DPPOS: No change to cancer risk with long-term metformin use
medwireNews: Among the latest findings from the DPP Outcomes Study (DPPOS) is that long-term use of metformin does not affect the risk for cancer.
In a dedicated session at the virtual ADA 80th Scientific Sessions, the investigators also reported a persistent effect of initial treatment allocation on the risk for diabetes, and on some cardiovascular risk factors, but not on the risk for microvascular and macrovascular complications.
Presenting the cancer outcomes, Brandy Heckman-Stoddard, from the National Cancer Institute in Bethesda, Maryland, USA, noted that screening adherence was relatively high among the DPPOS participants.
During follow-up, which has now reached approximately 20 years, there were 523 cancer cases overall, mostly of the breast and prostate, among the 2779 people who continued into the DPPOS (88% of the DPP cohort). The incidence according to randomized treatment assignment in DPP was 21.5%, 19.3%, and 20.8% for placebo, metformin, and intensive lifestyle, respectively, with no significant difference between the groups. The same was true for obesity-related cancers.
In subgroup analyses, there were no differences by sex or race, but there was some (nonsignificant) evidence for a protective effect of metformin versus placebo in people who were younger than 45 years at DPP entry and for intensive lifestyle versus placebo in those aged 60 years or older.
In addition, metformin use was associated with decreased cancer risk among people who subsequently developed diabetes, when compared with placebo, with this just attaining statistical significance. However, the presenter stressed that the subgroup findings were not adjusted for multiplicity and “need to be analyzed with caution.”
Metformin was frequently prescribed outside of the original treatment group, due to people in other groups developing diabetes. But the average metformin exposure remained markedly higher among people originally assigned to it, at approximately 11 versus 2–3 years, and there were no changes to the main findings after accounting for out-of-study exposure by various methods. Metformin was continued throughout DPPOS in the group originally assigned to it, while the former placebo and lifestyle groups both received lifestyle interventions.
Lasting protective effect not extended to complications
All DPP participants were at high risk for developing diabetes, and David Nathan (Massachusetts General Hospital, Boston, USA) revealed that the previously reported pattern of reduced risk in those who received metformin or intensive lifestyle intervention has continued, at respective 18% and 25% reductions versus placebo.
The interventions delayed the onset of diabetes among participants who did develop it, with median times to onset of 12 and 14 years in the metformin and lifestyle intervention groups, compared with 9.5 years in the placebo group.
But despite this, Mark Molitch (Northwestern University Feinberg School of Medicine, Chicago, Illinois) and Ronald Goldberg (University of Miami Miller School of Medicine, Florida) reported that, overall, the original treatment assignments had no lasting effect on participants’ risk for developing microvascular or macrovascular complications.
The risks for retinopathy and nephropathy did not differ as per original treatment allocation, despite people who developed diabetes having a significantly increased risk for both outcomes.
The only treatment-related difference detected was a significant 2.96-fold increased risk for nephropathy in study participants who were aged 60 years or older and assigned to the metformin group at baseline, compared with participants of the same age who were assigned to placebo. This was driven by an increased likelihood for developing an estimated glomerular filtration rate below 45 mL/min per 1.73 m2.
However, Molitch said that this risk, which appeared only after 10 years of metformin use, was based on a small number of events and should be considered in the context of the known benefits of metformin.
Similar to microvascular outcomes, the incidence of major adverse cardiovascular events did not vary according to randomized treatment assignment. This was despite a 39% reduction in risk for people who did not develop diabetes, compared with those who did, leading Goldberg to describe the lack of treatment effect as “perplexing.”
In subgroup analyses there was some indication of a reduction in risk with metformin versus placebo for participants who were younger than 45 years at baseline, and an increased risk for women originally in the intensive lifestyle group. And for the individual outcome of stroke, there was a trend toward a reduced risk with metformin versus placebo.
Some benefits for age-sensitive outcomes
Finally, Jose Luchsinger-Stuart (Columbia University Medical Center, New York) presented findings for age-sensitive outcomes, reporting no differences in global cognition, executive function, or memory according to either treatment allocation or development of diabetes.
Despite this, the team found a cross-sectional association between higher glycated hemoglobin level and lower cognitive function at all three timepoints (study years 8, 10, and 15).
Treatment allocation was not associated with participants’ scores on the Healthy Aging Index; however, the risk for being classified as frail was significantly reduced in those who had been in the intensive lifestyle rather than the placebo group.
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