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1

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Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH

Li, Josephine H. ; Brenner, Laura N. ; Kaur, Varinderpal ; [weitere]

Springer Science and Business Media LLC ; 2023

In: Diabetologia Vol. 66, No. 7 ( 2023-07), p. 1260-1272

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In: Diabetologia, Springer Science and Business Media LLC, Vol. 66, No. 7 ( 2023-07), p. 1260-1272

Materialart: Online-Ressource

ISSN: 0012-186X , 1432-0428

URL: Article

DOI: 10.1007/s00125-023-05922-7

RVK:

XA 40615

Sprache: Englisch

Verlag: Springer Science and Business Media LLC

Publikationsdatum: 2023

ZDB Id: 1458993-X

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2

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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)

Li, Josephine H. ; Perry, James A. ; Jablonski, Kathleen A. ; [weitere]

American Diabetes Association ; 2023

In: Diabetes Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172

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In: Diabetes, American Diabetes Association, Vol. 72, No. 8 ( 2023-08-01), p. 1161-1172

Kurzfassung: Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P & lt; 9 × 10−9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50] ; P = 2.8 × 10−12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = −7.55 [95% CI −9.88, −5.22]; P = 3.2 × 10−10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) & lt; 1.0 × 10−4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.

Materialart: Online-Ressource

ISSN: 0012-1797

URL: Article

DOI: 10.2337/db22-0702

Sprache: Englisch

Verlag: American Diabetes Association

Publikationsdatum: 2023

ZDB Id: 1501252-9

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3

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The Effect of Interventions to Prevent Type 2 Diabetes on the Development of Diabetic Retinopathy: The DPP/DPPOS Experience

White, Neil H. ; Pan, Qing ; Knowler, William C. ; [weitere]

American Diabetes Association ; 2022

In: Diabetes Care Vol. 45, No. 7 ( 2022-07-07), p. 1640-1646

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In: Diabetes Care, American Diabetes Association, Vol. 45, No. 7 ( 2022-07-07), p. 1640-1646

Kurzfassung: To determine whether interventions that slow or prevent the development of type 2 diabetes in those at risk reduce the subsequent prevalence of diabetic retinopathy. RESEARCH DESIGN AND METHODS The Diabetes Prevention Program (DPP) randomized subjects at risk for developing type 2 diabetes because of overweight/obesity and dysglycemia to metformin (MET), intensive lifestyle intervention (ILS), or placebo (PLB) to assess the prevention of diabetes. During the DPP and DPP Outcome Study (DPPOS), we performed fundus photography over time on study participants, regardless of their diabetes status. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study grading system, with diabetic retinopathy defined as typical lesions of diabetic retinopathy (microaneurysms, exudates, or hemorrhage, or worse) in either eye. RESULTS Despite reduced progression to diabetes in the ILS and MET groups compared with PLB, there was no difference in the prevalence of diabetic retinopathy between treatment groups after 1, 5, 11, or 16 years of follow-up. No treatment group differences in retinopathy were found within prespecified subgroups (baseline age, sex, race/ethnicity, baseline BMI). In addition, there was no difference in the prevalence of diabetic retinopathy between those exposed to metformin and those not exposed to metformin, regardless of treatment group assignment. CONCLUSIONS Interventions that delay or prevent the onset of type 2 diabetes in overweight/obese subjects with dysglycemia who are at risk for diabetes do not reduce the development of diabetic retinopathy for up to 20 years.

Materialart: Online-Ressource

ISSN: 0149-5992

URL: Article

DOI: 10.2337/dc21-2417

Sprache: Englisch

Verlag: American Diabetes Association

Publikationsdatum: 2022

ZDB Id: 1490520-6

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4

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Association of Metformin With the Development of Age-Related Macular Degeneration

Domalpally, Amitha ; Whittier, Samuel A. ; Pan, Qing ; [weitere]

American Medical Association (AMA) ; 2023

In: JAMA Ophthalmology Vol. 141, No. 2 ( 2023-02-01), p. 140-

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In: JAMA Ophthalmology, American Medical Association (AMA), Vol. 141, No. 2 ( 2023-02-01), p. 140-

Kurzfassung: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD. Objective To investigate the association between metformin use and age-related macular degeneration (AMD). Design, Setting, and Participants 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 posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Interventions Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Main Outcomes and Measures Prevalence of AMD in the treatment arms. Results 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. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. 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 (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02). Conclusions and Relevance These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.

Materialart: Online-Ressource

ISSN: 2168-6165

URL: Article

DOI: 10.1001/jamaophthalmol.2022.5567

Sprache: Englisch

Verlag: American Medical Association (AMA)

Publikationsdatum: 2023

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5

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The Impact of Physical Activity on the Prevention of Type 2 Diabetes: Evidence and Lessons Learned From the Diabetes Prevention Program, a Long-Standing Clinical Trial Incorporating Subjective and Objective Activity Measures

Kriska, Andrea M. ; Rockette-Wagner, Bonny ; Edelstein, Sharon L. ; [weitere]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 1 ( 2021-01-01), p. 43-49

