Diabetes Is On-Target Effect of Statins, Genetic Study Finds

September 25, 2014

LONDON, UK — A new analysis confirms that statin therapy is associated with a significantly increased risk of type 2 diabetes and the reason for this, according to researchers, is partially explained by genetic variants near the gene encoding the HMG-coenzyme A (HMG-CoA) reductase protein[1].

The researchers, led by Dr Daniel Swerdlow (University College London, UK) and Dr David Preiss (University of Glasgow, Scotland), also suggest a potential new mechanism for the increased risk of diabetes. Among statin-treated patients in their analysis, the alleles associated with lower LDL cholesterol and increased diabetes risk were also associated with a small but statistically significant increase in weight.

Each additional allele of one single nucleotide polymorphism (SNP), for example, was associated with an increased body weight of 0.30 kg. In the randomized trial data, statin-treated patients gained 0.24 kg, which is consistent with the genetic analysis, say researchers.

"This study has pooled all available trial data to give us the most accurate idea of the extent to which statin therapy affects diabetes risk," Preiss told heartwire . "The weight increase we found was small and not clinically relevant, but it is possible that it relates to the increased diabetes risk. Notably, the corresponding genetic results provide evidence that these findings from the major statin trials represent a mechanism-based effect."

In an editorial[2], Dr Timothy Frayling (University of Exeter Medical School, UK) says the results provide a "new angle" to the ongoing saga debating the adverse effects 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," he writes.

The results of the study and editorial are published September 24, 2014 in the Lancet.

Statins and Diabetes Risk

The association between statin use and diabetes emerged a few years ago when researchers performed a meta-analysis of some of the major statin trials. It showed a small but significant increase in the diabetes risk that was confirmed in other studies and appeared to be dose related. In 2012 the US Food and Drug Administration (FDA) mandated changes to the label of statins to warn the drugs can increase blood sugar and glycosylated hemoglobin (HbA1c) levels.

Speaking with heartwire , Swerdlow said there wasn't a lot known about the underlying mechanisms for the increased diabetes risk. The big question, he said, was whether or not the heightened diabetes risk was the result of an on- or off-target drug effect. In their study, the researchers sought to determine whether the increased risk was the result of inhibiting HMG-CoA reductase, the drug target of statin therapy.

"This led from work we and others had done looking at genetic variants lying within the genes that encode the protein target of drugs," said Swerdlow. In this case, they focused on SNPs in the HMGCR gene. In the first step of the study, they validated the SNPs—rs17238484 and rs12916—by looking at their effects on LDL-cholesterol levels so that the SNPs could serve as a proxy for statin therapy when they examined data from randomized trials.

In total, the researchers had data from 223 463 individuals participating in 43 genetic studies. Each additional allele of rs17238484-G was associated with a mean 0.06-mmol/L lower LDL-cholesterol level. Similar reductions were associated with the rs12916 SNP. In addition, they found that each additional allele of rs17238484-G was associated with a higher body weight (0.30 kg), waist circumference (0.32 cm), and plasma insulin concentration (1.62%) and plasma glucose concentration (0.23%). Again, the rs12916 SNP had similar effects.

Overall, each additional rs17238484-G allele was associated with a higher risk of diabetes (hazard ratio 1.02; 95% CI 1.00–1.05). Each rs12916-T allele also increased the risk of diabetes (hazard ratio 1.06; 95% CI 1.03–1.09).

"The purpose of the overall project was to investigate the mechanisms underlying this already-known effect of statins on diabetes," said Swerdlow. "We wanted to look at several aspects of that, so we looked at the associations between the genetic variants and LDL cholesterol and also on associations with different aspects of dysglycemia. We looked at the risk of diabetes itself but also at body weight, because we wanted to compare the effects seen in the randomized trials of statins."

When the researchers turned their attention to 129 170 individuals participating in 20 randomized trials of statin therapy, studies that included JUPITER , the Heart Protection Study (HPS), and PROVE-IT , among others, they found that statins decreased LDL-cholesterol levels 0.92 mmol/L after one year of follow-up. Compared with placebo, patients had a mean increase in body weight of 0.24 kg and a 12% increased risk of type 2 diabetes mellitus.

Shared Effect on Weight Gain, LDL Reduction

To heartwire , Swerdlow said that because the gene variants and statin therapy share the effect on body weight and diabetes, the effect of statins on body weight plays a partial role in the adverse association between the lipid-lowering drugs and the onset of new diabetes. While they can't say if the effect is exclusively on- or off-target, they can state that at least some of the diabetic risk is a direct effect of drug therapy and that this might be facilitated through increases in body weight.

In the editorial, Frayling says the results provide more evidence to suggest a "slight on-target type 2 diabetes side effect of statins." This study is the first to show that diabetogenic effect of statins likely operates through the same pathway that is used to lower LDL-cholesterol levels.

Within the clinical sphere, however, Swerdlow said that there should be no implications for changing statin prescribing. Preiss agrees.

"The risk of diabetes with statins was already known, and other studies have shown it to be very much outweighed by the cardiovascular benefit of statins, so we would definitely recommend that patients continue to take statins as recommended by their doctors and that clinicians continue to follow the national guidelines," according to Preiss. "Nothing in our study shifts that. However, it seems reasonable to emphasize that patients need to eat healthily and be as physically active as possible when on a statin. From a scientific perspective, the results suggest that further work is needed to look at the relationship between LDL cholesterol and diabetes risk."

Swerdlow and Preiss report no conflicts of interest. Frayling has consulted in the past for Boehringer Ingelheim.

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