PCSK9 and carbohydrate metabolism: A double-edged sword

Table 1 Studies that examined the association of proprotein convertase subtilisin/kexin type 9 with carbohydrate metabolism

Ref.	Type	Main findings
Studies pointing to a positive effect of PCSK9 on carbohydrate metabolism
Mbikay et al[14]	Experimental (mice)	PCSK9-null male mice over 4 mo of age carried more LDLR and less insulin in their pancreas; islets exhibited signs of malformation, apoptosis and inflammation
Awan et al[11]	Genetic study	Carriage of the loss-of-function PCSK9 p.R46L mutation was associated with insulin resistance in subjects with apolipoprotein E3/E2 genotype
Studies pointing to a negative effect of PCSK9 on carbohydrate metabolism
Langhi et al[13]	Experimental (mice)	PCSK9 deficiency does not alter insulin secretion and glucose tolerance
Baass et al[18]	Clinical study (children)	Significant correlation of PCSK9 levels with glucose, insulin and HOMA-IR levels; an increase in PCSK9 levels by 1%-2% was associated with 10% higher fasting insulin levels in both sexes
Arsenault et al[21]	Clinical study (abdominally obese men)	PCSK9 levels are associated with dyslipidemia and with increased HOMA-IR
Studies pointing to a neutral effect of PCSK9 on carbohydrate metabolism
Bonnefond et al[12]	Genetic study	The p.R46L mutation is not associated with markers of glucose homeostasis; p.R46L carriers did not experience an increased risk of new-onset diabetes mellitus
Colhoun et al[22]	Analysis of 10 phase 3 clinical trials with alirocumab (3448 non-diabetic individuals)	Hazard ratio for diabetes-related treatment adverse effects 0.64 (95%CI: 0.36-1.14) in alirocumab-treated patients vs placebo-treated and 0.55 (95%CI: 0.22-1.41) vs ezetimibe-treated patients
Blom et al[23]	Post hoc analysis of the DESCARTES trial (evolocumab)	No changes in parameters of carbohydrate metabolism in patients with pre-existing dysglycemia or metabolic syndrome
Ongoing trials that may better delineate the role of PCSK9 inhibition on carbohydrate metabolism
Fourier trial (ClinicalTrials.gov Identifier: NCT01764633)	Ongoing trial	Primary hypothesis is that additional LDL-c lowering with evolocumab decreases the risk of cardiovascular events in subjects with clinically evident cardiovascular disease
Odyssey trial (ClinicalTrials.gov Identifier: NCT01663402)	Ongoing trial	Primary hypothesis is that additional LDL-c lowering with alirocumab decreases the risk of cardiovascular events in patients who have experienced an acute coronary syndrome event 4 to 52 wk prior to randomization

PCSK9: Proprotein convertase subtilisin/kexin type 9; LDLR: Low-density lipoprotein receptors; HOMA-IR: Homeostasis model assessment-insulin resistance; LDL-c: Low-density lipoprotein cholesterol.

Table 2 Proprotein convertase subtilisin/kexin type 9 inhibitors and diabetes mellitus: Results of the mendelian randomization studies

PCSK9 variants	Decrease in serum LDL cholesterol	Odds ratio for type 2 diabetes mellitus
rs 11591147[15]	1 mmol/L (38.4 mg/dL)	1.19 (95%CI: 1.02-1.38)
14 independent variants[16] (rs 11583680, rs 11591147, rs 2479109, rs 11206510)	1 mmol/L (38.4 mg/dL)	1.29 (95%CI: 1.11-1.50)
2Genetic score[17]	10 mg/dL	1.11 (95%CI: 1.04-1.19)

¹Associations with fasting glucose, body weight and waist-to-hip ratio were also noticed;

²The increased risk of diabetes was observed only in individuals with impaired fasting glucose levels. PCSK9: Proprotein convertase subtilisin/kexin type 9; LDL: Low-density lipoprotein; CI: Confidence interval.