PCSK9 and HMGCR genetic variants are associated to risk of type 2 diabetes
PCSK9 and HMGCR genetic variants are associated to risk of type 2 diabetesLiterature - Ference et al., NEJM and Schmidt et al., Lancet Diabetes Endocrinol
In the study of Ference and colleagues, 7 variants of PCSK9 and 6 variants of HMGCR were included.
- Individuals in the group with higher PCSK9 genetic scores had lower mean LDL-c levels than those with lower PCSK9 scores (difference of -4.2 mg/dL/-0.11 mmol/L, P=5.6*10-16).
- Similarly for non-HDL (difference of -4.5 mg/dL/-0.12 mmol/L, P=1.8*10-16), triglycerides (difference of -5.3 mg/dL/-0.06 mmol/L, P=6.8*10-10) and HDL-c (difference of 0.5 mg/dL/0.01 mmol/L, P=5.4*10-5).
- Participants in the group with higher PCSK9 scores had an 8.4% lower risk of primary endpoint, as well as lower risks of major coronary events, major vascular events, MI and death from CHD. They also had a 6.1% higher risk of diabetes.
- Individuals in the group with higher HMGCR genetic scores had lower mean LDL-c levels than those with lower HMGCR scores (difference 3.2 mg/dL/0.08 mmol/L, P=2.9*10-15).
- Participants in the group with higher HMGCR scores had and 6.6% lower risk of MI or death from CHD, which was consistent for all secondary endpoints. They also had a 5% higher risk of diabetes.
- PCSK9 and HMGCR genetic scores had additive effects on LDL-c levels and corresponding risk of cardiovascular events.
- A genetic score consisting of variants in the LDL receptor gene had a very similar effect on the risk of diabetes per unit decrease in the LDL receptor levels.
Combining 50 studies including 245,942 individuals and data from repositories including another 322,506 individuals, Schmidt and colleagues observed 51,623 cases of incident or prevalent T2DM.
- The 4 selected PCSK9 variants were associated with reductions in LDL-c; -0.02 mmol/L (95% CI: -0.03 to -0.02) for rs11583680, -0.04 (95% CI: -0.05 to -0.04) for rs2479409, -0.06 (95% CI: -0.07 to -0.05) for rs11206510 and -0.34 mmol/L (95% CI: -0.36 to -0.32) for rs11591147.
- 1 mmol/L lower LDL-c was associated with an increase in body weight of 1.03 kg (95% CI: 0.24 to 1.82), an increase of 0.006 (95% CI: 0.003 to 0.010) in waist-to-hip ratio but a potentially neutral association with BMI (0.11 kg/m2, 95% CI: -0.09 to 0.30).
- 1 mmol/L lower LDL-c was associated with 0.09 mmol/L (95% CI: 0.02 to 0.15) higher fasting plasma glucose, HbA1c of 0.03% (95% CI: -0.01 to 0.08) but no change in fasting insulin.
- Surprisingly, there was an effect on height with a mean difference of 0.008 m (95% CI: 0.0008 to 0.015).
- 1 mmol/L lower LDL-c was associated with an increased risk of T2DM (OR 1.29, 95% CI: 1.11-1.50). Separate analysis showed an OR of 1.15 (95% CI: 0.76-1.72) for incident T2DM and 1.26 (95% CI: 0.88-1.80) for prevalent T2DM.
Both studies showed that genetic variants that mimic the effect of PCSK9 inhibitors had effects on lower LDL-c levels and the risk of cardiovascular events and the risk of diabetes. This was similar to variants that mimic the effect of statins when measured per unit change in the LDL-c level. Furthermore, it was shown that both variants together were independent and additive. These data suggest that treatment with a PCSK9 inhibitor, used either alone or in combination with a statin, should reduce the risk of cardiovascular events by approximately 20% per decrease of 1mmol/L in LDL-c but also may increase the risk of new-onset diabetes. However, the corresponding proportional reduction in cardiovascular risk was much greater than the increased risk of diabetes.