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 1 ( 2021-01-01), p. 43-49

Kurzfassung: Across the Diabetes Prevention Program (DPP) follow-up, cumulative diabetes incidence remained lower in the lifestyle compared with the placebo and metformin randomized groups and could not be explained by weight. Collection of self-reported physical activity (PA) (yearly) with cross-sectional objective PA (in follow-up) allowed for examination of PA and its long-term impact on diabetes prevention. RESEARCH DESIGN AND METHODS Yearly self-reported PA and diabetes assessment and oral glucose tolerance test results (fasting glucose semiannually) were collected for 3,232 participants with one accelerometry assessment 11–13 years after randomization (n = 1,793). Mixed models determined PA differences across treatment groups. The association between PA and diabetes incidence was examined using Cox proportional hazards models. RESULTS There was a 6% decrease (Cox proportional hazard ratio 0.94 [95% CI 0.92, 0.96]; P & lt; 0.001) in diabetes incidence per 6 MET-h/week increase in time-dependent PA for the entire cohort over an average of 12 years (controlled for age, sex, baseline PA, and weight). The effect of PA was greater (12% decrease) among participants less active at baseline ( & lt;7.5 MET-h/week) (n = 1,338) (0.88 [0.83, 0.93]; P & lt; 0.0001), with stronger findings for lifestyle participants. Lifestyle had higher cumulative PA compared with metformin or placebo (P & lt; 0.0001) and higher accelerometry total minutes per day measured during follow-up (P = 0.001 and 0.047). All associations remained significant with the addition of weight in the models. CONCLUSIONS PA was inversely related to incident diabetes in the entire cohort across the study, with cross-sectional accelerometry results supporting these findings. This highlights the importance of PA within lifestyle intervention efforts designed to prevent diabetes and urges health care providers to consider both PA and weight when counseling high-risk patients.

Materialart: Online-Ressource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc20-1129

Sprache: Englisch

Verlag: American Diabetes Association

Publikationsdatum: 2021

ZDB Id: 1490520-6

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6

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Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience

White, Neil H. ; Pan, Qing ; Knowler, William C. ; [weitere]

American Diabetes Association ; 2022

In: Diabetes Care Vol. 45, No. 11 ( 2022-11-01), p. 2653-2661

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In: Diabetes Care, American Diabetes Association, Vol. 45, No. 11 ( 2022-11-01), p. 2653-2661

Kurzfassung: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20–0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46–1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Materialart: Online-Ressource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc22-0860

Sprache: Englisch

Verlag: American Diabetes Association

Publikationsdatum: 2022

ZDB Id: 1490520-6

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7

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The 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) score and diabetes risk in the Diabetes Prevention Program Outcomes Study (DPPOS)

Shams-White, Marissa M. ; Tjaden, Ashley H. ; Edelstein, Sharon L. ; [weitere]

Springer Science and Business Media LLC ; 2022

In: BMC Nutrition Vol. 8, No. 1 ( 2022-09-21)

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In: BMC Nutrition, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2022-09-21)

Kurzfassung: The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 3rd expert report highlights up-to-date Cancer Prevention Recommendations that may reduce burdens of many chronic diseases, including diabetes. This study examined if following a lifestyle that aligns with the recommendations – assessed via the 2018 WCRF/AICR Score – was associated with lower risk of type 2 diabetes in high-risk adults participating in the Diabetes Prevention Program Outcomes Study (DPPOS). Methods The Diabetes Prevention Program (DPP) randomized adults at high risk for diabetes to receive a lifestyle intervention (ILS), metformin (MET) or a placebo (PLB) (mean: 3.2 years), with additional follow-up in DPPOS for 11 years (mean: 15 years total). 2018 WCRF/AICR Scores included seven components: body weight, physical activity, plant-based foods, fast foods, red and processed meat, sugar-sweetened beverages, and alcohol; the optional breastfeeding component was excluded. Scores ranged 0-7 points (with greater scores indicating greater alignment with the recommendations) and were estimated at years 0, 1, 5, 6, 9, and 15 ( N =3,147). Fasting glucose and HbA1c were measured every six months and oral glucose tolerance tests were performed annually. Adjusted Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were used to examine the association of both Score changes from years 0-1 and time-dependent Score changes on diabetes risk through DPP and year 15. Results Scores improved within all groups over 15 years ( p 〈 0.001); ILS Scores improved more than MET or PLB Scores after 1 year ( p 〈 0.001). For every 1-unit improvement from years 0-1, there was a 31% and 15% lower diabetes risk in ILS (95% CI: 0.56-0.84) and PLB (95% CI: 0.72-0.97) through DPP, and no significant association in MET. Associations were greatest among American Indian participants, followed by non-Hispanic White and Hispanic participants. Score changes from years 0-1 and time-dependent Score changes in ILS and PLB remained associated with lower risk through year 15. Conclusions Score improvements were associated with long-term, lower diabetes risk among high-risk adults randomized to ILS and PLB, but not MET. Future research should explore impact of the Score on cancer risk. Trial registration Diabetes Prevention Program: NCT00004992 ; Diabetes Prevention Program Outcomes Study: NCT00038727

Materialart: Online-Ressource

ISSN: 2055-0928

URL: Article

DOI: 10.1186/s40795-022-00596-7

Sprache: Englisch

Verlag: Springer Science and Business Media LLC

Publikationsdatum: 2022

ZDB Id: 2809847-X

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8

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Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

Lee, Christine G. ; Heckman-Stoddard, Brandy ; Dabelea, Dana ; [weitere]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 12 ( 2021-12-01), p. 2775-2782

Kurzfassung: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS Over a median of 21 years (interquartile range 20–21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52] ), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28] ), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81] ) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.

Materialart: Online-Ressource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc21-1046

Sprache: Englisch

Verlag: American Diabetes Association

Publikationsdatum: 2021

ZDB Id: 1490520-6

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