Diabetes Prevention Program Outcomes Study Research Articles

The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study

ObjectiveDysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet β-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. Research design and methodsIResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. ResultsHigher IResp was associated with poorer performance on the DSST (−0.69 points per 100 unit increase in IGI, 95 % CI: −1.37, −0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. ConclusionsThese results suggest that a greater β-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

Prevalence and predictors of female sexual dysfunction among sexually active women in the diabetes prevention program outcomes study.

To determine the burden and identify correlates of female sexual dysfunction (FSD) among women with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). The DPPOS visit included the Female Sexual Function Index (FSFI) to determine sexual function. Of 1464 participants, 1320 (90%) completed the (FSFI) and 426 were sexually active. A backward selection multivariable logistic regression model estimated the odds of FSD for sociodemographic, clinical, and diabetes-related covariates. One hundred and eighty-five(43%) had a score of ≤26.55 and met the criteria for FSD. After adjustment for DPP treatment and age, urinary incontinence (UI) (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.15-3.17) and hysterectomy (OR = 1.89, 95%CI = 1.01-3.53) were associated with increased odds of FSD. Increased body mass index was protective for FSD (OR = 0.93 per kg/m2, 95%CI = 0.89-0.96). Michigan Neuropathy Screening Instrument-based peripheral neuropathy (mean±SD scores 1.1±1.3 vs. 0.9±1.1, p < 0.0001) and Electrocardiogram (ECG)-based autonomic dysfunction measures (mean ± SD heart rate levels 64.3 ± 6.8 vs. 65.6 ± 10.2, p = 0.008) were associated with FSD. There were no differences in diabetes rates between women who did (66.5%) and did not (66%) have (p = 0.7). FSD is prevalent in women with PreD and T2D. Our findings suggest that FSD is associated with neuropathic complications commonly observed in PreD and T2D.

Prevalence and predictors of erectile dysfunction among men in the diabetes prevention program outcomes study

ObjectiveTo determine burden and identify correlates of erectile dysfunction (ED) among men with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). Research design and methodsThe 2017 DPPOS visit included administration of the International Index of Erectile Function. Of 648 male participants, 88 % (n = 568) completed the survey. Associations between sociodemographic, behavioral, clinical, and glycemic measures at time of ED assessment, and ED were examined using multivariable logistic regression models in men with PreD and T2D separately. ResultsOverall, 218 (38 %) men met ED criteria. Prevalence was similar in men with PreD (41 %) and T2D (37 %) (p = 0.4). In all men, age (p < 0.001) increased odds of ED. Among men with PreD, those assigned to intensive lifestyle intervention (ILS), but not metformin, had decreased odds of ED compared with the placebo group (OR = 0.35, 95 % CI = 0.13, 0.94). Non-Hispanic White race was associated with increased odds of ED compared with other races (OR = 4.3; 95 % CI = 1.92, 9.65). Among men with T2D, ED risk did not differ by DPP treatment assignment; however, individuals with metabolic syndrome defined by National Cholesterol Education Program criteria, had increased odds of ED (OR = 1.85, 95 % CI = 1.14, 3.01), as did individuals with depression (OR = 2.05; 95 % CI = 1.10, 3.79). ConclusionsED is prevalent in men with PreD and T2D. Our finding of reduced odds of ED in men randomized to ILS and with PreD suggests a potential opportunity for risk mitigation in the prediabetes interval. In men who have progressed to T2D, metabolic factors appear to be associated with ED.

