Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis

Abstract

Background The relationship between lowering LDL (low-density lipoprotein) cholesterol with contemporary lipid-lowering therapies and incident diabetes mellitus ( DM ) remains uncertain. Methods and Results Thirty-three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline , Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid-lowering therapy. More intensive lipid-lowering therapy was defined as the more potent pharmacological strategy ( PCSK 9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta-analyses were conducted using a random-effects model. No significant association was noted between 1-mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid-lowering therapy (risk ratio: 0.95; 95% CI , 0.87-1.04; P=0.30; R²=14%) or for statins or PCSK 9 inhibitors. More intensive lipid-lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI , 1.03-1.11; P<0.001; I²=0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI , 1.05-1.15; P<0.001; I²=0%), whereas PCSK 9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI , 0.93-1.07; P=0.96; I²=0%; P=0.02 for interaction). Conclusions Among intensive lipid-lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM . The risk of incident DM was higher with statins, whereas PCSK 9 inhibitors had no association with risk of incident DM .

Keywords: LDL (low‐density lipoprotein) cholesterol; PCSK9 (proprotein convertase subtilisin/kexin type 9); diabetes mellitus; statin.

Figure 1

Study selection according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. CENTRAL indicates Cochrane Central Register of Controlled Trials; DM, diabetes mellitus.

Figure 2

Metaregression showing association of between‐group differences in achieved LDL (low‐density lipoprotein) cholesterol (LDL‐C) levels (mmol/L) and risk ratio of incident diabetes mellitus. Each trial is represented by a data marker, the size of which is proportional to the weight in the metaregression. The metaregression slope (predicted risk for degree of LDL‐C reduction) is represented by a red line, and 95% CIs are presented as dashed lines. The horizontal lines through each square represent ±1 SE for the associated absolute change in LDL‐C, and the vertical line through each square represents the 95% CI for relative risk. For converting millimoles to milligrams, multiply by 38.5. PCSK9 indicates proprotein convertase subtilisin/kexin type 9.

Figure 3

Metaregression showing association between percentage reduction of LDL (low‐density lipoprotein) cholesterol (LDL‐C) in the active arm and relative risk of incident diabetes mellitus. Each trial is represented by a data marker, the size of which is proportional to the weight in the metaregression. The metaregression slope (predicted risk for degree of LDL‐C reduction) is represented by a red line, and 95% CIs are presented as dashed lines. The horizontal lines through each square represent ±1 SE for the associated absolute change in LDL‐C, and the vertical line through each square represents the 95% CI for relative risk.

Figure 4

Forest plot showing subgroup analysis according to weighted between‐group difference in LDL (low‐density lipoprotein) cholesterol (LDL‐C) achieved (mmol/L) among interventions and risk of incident diabetes mellitus. PCSK9 indicates proprotein convertase subtilisin/kexin type 9.

Figure 5

Forest plot comparing risk of incident diabetes mellitus among interventions. PCSK9 indicates proprotein convertase subtilisin/kexin type 9.

Figure 6

Sensitivity analysis, forest plot showing subgroup analysis of statin therapy on incident diabetes mellitus.

Figure 7

Sensitivity analysis, forest plot comparing risk of incident diabetes mellitus among interventions in trials with sample sizes ≥500 patients and follow‐up ≥1 year. PCSK9 indicates proprotein convertase subtilisin/kexin type 9.