Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2019 Apr 2;8(7):e011581.
doi: 10.1161/JAHA.118.011581.

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

Safi U Khan  1 , Hammad Rahman  2 , Victor Okunrintemi  3   4 , Haris Riaz  5 , Muhammad Shahzeb Khan  6 , Sudhakar Sattur  7 , Edo Kaluski  7 , A Michael Lincoff  5 , Seth S Martin  8 , Michael J Blaha  8
Affiliations
Meta-Analysis

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

Safi U Khan et al. J Am Heart Assoc. .

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.

PubMed Disclaimer

Figures

Figure 1
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
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
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
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
Figure 5
Forest plot comparing risk of incident diabetes mellitus among interventions. PCSK9 indicates proprotein convertase subtilisin/kexin type 9.
Figure 6
Figure 6
Sensitivity analysis, forest plot showing subgroup analysis of statin therapy on incident diabetes mellitus.
Figure 7
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.
See this image and copyright information in PMC

References

    1. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, Braunwald E, Sabatine MS. Association between lowering LDL‐C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta‐analysis. JAMA. 2016;316:1289–1297. - PubMed
    1. Koskinas KC, Siontis GCM, Piccolo R, Mavridis D, Raber L, Mach F, Windecker S. Effect of statins and non‐statin LDL‐lowering medications on cardiovascular outcomes in secondary prevention: a meta‐analysis of randomized trials. Eur Heart J. 2018;39:1172–1180. - PubMed
    1. Khan SU, Talluri S, Riaz H, Rahman H, Nasir F, Bin Riaz I, Sattur S, Ahmed H, Kaluski E, Krasuski R. A Bayesian network meta‐analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes. Eur J Prev Cardiol. 2018;25:844–853. DOI: 10.1177/2047487318766612. - DOI - PubMed
    1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd‐Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–2934. - PubMed
    1. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37:2999–3058. - PubMed

MeSH terms