Effects of metformin and intensive lifestyle interventions on the incidence of kidney disease in adults in the DPP/DPPOS

AimsWe analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). MethodsThe current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). ResultsAt a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. ConclusionsDevelopment of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. Clinical trial registrationsDiabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727

342-OR: The Impact of Insulin Secretion and Insulin Sensitivity on Cognition in Adults with Prediabetes—The Diabetes Prevention Program Outcomes Study (DPPOS)

Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant of dysglycemia, impaired insulin sensitivity (ISens) or insulin secretion (ISecr), or both, contributes to poorer cognitive function is not established. Among 1,054 adults with prediabetes (PreD) from the DPPOS, who did not develop diabetes, we investigated the relationship between ISecr, ISens and cognitive function, hypothesizing that lower ISens and/or lower ISecr is associated with worse cognition. Early ISecr was estimated by the mean insulinogenic index (IGI; pmol/mmol) from repeated annual oral glucose tolerance tests and ISens was estimated by the mean 1/fasting insulin from repeated fasting blood draws. ISecr and ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and processing speed (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Separate linear regression models were run for each cognitive outcome. Models included both mean ISecr and mean ISens as the main predictor variables and were adjusted for demographic, lifestyle, cardiovascular factors, and medications. Contrary to our hypothesis and to prior studies, higher mean ISecr was associated with poorer performance on the DSST (-0.74 points per SD increase in IGI, 95% CI: -1.43, -0.05; p=0.03). Mean ISens was not associated with DSST, nor were mean ISecr or mean ISens associated with SEVLT. These results suggest that higher insulin secretion in people with longstanding PreD may negatively impact processing speed, a critical component of executive control. This relationship could reflect a compensatory response of insulin in people with worsening metabolic dysregulation, who may also have poorer cognition. Further study is needed to replicate these findings and to understand the role of insulin in cognitive function. Disclosure A. Shapiro: None. A.H. Tjaden: None. S. Edelstein: None. S.E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc. Other Relationship; Novo Nordisk. P. Srikanthan: None. W.C. Knowler: None. E.M. Venditti: None. S. Golden: Advisory Panel; Abbott Diabetes, Medtronic. O. Carmichael: Research Support; Eli Lilly and Company. Advisory Panel; Novo Nordisk. Research Support; Nestlé Health Science. K.M. Gadde: Research Support; BioKier, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. J.A. Luchsinger: Consultant; Merck KGaA. Other Relationship; Wolters Kluwer Health. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)

320-OR: ADA Presidents' Select Abstract: Risk Factors for Distal Symmetrical Polyneuropathy (DSPN) in the Diabetes Prevention Program (DPP) and the DPP Outcomes Study (DPPOS)

Objective: To evaluate how DSPN differs across the randomized DPP treatment groups and is associated with diabetes (DM) status, DM duration, and cumulative glycemic exposure. Methods: In the DPP, adults ≥25 years of age at high risk for DM (n=3234) were randomized to determine the effects of intensive lifestyle modification (ILS) or metformin (MET) compared to placebo (PLA) on incident diabetes. After DPP ended, participants were invited to join the DPPOS during which metformin was continued in those randomized to receive it. DSPN was rigorously assessed in 1,792 participants at DPPOS year 17 based on both symptoms and signs (pinprick, vibration, and monofilament). Multivariable logistic regression models were used to determine whether DSPN was associated with randomized treatment group, DM status and duration, and cumulative glycemic exposure. Results: At 21 years following DPP randomization, 66% had developed DM with median duration of 15 years. The prevalence of DSPN did not differ by DPP treatment group (21.5%, 21.5% and 21.9% in ILS, MET and PLA, respectively), but was slightly lower for those at risk for DM (19.6%) vs. those with DM (22.7%). There was a significant effect modification by age of the association between DPP treatment group and DSPN (p&amp;lt;0.05): the odds ratio (OR) for DSPN with ILS vs PLA decreased by 3.7% (95% CI 0.6-6.7) with each 1 year increase in age. MET vs. PLA was not associated with DSPN and age did not influence the null association. In models adjusted for treatment group, demographics, cardiometabolic risks, and low vitamin B12 or B12 supplement use, DSPN was associated with DM status (OR 1.40, p&amp;lt;0.001 vs. no DM), greater DM duration (OR 1.04 per 1 year, p&amp;lt;0.001), and higher time-weighted HbA1c (OR 1.85 per 1% increase, p&amp;lt;0.001). Conclusions: The likelihood of DSPN was higher for those with DM, longer DM duration, and higher cumulative glycemic exposure. Although ILS did not prevent DSPN overall, there were ILS benefits with increasing age. Disclosure C.Lee: Employee; Pfizer Inc. N.White: None. W.H.Herman: Advisory Panel; National Committee for Quality Assurance, Consultant; Merck Sharp &amp; Dohme Corp., Other Relationship; National Institutes of Health, American Diabetes Association. D.Research group: None. A.Ciarleglio: None. S.Edelstein: None. J.P.Crandall: Research Support; Abbott Diabetes. D.Dabelea: None. R.B.Goldberg: None. S.E.Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Other Relationship; Novo Nordisk. W.C.Knowler: None. M.Ma: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)

