Do statins really cause diabetes?

Statins are often prescribed to people with diabetes to reduce their risk of cardiovascular disease. But some clinical trials have reported cases of new-onset diabetes among statin users. Dr Susan Aldridge reports on discussions of this key safety issue at the recent American Diabetes Association Scientific Sessions.

Since 1994, there have been many randomised clinical trials of statins and the newer low-density lipoprotein (LDL)-lowering drugs, such as PCSK9 inhibitors and inclisiran. “Summing these up, even a modest dose will reduce LDL by one point and the risk of cardiovascular disease by 25% and, if you intensify the dose, you can reduce this risk even further,” says Professor David Preiss of the University of Oxford. “So, even though we’re going to talk about new-onset diabetes and statins, we don’t want to detract from their benefits.”

It was the JUPITER trial of rosuvastatin in 2008 that first revealed a potential diabetes risk with statins – with 270 new cases in the intervention group compared with 216 on placebo. David worked with Naveed Sattar in Glasgow to investigate this and they published three meta-analyses, going back to the researchers in 13 statin trials, and they did find some evidence of increased new-onset diabetes risk. They were left with multiple questions, however. Is this a real risk, and what is the mechanism? Is it a modest increase in glycaemia, tipping someone in prediabetes over the edge? And, importantly, is it clinically significant?  

“The world of statin therapy can be like a random news generator,” says David. “Once we published our analysis, lots of other papers appeared which exaggerated the risk. These exaggerated the effect, were not randomised or had other flaws. For instance, one meta-analysis suggested a 44% increased risk of new-onset diabetes, which is four times greater than what we observed.” However, one study used HMGCR (3-hydroxy-3-methylglutaryl-coenzyme-A) as a proxy for statin therapy, showing an increase in diabetes. Given that HMGCR inhibition is the target for statins, this makes these findings rather more credible.

What is the mechanism?

There is weight gain in some people on statins, but it’s not clear if this plays a role in new-onset diabetes. There may also be an increase in insulin resistance in liver or muscle, or a decrease in beta cell function. Another possible mechanism may involve the upregulation of the LDL receptor in hepatocytes and probably also in the pancreas. 

Could there be a genetic influence? The genetic disorder familial hypercholesterolaemia (FH) represents the opposite of the effect of statin therapy, in that LDL levels are abnormally high. The Netherlands is a world leader in FH and researchers there looked at diabetes prevalence and found it was lower in FH, at 1.75% versus 2.93% in unaffected relatives. “This is an intriguing additional thread to the story,” says David.  

The blame game

There were a number of issues with the data in the trials that showed a link with statins and new-onset diabetes. Non-standard criteria were used to diagnose diabetes, for instance, and there was no consistency over which diabetes adverse events were counted. There was also little information on worsening glycaemia. It’s also not clear whether some subgroups of patients are more at risk of new-onset diabetes when they take statins. “We don’t want to question the use of statins in diabetes, because they are hugely beneficial. But we really don’t know what happens to glycaemic control overall,” David says.

Statins get blamed for many things, especially in the UK, which leads to uncertainty among patients and doctors, he continues. Muscle problems are particularly highlighted but there have also been reports of depression, cognitive impairment, sleep problems and so on. 

“Statins are among the most prescribed drugs, so this is a major public health issue. We have people stopping them – or not starting – because they think they’re exposed to risk. We need to be able to give people accurate information. So we need more complete understanding of all the effects of statins, both adverse and beneficial,” David says.

A new approach to statin safety

Earlier, the Cholesterol Treatment Triallists Collaboration (CTTC) provided strong evidence of the benefit of statins in the prevention of cardiovascular disease. The Collaboration has been collecting individual patient data from trials and now has a database of 175,000 participants. This work has been influential in drawing up cardiovascular guidelines.

The current project of the CTTC is to extend this database to include all adverse events, including reasons for stopping statins. This involves data sharing in 28 statin trials. Later this year, some hard analysis can start to emerge. 

The CTTC has 38 million records, covering 1.2 million adverse events. “This gives us huge power to look at anything of interest,” says David. The current challenge is standardising the adverse events into a homogeneous format. For this, they will be looking at how new-onset and worsening diabetes is mentioned as an adverse event, whether this is in the form of glucose measurements, diagnosis, need for more medication, or diabetes complications. The findings of this new project are eagerly anticipated as they will help healthcare professionals and people with diabetes alike consider whether the risk of statins really outweigh their substantial cardiovascular benefit.

For more on the causes of type 2 diabetes, enrol on the following EASD e-Learning modules:

• Obesity and the pathogenesis and outcomes of type 2 diabetes, written and presented by Professor Naveed Sattar
• Understanding the causes of type 2 diabetes and how to achieve remission, written and presented by Professor Roy Taylor
• Insulin resistance, the metabolic syndrome and type 2 diabetes, written and presented by Professor Kåre Birkeland

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.