Metformin or lifestyle changes initiated for diabetes prevention may not reduce risk of AMD: JAMA

The Diabetes Prevention Program Outcomes Study (DPPOS) is a follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (DPP), to investigate the effects of treatment with metformin or an intensive lifestyle modification (lifestyle) compared with placebo on preventing the onset of type 2 diabetes in a population at high-risk of developing diabetes. As per the DPP protocol, eligibility criteria included age 25 years or older, a body mass index of 24 or higher, and a plasma glucose concentration of 95 to 125mg/dL in the fasting state and 140 to 199 mg/dL 2 hours after a 75-g oral glucose load. As part of an annual follow-up visit at year 16 of DPPOS, retinal images were acquired and AMD was evaluated. The DPPOS provides a unique opportunity to study the association of metformin and lifestyle changes with preventing or delaying the development of AMD.

The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years post trial were included. Analysis took place between October 2019 and May 2022. S Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.

Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (P = .02).

In the DPPOS, there was no difference in AMD presence or severity between metformin, intensive lifestyle intervention, and placebo arms at median time of 21 years since randomization. Using masked reading center interpretation of images, the DPPOS cohort is unique in its ability to examine the role of metformin in protecting against development of AMD due to both the randomization intervention arm and the duration of follow-up with known exposure to metformin. In addition, authors assessed associations of metformin use with AMD severity. Authors found no association of metformin use with the presence or severity of AMD, nor did they find an association between any use of metformin or number of years of metformin with AMD. Lastly, they found no association between in-study and out-of study metformin use and AMD.

To summarize, in the DPPOS cohort with 1592 participants randomized to metformin for over 20 years, there was no association between metformin use and prevalence of AMD. There was also no association with stages of AMD classified from multimodal imaging, nor was there an association with duration of metformin use. Until randomized data are available, the DPPOS provides strong evidence that does not support the use of metformin in the treatment of any stage of AMD.

Source: Amitha Domalpally, Samuel A. Whittier, Qing Pan; JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2022.5567