732-P: Biomarkers of Inflammation and Long-Term Microvasculature Integrity in Weight Loss–Induced Prediabetes Remission

The Diabetes Prevention Program Outcomes Study demonstrated that even temporary resolution of prediabetes (remission) to normal glucose regulation (NGR) prevents development of T2D and vascular complications. However, cellular mechanisms are unknown. We have previously shown in the Prediabetes Lifestyle Intervention Study, a German Center for Diabetes Research multicenter study (n = 1105), that lifestyle intervention (LI)-mediated weight loss-induced remission of prediabetes to NGR vs. non-remission is largely driven by improved insulin sensitivity. We hypothesized that these two groups differ by markers of chronic low-grade inflammation. Therefore, we analyzed 31 cytokines implicated in energy metabolism and T2D complications before and after LI in subjects losing ≥5% body weight (n = 113) to compare responders achieving NGR (R, n = 40) to non-responders not achieving NGR (NR, n = 73). Cytokines linked to insulin resistance and T2D such as TNF-α (p = 0.73), IFNγ (p = 0.45) and IL-6 (p = 0.34) did not differ between groups. However, responders showed a significantly stronger reduction of lymphotoxin α (LTα, -0.15 ± 0.29-fold in NR vs. -0.23 ± 0.32 in R, p = 0.02). VCAM (-0.04 ± 0.14 NR vs. -0.08 ±10.9 R, p = 0.02) and ICAM (-0.11 ±0.15 NR vs. -0.16 ± 0.14 R, p = 0.02), which are induced by LTα and have been implied in mediating cardiovascular complications, were also more strongly reduced in responders. To assess if this is linked with long-term microvasculature integrity, we applied optoacoustic mesoscopy up to 5 years after LI (n = 22). Total vessel and junction density and number of junction to endpoint branches (NJEB) were higher in responders at follow-up (NJEB: 154.9 ± 25.3 vs. 186.9 ± 16.1, p &amp;lt; 0.01). These data describe a distinct pattern of reduced low-grade inflammation characterizing remission of prediabetes to NGR. Although limited by low n, this pattern may help explain the positive effects of prediabetes remission on vascular complications. Disclosure A.Sandforth: None. J.Szendroedi: None. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. L.Fritsche: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.L.Birkenfeld: None. S.Katzenstein: None. J.Seissler: None. S.R.Bornstein: None. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. S.Kabisch: Other Relationship; Berlin-Chemie AG, Sanofi, Lilly, Boehringer Ingelheim Inc., JuZo Akademie, Research Support; J. Rettenmaier / Söhne, Wilhelm-Doerenkamp Foundation, German Center of Diabetes Research. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. H.Häring: None. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH.

MP45-11 FEMALE SEXUAL DYSFUNCTION AND TYPE 2 DIABETES: RESULTS FROM THE DIABETES PREVENTION PROGRAM OUTCOMES STUDY (DPPOS)

