Statins and type 2 diabetes: genetic studies on target
Authors: Timothy M Frayling
Journal: The Lancet (2014)

The topic of the side-effects of statin treatment is important and controversial. In The Lancet, Daniel Swerdlow and colleagues1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar used an updated meta-analysis of trials to investigate whether or not statins increased the risk of type 2 diabetes, and a genetic approach to address how statins might increase the risk of the disorder. Using data from 20 randomised controlled trials, they confirm findings from previous reports that statin treatment increased the risk of incident type 2 diabetes, with an odds ratio (OR) of 1·12 (95% CI 1·06–1·18) versus controls. In contrast to previous efforts, they then studied common genetic variants near the gene encoding the HMG-coenzyme A (HMGCoA) reductase protein—the enzyme inhibited by statins to lower LDL cholesterol. Genome-wide association studies had previously identified these variants as associated with altered circulating LDL cholesterol concentrations with robust levels of statistical confidence.2Teslovich TM Musunuru K Smith AV et al.Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2882) Google Scholar Using these genetic variants and a combination of their own and published data, the investigators provide evidence that reduced HMGCoA activity causes a slight increased risk of type 2 diabetes (rs17238484-G allele OR per allele 1·02, 95% CI 1·00–1·05; rs12916 allele 1·06, 1·03–1·09), and therefore surmise that an increased risk of type 2 diabetes is at least partly conferred by an on-target effect of statins. These results are important because they suggest that any attempts to make statins more specific and reduce off-target effects will not reduce the risk of the diabetogenic side-effect. The investigators also provide a new potential mechanism of statins’ diabetogenic action—the alleles associated with lower circulating LDL cholesterol and increased type 2 diabetes risk were also associated with increased body-mass index (0·11 kg/m2 higher with the rs17238484-G allele than in controls, 95% CI 0·07–0·14; p=1·77 × 10−7). Consistent with the genetic association, the investigators also described a subtle increase in weight caused by statins in the trial data (0·30 kg higher, 0·18–0·43; p=3·15 × 10−6). Swerdlow and colleagues1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar provide a new angle to the debate about the adverse side-effects of statins. They used a genetic approach—mendelian randomisation—that has proven a valuable method to help understand disease mechanisms.3Lawlor DA Harbord RM Sterne JA Timpson N Davey Smith G Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.Stat Med. 2008; 27: 1133-1163Crossref PubMed Scopus (1908) Google Scholar, 4Smith GD Lawlor DA Harbord R Timpson N Day I Ebrahim S Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology.PLoS Med. 2007; 4: e352Crossref PubMed Scopus (358) Google Scholar Mendelian randomisation is based on a fundamental principle of biology—that inherited DNA sequence variation is randomised during meiosis independently of the environment and disease processes. Mendelian randomisation approaches have been useful in understanding causality of potentially modifiable risk factors for cardiovascular disease. For example, several studies have used common genetic variants near the gene encoding C-reactive protein (CRP) to show that raised high-sensitivity CRP is unlikely to affect the risk of heart disease causally.5C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC)Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data.BMJ. 2011; 342: d548Crossref PubMed Scopus (229) Google Scholar More recently, studies of genetic variants altering circulating HDL cholesterol concentrations have provided evidence that higher total HDL cholesterol concentrations are unlikely to reduce the risk of coronary artery disease, independently of any effects on LDL cholesterol or triglycerides.6Do R Willer CJ Schmidt EM et al.Common variants associated with plasma triglycerides and risk for coronary artery disease.Nature Genet. 2013; 45: 1345-1352Crossref PubMed Scopus (646) Google Scholar, 7Voight BF Peloso GM Orho-Melander M et al.Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580Summary Full Text Full Text PDF PubMed Scopus (1736) Google Scholar Of more direct relevance to the debate on statins, common genetic variants that alter LDL cholesterol concentrations are also associated with coronary artery disease.7Voight BF Peloso GM Orho-Melander M et al.Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580Summary Full Text Full Text PDF PubMed Scopus (1736) Google Scholar, 8Willer CJ Sanna S Jackson AU et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nature Genet. 