Another benefit of the glucose-lowering medication metformin has been revealed in a new study, in which it was associated with reduced odds of venous thromboembolism (VTE) in a large primary care population of diabetes patients in England.

The analysis also showed that VTE is two to three times more common in patients with type 2 diabetes, compared with people with type 1, or those without diabetes.

The results of the retrospective cohort study were presented here at the Diabetes UK Professional Conference (DUPC) 2019 by research fellow, and study lead, William Hinton, MSc, from the University of Surrey, United Kingdom.

"Aspirin is clinically effective for VTE prophylaxis, but comes at the cost of increased risk of bleeding," remarked Hinton. "Our data suggest that metformin may provide a VTE-lowering effect of comparative magnitude in individuals with type 2 diabetes."

Strengths of the study included its very large size and the fact that data were drawn from a real-world clinical practice setting. The analysis also distinguished between the prevalence of VTE in the different diabetes types.

Anne Dornhorst, MD, from Imperial College Healthcare NHS Trust, London, UK, moderated the session and was impressed with what she saw.

"The wonders of metformin just go on and on. It is a wonder drug," she told Medscape Medical News.

"[But] we must get the message out to primary cary, if they start [metformin] too quickly and increase the dose too much, there are many people saying that they are intolerant," Dornhorst said. "We should start slowly and it doesn't matter if it takes 2 months to get someone up to a decent dose."

VTE Risk in Diabetes: The Chicken or the Egg? 

Hinton said data from previous meta-analyses have suggested that diabetes is associated with an increased risk of VTE, but this has been challenged by other research that implies any increased risk of VTE is due to confounders rather than the effects of diabetes.

"Also, many studies have not sufficiently distinguished between type 1 and type 2 diabetes, and this is important because insulin resistance has been suggested as a key component driving the prothrombotic environment," he explained.

Three main pathways exist that implicate diabetes in thrombosis: platelet activation, low grade inflammation, and hypofibrinolysis with increased levels of plasminogen activator inhibitor 1 (PAI-1 inhibitor).

 "Debate exists pertaining to whether these pathways relate to hyperglycemia, insulin resistance, or both, but evidence suggests that metformin affects these three pathways to reduce thrombosis," Hinton indicated.

The new analysis aimed to look at the prevalence of VTE according to diabetes type, as well as in people without diabetes, drawn from a national population, and also to determine the effect of metformin on VTE in the context of various risk factors for type 2 diabetes. 

Using the Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) network, data were sourced from 164 GP practices and approximately 3 million patients in a nationally representative sample. All people were identified according to medication, confirmatory blood glucose levels for diabetes, or HbA1c. In a second step, participants were identified according to type of diabetes.

VTE codes were sought for diagnoses and procedures that were consistent with pulmonary embolism or deep vein thrombosis, explained the researcher.

The prevalence of VTE in the adult population was calculated and stratified by diabetes type, or no diabetes.

Confounders such as age, sex, body mass index (BMI), smoking status, chronic kidney disease, atrial fibrillation, and HbA1c were adjusted for; in addition, treatment with aspirin, statins, metformin, SGLT2 inhibitors, and GLP-1 receptor agonists was taken into account.

Average age was around 70 years for type 2 diabetes, 44 years for type 1 diabetes, and 47 years in patients with no diabetes. BMI was a mean of 30 kg/m2 in type 2 diabetes and less in the other groups.

Of those with type 2 diabetes, 63% had ever used metformin, compared with 15% of patients with type 1 diabetes. Mean HbA1c at diagnosis was 7.8% and 9.6% in type 2 and type 1 diabetes patients, respectively.

There was a much higher proportion of VTE in the type 2 diabetes group (n = 145,069), at 5.5%, compared with the type 1 diabetes group (n = 10,707), at 1.9%, and those without diabetes (n = 2,363,765), at 1.7%.

Metformin Impacts Thrombosis but No Association Between HbA1c and VTE

There was an association with increasing age, in the form of a 3% increase in odds for VTE with each year, and for BMI there was a 4% increase in odds of nonspecific VTE for each BMI unit increase, Hinton noted.

Looking at risk factors for VTE, the analysis showed that being female [odds ratio (OR) 1.22] and being a current smoker [OR 1.24] increased the odds of VTE, as did having chronic kidney disease [OR 1.39] and atrial fibrillation [1.38], reported Hinton.

"Aspirin reduced odds of VTE, as expected, but interestingly metformin use also reduced the odds of VTE [approximately OR 0.92; p = 0.002]," he said.

Hinton's co-investigator, Martin Whyte, PhD, clinical lecturer in metabolic medicine at the University of Surrey, explained: "We were looking at HbA1c as a potential risk factor for VTE, and adjusted for HbA1c in the analysis, as this could have been a potential confounder for the finding that metformin reduced the odds of VTE."

"However, no association between HbA1c and VTE was found, and our work adds to mechanistic studies that have suggested that metformin may reduce prothrombotic tendency through a reduction of platelet activation, reducing PAI-1 and/or improving endothelial function," he told Medscape.

Hinton did caution, however, that it "remains to be determined" whether the benefit seen with metformin with regards to VTE "is a true physiologic effect or whether it relates to unmeasured confounders."

Diabetes UK Professional Conference (DUPC) 2019: Abstract A40, P339. Presented March 7, 2019.



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