You have accessJournal of UrologyCME1 Apr 2023MP45-11 FEMALE SEXUAL DYSFUNCTION AND TYPE 2 DIABETES: RESULTS FROM THE DIABETES PREVENTION PROGRAM OUTCOMES STUDY (DPPOS) Priyanka Gupta, Lindsay Doherty, Marinella Temprosa, Hunter Wessells, Rodica Pop-Busui, Kishore Gadde, Arthur H. Owora, Aruna V. Sarma, and DPP Research Group Priyanka GuptaPriyanka Gupta More articles by this author , Lindsay DohertyLindsay Doherty More articles by this author , Marinella TemprosaMarinella Temprosa More articles by this author , Hunter WessellsHunter Wessells More articles by this author , Rodica Pop-BusuiRodica Pop-Busui More articles by this author , Kishore GaddeKishore Gadde More articles by this author , Arthur H. OworaArthur H. Owora More articles by this author , Aruna V. SarmaAruna V. Sarma More articles by this author , and DPP Research Group More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003291.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Female sexual dysfunction (FSD) has been reported to be more common in women with T2D. However, detailed risk profiles are lacking. We sought to determine the burden and correlates of FSD in a well characterized cohort of women with Prediabetes (PreD) and T2D enrolled in the DPPOS. METHODS: Between 1996-1999, 3,234 adults with PreD were randomized to intensive lifestyle intervention, masked metformin, or placebo in the DPP. In 2001, open-label metformin was continued for those originally randomized to it and modified lifestyle intervention offered to all. In 2016-2017, 1320 of 1464 participants completed the Female Sexual Function Index (FSFI). 426 women were sexually active and included in the current report. FSD was defined as FSFI≥26.55. A backwards selection multivariable logistic regression model estimated odds of FSD for sociodemographic, clinical, and diabetes-related covariates significant in bivariate analysis. RESULTS: Overall, 185 (43%) women met the criteria for FSD. After adjustment for treatment arm, age and race, depression (defined by the Beck Depression inventory or antidepressant use) and weekly urinary incontinence were both associated with over a two-fold (OR=2.81, 95%CI=1.57, 5.02; and OR=2.14, 95%CI=1.31, 3.51) increase in odds of FSD, respectively. Women who reported hysterectomy were 1.95 times more likely (95%CI=1.07, 3.54) to report FSD. Mean study BMI was slightly protective for FSD (OR=0.93, 95%CI=0.89, 0.96). Neither DPP treatment group nor any diabetes-related factors were associated with FSD. CONCLUSIONS: FSD is highly prevalent in this population of women with PreD and T2D. Our findings suggest that FSD in this cohort is most strongly associated with depression. The lack of association between any measures of diabetes or glycemic control suggests that the sexual response in women is more likely to be affected by psychosocial aspects than by metabolic control or complications of diabetes. Source of Funding: National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e625 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Priyanka Gupta More articles by this author Lindsay Doherty More articles by this author Marinella Temprosa More articles by this author Hunter Wessells More articles by this author Rodica Pop-Busui More articles by this author Kishore Gadde More articles by this author Arthur H. Owora More articles by this author Aruna V. Sarma More articles by this author DPP Research Group More articles by this author Expand All Advertisement PDF downloadLoading ...

PD26-08 ERECTILE DYSFUNCTION IN MEN WITH PREDIABETES AND TYPE 2 DIABETES: THE DIABETES PREVENTION PROGRAM OUTCOMES STUDY (DPPOS)