2008; 40: 161-169Crossref PubMed Scopus (1346) Google Scholar The effect of common genetic variants is often subtle, but in some instances it provides great potential for improving mechanistic understanding. The genetic variants in the HMGCR gene have small effects on circulating LDL cholesterol (0·06 mmol/L) compared with other variants, which alter LDL concentrations by up to 0·36 mmol/L. Yet the variants in HMGCR provide proof of principle that genetics can be used to identify therapeutic targets. Swerdlow and colleagues1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar used their own set of 26 236 cases and 164 021 controls as well as those from published studies. The results provide an important addition to a cascade of evidence that suggests a slight on-target type 2 diabetes side-effect of statins (figure). This cascade includes individual randomised controlled trials that provided some evidence of causality, although the different statins and definitions of diabetes used made results hard to interpret.9Carter AA Gomes T Camacho X Juurlink DN Shah BR Mamdani MM Risk of incident diabetes among patients treated with statins: population based study.BMJ. 2013; 346: f2610Crossref PubMed Scopus (320) Google Scholar, 10Sattar N Taskinen MR Statins are diabetogenic—myth or reality?.Atheroscler Suppl. 2012; 13: 1-10Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar Observational associations between increased statin use and higher incidence of type 2 diabetes were consistent with the early trial data, but were probably heavily confounded by obesity and other factors.10Sattar N Taskinen MR Statins are diabetogenic—myth or reality?.Atheroscler Suppl. 2012; 13: 1-10Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar Meta-analyses of randomised controlled trials followed12Rajpathak SN Kumbhani DJ Crandall J Barzilai N Alderman M Ridker PM Statin therapy and risk of developing type 2 diabetes: a meta-analysis.Diabetes Care. 2009; 32: 1924-1929Crossref PubMed Scopus (365) Google Scholar with, for example, an analysis of ten trials11Sattar N Preiss D Murray HM et al.Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.Lancet. 2010; 375: 735-742Summary Full Text Full Text PDF PubMed Scopus (1977) Google Scholar showing an increased risk of type 2 diabetes. An analysis of intensive-dose versus moderate-dose statin treatment showed a dose–response effect, with individuals randomly assigned to intensive-dose treatment having a relative risk of 1·12 (95% CI 1·04–1·22) for diabetes compared with individuals assigned to moderate-dose treatment.13Preiss D Seshasai SR Welsh P et al.Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.JAMA. 2011; 305: 2556-2564Crossref PubMed Scopus (1174) Google Scholar However, none of these studies could establish whether or not the diabetogenic effect of statins operated through the same pathway as the lipid-lowering HMGCoA-reductase effect or an off-target effect. Swerdlow and colleagues1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar answer this question—because the genetic variant lies near HMGCR, the diabetogenic effect of statins probably operates through the same mechanism as the lipid-lowering effect. The findings imply that new types of statin that more specifically target HMGCoA-reductase would not reduce the adverse side-effect of increased risk of type 2 diabetes. There are some limitations to the study.1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar First, the subtle effects of the HMGCR variants meant that the investigators had to use large numbers of cases and controls, and the associations between the variants and type 2 diabetes are not statistically beyond reproach—more cases and controls would help confirm the findings. Second, we cannot be certain that the variants operate directly and solely through the HMGCR gene, although there is some evidence that these variants alter splicing of HMGCR transcripts.14Burkhardt R Kenny EE Lowe JK et al.Common SNPs in HMGCR in Micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.Arterioscler Thromb Vasc Biol. 2008; 28: 2078-2084Crossref PubMed Scopus (106) Google Scholar Finally, genetic studies are not completely exempt from the confounders and biases of epidemiological studies—survival and index event biases can affect genetic studies, and further work with larger numbers of incident cases would provide more reassurance that the genetic associations with type 2 diabetes are real. However, the associations with body-mass index seem to be statistically robust and provide a mechanism downstream of the HMGCoA-reductase effect (increased body-mass index leading to increased insulin resistance, and to increased diabetes). In summary, Swerdlow and colleagues1Swerdlow DI Preiss D Kuchenbaecker KB et al.HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.Lancet. 2014; (published online Sept 24.)http://dx.doi.org/10.1016/S0140-6736(14)61183-1PubMed Google Scholar have used naturally occurring human genetic variation to provide another piece of evidence about the side-effects of statins, but have not cast any doubt on the evidence that the benefits of statins vastly outweigh their risks. I have consulted for Boehringer Ingelheim. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trialsThe increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. Full-Text PDF Open Access