PCSK9 inhibitors vs placebo (control) that were at least 12 weeks long, with primary outcomes of change in HbA1c and fasting blood glucose from baseline, and secondary outcomes of risk of incident or worsening type 2 diabetes.

They identified 20 randomized PCSK9 inhibitor trials with a total of 68,123 participants that included the GAUSS and ODYSSEY trials of alirocumab (Praluent, Sanofi/Regeneron), DESCARTES, MENDEL, GLAGOV, and FOURIER trials of evolocumab, and the SPIRE trials of bococizumab (Pfizer). The Pfizer drug is no longer in development.

Aside from the short follow-up periods in the included studies, important limitations of the analysis include a low incident rate of diabetes, about 3%, and no information on how antidiabetic medications were used, the researchers note.

At baseline, the participants had a mean fasting plasma glucose of 103 mg/dL and a mean HbA1c of 5.89%; 28% had diabetes. They had a mean age of 60, 58% were male, 84% were white, 61% had hypertension, 39% had CAD, and 18% were smokers.

After a mean follow-up of 42 weeks, patients taking a PCSK9 inhibitor had a fasting plasma glucose that averaged 1.88 mg/dL higher compared with control patients (P<0.001). They also had had an HbA1c that averaged 0.032% higher compared with control patients (P<0.001).

However, these glycemic changes did not translate into increased risk of either new or worsening diabetes (RR 1.04, 95% CI 0.95–1.15; P=0.43) or new type 2 diabetes (RR 1.04, 95% CI 0.90–1.14; P=0.35) over a mean follow-up of 1.5 years.

Nor were PCSK9 inhibitors associated with increased risk of incident type 2 diabetes diagnosis considering only trials with a follow-up exceeding 48 weeks (RR 1.06, 95% CI 0.96–1.17; P=0.26).

Carvalho said there was small significant risk of incident or worsening type 2 diabetes in the exploratory analyses, adjusted for age and sex, among patients whose LDL cholesterol had been reduced by at least 55% and to 30 mg/dL or lower and who had been receiving a PKSK9 inhibitor for more than a year.

The study was funded by study was sponsored by the State University of Campinas (UNICAMP). The authors have no relevant financial relationships.

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