You have accessJournal of UrologyCME1 Apr 2023PD26-08 ERECTILE DYSFUNCTION IN MEN WITH PREDIABETES AND TYPE 2 DIABETES: THE DIABETES PREVENTION PROGRAM OUTCOMES STUDY (DPPOS) Yooni Blair, Lindsay Doherty, Marinella Temprosa, Hunter Wessells, Rodica Pop-Busui, Kishore Gadde, Prachi Singh, Aruna V. Sarma, and DPP Research Group Yooni BlairYooni Blair More articles by this author , Lindsay DohertyLindsay Doherty More articles by this author , Marinella TemprosaMarinella Temprosa More articles by this author , Hunter WessellsHunter Wessells More articles by this author , Rodica Pop-BusuiRodica Pop-Busui More articles by this author , Kishore GaddeKishore Gadde More articles by this author , Prachi SinghPrachi Singh More articles by this author , Aruna V. SarmaAruna V. Sarma More articles by this author , and DPP Research Group More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003304.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Erectile dysfunction (ED) is more common and less responsive to pharmacotherapy in men with T2D. Data in men with prediabetes (PreD) and risk profiles in those with T2D, are lacking. We determined the burden and risk factors for ED in men with PreD and with T2D enrolled in the DPPOS. METHODS: Between 1996-1999, 3,234 adults with PreD were randomized to intensive lifestyle intervention, metformin, or placebo in the DPP. In 2001, metformin was continued for those originally randomized with modified lifestyle intervention offered to all. In 2016-2017, 568 (88%) of 648 male participants completed the International Index of Erectile Function (IIEF). ED was defined as having low or very low confidence getting and keeping an erection and/or ED medication use. Backwards selection multivariable logistic regression models including DPP treatment estimated odds of ED for covariates significant in bivariate analysis in men with persistent PreD and T2D. RESULTS: Overall, 218 (38%) men met ED criteria. Prevalence of ED was similar in men with PreD (41%) and T2D (37%) (p=0.4). In all men, older age (p<0.001), non-white race (p<0.001) and depression (defined by Beck Depression Inventory or antidepressant use) (p<0.01) were associated with ED. Among men with PreD, those assigned to intensive lifestyle intervention, but not metformin, had decreased odds of ED compared with the placebo group (OR=0.26, 95% CI=0.09, 0.77). Among men with T2D, metabolic syndrome (MetS), defined by NCEP ATP III criteria, was associated with increased odds of ED (OR=1.72, 95% CI=1.05, 2.83). CONCLUSIONS: ED is highly prevalent in men with PreD and with T2D. In addition to demonstrated factors typically observed in the general population such as younger age and absence of depression, intensive lifestyle intervention was protective in men at increased risk for T2D. In men with T2D, ED was associated with MetS. Our findings suggest metabolic mechanisms contribute to the pathogenesis of ED in T2D. Source of Funding: National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e738 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yooni Blair More articles by this author Lindsay Doherty More articles by this author Marinella Temprosa More articles by this author Hunter Wessells More articles by this author Rodica Pop-Busui More articles by this author Kishore Gadde More articles by this author Prachi Singh More articles by this author Aruna V. Sarma More articles by this author DPP Research Group More articles by this author Expand All Advertisement PDF downloadLoading ...

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

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. To investigate the association between metformin use and age-related macular degeneration (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 posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Prevalence of AMD in the treatment arms. 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). 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.

LBODP056 Factors That Associate With Under-diagnosing Prediabetes In Primary Care: A Retrospective Study

Abstract Diabetes is the leading risk factor for cardiovascular diseases and other comorbidities that significantly reduce the quality of life. Prediabetes is the preceding condition that increases the risk of Type 2 Diabetes Mellitus (T2DM). The Diabetes Prevention Program Outcomes Study (2002-2014) shows that regression from prediabetes to normoglycemic level is associated with a reduction in cardiovascular risk, while such reduction going from diabetes to normal glucose was not statistically significant. As such, it is critical that patients are screened, diagnosed, and counseled for the treatment of prediabetes. This study investigates how well a large hospital system in suburban San Diego, California diagnoses prediabetes and determines if patient demographics could help explain the missed diagnoses. Patient records from five outpatient clinics under Scripps Health who qualified for the diagnosis of prediabetes determined from either more than one fasting blood glucose (FBG) 100-125 mg/dL, or Hemoglobin A1c (HbA1c) 5.7-6.4% between 2018-2020 were reviewed. Factors such as age, race, sex, body mass index (adjusted for different races), and comorbidities were compared between the correctly diagnosed and missed diagnosed. Only 37% of the qualifying patients were diagnosed with prediabetes or impaired fasting blood glucose; of these patients 93% qualified by HbA1c. Of the factors reviewed, overweight and obesity, female sex, Asian race, comorbidities including lipid disorders, and conditions requiring systemic steroids are positively correlated with a correct diagnosis of prediabetes. Factors like male sex, Black/African American race, comorbidities requiring immunosuppressants, antineoplastics, and iron replacements are negatively correlated with a correct diagnosis. This study demonstrates that prediabetes was grossly underdiagnosed, and the diagnosis seems to be made primarily by HbA1c. These data suggest that the convenience of HbA1c and patients’ BMI, race, gender and comorbidities play a role in healthcare providers’ screening for and making the diagnosis of prediabetes. Presentation: No date and time listed

