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Macrovascular Residual Risk Studies

21 May 2021
ODYSSEY OUTCOMES: Does PCSK9 inhibition increase the risk of diabetes?
Elevated lipoprotein(a) [Lp(a)] is regarded as a cardiovascular risk factor, attributed to its atherogenic, proinflammatory, and prothrombotic properties. Observational studies also suggest that low levels of Lp(a) associate with increased risk for incident (new-onset) diabetes. Whether pharmacological agents that lower Lp(a) also increase this risk remains controversial. Addressing this question, this analysis from ODYSSEY OUTCOMES suggests that patients with the greatest reduction in Lp(a) levels may have a slightly increased risk of developing type-2 diabetes. However, it is likely that this risk is far outweighed by the reduction in residual cardiovascular risk observed in the trial.
Schwartz GG, Szarek M, Bittner VA et al. Relation of lipoprotein(a) levels to incident type 2 diabetes and modification by alirocumab treatment. Diabetes Care 2021;
Objective: To investigate the relationship of Lp(a) concentration with incident type 2 diabetes and the effects of treatment with alirocumab, a PCSK9 inhibitor.
Study design: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled clinical trial comparing treatment with alirocumab versus placebo in patients with a recent acute coronary syndrome (ACS) on statin treatment. This latest report is based on a post hoc analysis of this trial.
Study population: 18,924 ACS patients; diabetes was present at baseline in 5,444 (29%) patients and not present in 13,480 patients. This post hoc analysis was based on the subgroup without diabetes at baseline.
Study outcome: Incident diabetes, identified from laboratory, medication, and adverse event data.
Methods: Median quartile Lp(a) levels were compared among patients without diabetes at baseline. The probability of incident type 2 diabetes during follow-up as a function of baseline Lp(a) was estimated for each treatment group by logistic regression. The change in Lp(a) concentration from baseline to month 4 with alirocumab was calculated, and within each group, this change was related to the subsequent risk of incident type 2 diabetes using Cox regression models. Hazard ratios per 10 mg/dL decrease in Lp(a) were reported.
Main results: In the subgroup without diabetes at baseline, 1,324 developed type 2 diabetes over a median follow-up of 2.7 years, 648 assigned to alirocumab and 676 to placebo. In the placebo group, a lower baseline Lp(a) level was associated with increasing risk of incident type 2 diabetes. In contrast, in the alirocumab group the incidence rate for type 2 diabetes was essentially similar across the range of baseline Lp(a) levels.
Treatment with alirocumab reduced Lp(a) concentration by a median of 23.2% over the follow-up period. The median absolute reduction in Lp(a) from baseline was greater in patients with higher baseline Lp(a) levels, ranging from 0 in quartile 1 (Lp(a) <6.9 mg/dL) to 20.2 mg/dL in quartile 4 (≥61.1 mg/dL).
Alirocumab tended to reduce the estimated risk of incident type 2 diabetes compared with placebo at low baseline Lp(a) levels, However, among patients with high baseline Lp(a) levels, alirocumab treatment led to greater absolute reductions in Lp(a) and tended to increase the estimated risk of incident type 2 diabetes compared with placebo.
Overall, each 10 mg/dL decrease in Lp(a) from baseline increased the risk of incident type 2 diabetes by 7% (unadjusted hazard ratio 1.07, 95% CI 1.0321.12; p=0.0002). This association was similar after adjustment for baseline Lp(a) level, and baseline demographic and clinical characteristics.
Conclusion: In patients with ACS, baseline Lp(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in Lp(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce Lp(a) is undetermined.


Therapeutic agents that target residual cardiovascular risk should also have a favourable benefit versus risk profile. Lipoprotein(a) has attracted attention as a potential contributor to this residual risk, supported by evidence from genetic and epidemiologic studies that it is an independent cardiovascular risk factor (1). Added to this, insights from the ODYSSEY OUTCOMES study showed that lowering of high baseline Lp(a) levels contributed to the cardiovascular benefit from PCSK9 inhibition beyond the substantial reduction in low-density lipoprotein cholesterol concentration (2). Questions remain, however, regarding the underlying mechanism(s) responsible for the cardiovascular benefit from Lp(a) lowering (3).

The other relevant issue is the long-term safety of lowering Lp(a) with pharmacologic intervention. Low plasma levels of Lp(a) have been associated with increased risk of type 2 diabetes, although whether this effect is causal is uncertain. Mendelian randomization studies which use genetic variants as proxies for exposure to low Lp(a) levels have been conflicting (4,5), and this is further unresolved by a meta-analysis of published studies (6). In a very recent analysis of the Copenhagen General Population Study there was no evidence that very low Lp(a) levels increase the risk of cancer or infection, but observational and genetic data regarding the risk for diabetes were discordant (7).

This post hoc analysis of the ODYSSEY OUTCOMES study adds new insights. First, the study showed that lower baseline Lp(a) levels in the placebo group increased incident type 2 diabetes, consistent with previous reports (5,6,8). Patients with higher baseline Lp(a) levels derived greater absolute reduction with alirocumab treatment, and this associated with a small increase in incident type 2 diabetes. Clearly, a caveat of this analysis is its post hoc nature. Furthermore, as alirocumab treatment was given against a background of intensive statin therapy, it is not possible to determine whether the effect of lowering Lp(a) with alirocumab on incident type 2 diabetes risk was independent of effects due to long-term statin treatment, which is also known to increase the risk of incident diabetes (9).

References 1. Hoogeveen RC, Ballantyne CM. Residual cardiovascular risk at low LDL: remnants, lipoprotein(a), and inflammation. Clin Chem 2021;67:143–53.
2. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–44.
3. Tsimikas S, Fazio S, Ferdinand KC, et al. NHLBI Working Group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol 2018;71:177–92.
4. Kamstrup PR, Nordestgaard BG. Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2013;1:220-7.
5. Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes 2014;63:332–42.
6. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol 2017;16:38.
7. Langsted A, Nordestgaard BG, Kamstrup PR. Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study. Eur Heart J 2021;42:1147-56.
8. Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol 2019;74:2982–94.
9. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42.
Key words residual cardiovascular risk; lipoprotein(a); incident diabetes risk; ODYSSEY OUTCOMES