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)

BackgroundThe 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).MethodsThe 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.ResultsScores 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.ConclusionsScore 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 registrationDiabetes Prevention Program: NCT00004992; Diabetes Prevention Program Outcomes Study: NCT00038727

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

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). 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. 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). 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.

87-OR: Female Sexual Dysfunction and Type 2 Diabetes: Results from the Diabetes Prevention Program Outcomes Study (DPPOS)

Introduction and Objective: Female sexual dysfunction (FSD) has been reported to be more common in women with T2D. However, detailed risk profiles are lacking. We sought to determine the burden and correlates of FSD in a well characterized cohort of women with Prediabetes (PreD) and T2D enrolled in the DPPOS. Methods: Between 1996-1999, 3,234 adults with PreD were randomized to intensive lifestyle intervention, masked metformin, or placebo in the DPP. In 2001, open-label metformin was continued for those originally randomized to it and modified lifestyle intervention offered to all. In 2016-2017, 1320 of 1464 participants completed the Female Sexual Function Index (FSFI) . 426 women were sexually active and included in the current report. FSD was defined as FSFI≥26.55. A backwards selection multivariable logistic regression model estimated odds of FSD for sociodemographic, clinical, and diabetes-related covariates significant in bivariate analysis. Results: Overall, 185 (43%) women met the criteria for FSD. After adjustment for treatment arm, age and race, depression (defined by the Beck Depression inventory or antidepressant use) and weekly urinary incontinence were both associated with over a two-fold (OR=2.81, 95%CI=1.57, 5.02; and OR=2.14, 95%CI=1.31, 3.51) increase in odds of FSD, respectively. Women who reported hysterectomy were 1.95 times more likely (95%CI=1.07, 3.54) to report FSD. Mean study BMI was slightly protective for FSD (OR=0.93, 95%CI=0.89, 0.96) . Neither DPP treatment group nor any diabetes-related factors were associated with FSD. Conclusions: FSD is highly prevalent in this population of women with PreD and T2D. Our findings suggest that FSD in this cohort is most strongly associated with depression. The lack of association between any measures of diabetes or glycemic control suggests that the sexual response in women is more likely to be affected by psychosocial aspects than by metabolic control or complications of diabetes. Disclosure P.Gupta: Consultant; Inspire . L.Doherty: None. M.Temprosa: None. H.Wessells: None. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. K.M.Gadde: Research Support; AstraZeneca, BioKier, Inc. A.H.Owora: None. A.V.Sarma: None. D.Research group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400)

1119-P: Persistent and Heterogeneous Long-Term Effects of the Diabetes Prevention Program (DPP) Intensive Lifestyle (ILS) Intervention on Diabetes Incidence

During the three years of the DPP, ILS reduced incidence of diabetes compared with placebo in high-risk adults. Diabetes was defined using ADA criteria based on 1) annual OGTT or semi-annual fasting glucose (the primary DPP outcome, diab-G, hazard ratio (HR) =0.42 and rate difference (RD) = -6.2 cases/100 person-years) or 2) annual HbA1c ≥ 6.5% (diab‑A1C, HR=0.51 and RD = -4.2) . After DPP ended, participants were unmasked, placebo was discontinued, and all participants were offered group-based ILS and followed in the DPP Outcomes Study. We now compare the original ILS and placebo groups over a mean of 21 years since randomization. We test heterogeneity across subgroups defined by demographics and baseline glucose, HbA1c, BMI, and history of gestational diabetes and express it by interaction p-values (P-het) . During the total follow-up, ILS, compared with placebo, significantly reduced incidence of diab‑G: HR=0.76 (95% CI=0.68, 0.85) , RD= -1.62 (-2.28, -0.97) and of diab-A1C: HR=0.80 (0.70, 0.92) , RD= -1.67 (‑2.24, -1.10) . Effects on diab-G were homogenous across subgroups except for fasting glucose (P-het &amp;lt;0.01) and HbA1c (P-het &amp;lt;0.02) with greater effects at higher baseline values. By contrast, ILS reduced incidence of diab-A1C more in older than younger persons (P-het &amp;lt;0.02) , and more in men than women (P-het &amp;lt;0.03) . Notably, ILS was highly effective in reducing incidence of diab‑A1C if baseline HbA1c was already elevated (HbA1c=6.0-6.4%: HR=0.62, RD= -3.27) but ineffective if baseline HbA1c was normal by ADA criteria (HbA1c &amp;lt;5.7%: HR=1.09, RD= +0.19; P-het &amp;lt;0.001) . In sum, ILS effects on reducing incidence of diab-G and diab-A1C persisted but decreased during total follow-up from that observed during DPP (i.e., HRs and RDs closer to 1 and 0) . ILS effects on diab-G were greater in those with higher baseline fasting glucose or HbA1c. Effects on diab-A1C were greater in men, older participants, and those with higher baseline HbA1c. Disclosure W.C. Knowler: None. S. Edelstein: None. P.H. Bennett: Stock/Shareholder; Baxter INTERNTN Health Care, Merck &amp; Co., Inc., UnitedHealth Group. D. Dabelea: None. M.A. Hoskin: None. S.E. Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. R. Kalyani: None. C. Kim: None. S. Raghavan: None. M. Temprosa: None. E.M. Venditti: Advisory Panel; PeopleOne Health. D.M. Nathan: None. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400)

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

OBJECTIVE 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.

Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study.

Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study). During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions. URL: https://www. gov; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

Comparison of ETDRS 7-Field to 4-Widefield Digital Imaging in the Evaluation of Diabetic Retinopathy Severity.

PurposeTo compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between two digital fundus imaging protocols for research studies of diabetic retinopathy: the gold standard 7-field (7F) imaging and the more recent 4-widefield (4W) imaging.MethodsTwo hundred twenty-two participants enrolled in the Diabetes Prevention Program Outcomes Study underwent concurrent 7F and 4W imaging. The ETDRS levels from 220 paired gradable images were determined by masked graders. Each image was graded by two independent graders with adjudication by a senior grader, if necessary. Percent agreement between graders and between imaging protocols was evaluated with kappa statistics and weighted kappa statistics.ResultsOf 220 gradable eyes, diabetic retinopathy was seen in 11.8%; this was mild in 10.4% and more than mild in 1.4% using 7F imaging. The ETDRS levels showed exact agreement of 95% between 7F and 4W imaging (weighted kappa 0.86). Intergrader agreement for each modality had exact agreement of 89% (weighted kappa of 0.73) for 7F and 91% (weighted kappa 0.77) for 4W.ConclusionsThere is substantial agreement in the ETDRS severity level between the 7F and 4W digital imaging protocols, demonstrating that the two imaging protocols are interchangeable. Both 4W and 7F digital imaging protocols can be used for assessing ETDRS levels, even in populations with minimal diabetic retinopathy.Translational RelevanceThe 4W protocol requires fewer images than the 7F, is more comfortable for the patients, is easier for photographic capture, and provides diabetic retinopathy data that is equivalent to the 7F imaging protocol.

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

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. 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. 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. 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.

Lifestyle intervention is superior to metformin in prevention of microvascular complications of diabetes in women, but socioeconomic barriers may lead to use of combination

A clinical decision report using: Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: The Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3(11):866-875. https://doi.org/10.1016/S2213-8587(15)00291-0 for a patient with pre-diabetes who is concerned about the prevention of microvascular complications through lifestyle intervention while managing her busy schedule as a traveling house cleaner.