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The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits., (© 2022. The Author(s).)

Importance: Despite rising costs and public scrutiny devoted to insulin, less is known regarding recent trends in its ambulatory use in the United States., Objective: To characterize trends in ambulatory insulin use, overall and based on insulin characteristics, among adults with type 2 diabetes in the United States from January 1, 2016, through December 31, 2020., Design, Setting, and Participants: This serial cross-sectional study included patients whose data were collected in IQVIA's National Disease and Therapeutic Index (NDTI), a 2-stage, all-payer, nationally representative audit of outpatient care. Approximately 4800 physicians each calendar quarter completed a form for 2 consecutive days regarding visits for each of their patients, including diagnoses, treatments, and demographic information. Data were collected from January 2016 through December 2020., Exposures: Ambulatory use of insulin., Main Outcomes and Measures: Nationally representative projections for ambulatory use of insulin (ie, treatment visits), overall and aggregated by insulin molecule (insulins regular, neutral protamine Hagedorn [NPH], lispro, glulisine, glargine, detemir, degludec, and aspart), delivery devices (vials/syringes or pens), therapeutic class (short-acting, rapid-acting, long-acting, intermediate-acting, and premixed insulin), insulin type (human, analog, and biosimilar), and date of approval (newer: before 2010; and older: after 2010)., Results: There were 27 860 691 insulin treatment visits between 2016 and 2020. Among all patient encounters that indicated use of insulin in 2020, 1 989 154 (43.9%) were among those aged 60 to 74 years; 2 372 629 (52.4%) among men; 2 646 247 (58.4%) among White patients; 811 639 (17.9%) among Black patients; and 701 912 (15.5%) among Hispanic patients. Insulin glargine was the most frequently used insulin from 2016 to 2020, accounting for approximately half of treatment visits (eg, 2020: 2.6 of 4.9 million visits; 95% CI, 2.1-3.1 million). Among insulin classes, long-acting insulin accounted for approximately two-thirds of treatment visits during this period (eg, 2020: 3.7 million visits; 95% CI, 3.0-4.4 million). Treatment visits for insulin pens increased from 36.1% in 2016 (2.2 of 6.0 million visits; 95% CI, 1.7-2.7 million) to 58.7% in 2020 (2.9 million visits; 95% CI, 2.3-3.5 million), while use of insulin vials/syringes declined in parallel. Analog insulin use predominated and accounted for more than 80% of total treatment visits across all years (eg, 2020: 4.3 million visits; 95% CI, 3.4-5.1 million). Newer insulins were increasingly used, from 18.1% of total treatment visits in 2016 (1.1 million visits; 95% CI, 0.8-1.4 million) to 40.9% in 2020 (2.0 million visits; 95% CI, 1.5-2.5 million). The use of biosimilar insulin, which was first approved in 2015, increased from 2.6% in 2017 (0.1 of 5.3 million visits; 95% CI, 0.04-0.2 million) to 8.2% in 2020 (0.4 million visits; 95% CI, 0.2-0.6 million) of total insulin treatment visits. The total number of insulin treatment visits declined from a peak of 6.0 million visits in 2016 to a nadir of 4.9 million visits in 2020 (approximately 18% decline)., Conclusions and Relevance: In this study, ambulatory insulin use in the United States during the past 5 years remained dominated by the use of insulin analogs and insulin pen delivery devices, with increasing uptake of newer products as they have been brought to market.

Objective: To examine trends in the noninsulin drug treatment of type 2 diabetes, including first- and second-line therapies on top of metformin, from 2015 to 2019., Participants and Methods: We conducted a descriptive analysis of cross-sectional data using the IQVIA National Disease and Therapeutic Index, a nationally representative audit of ambulatory physician practices in the United States. We focused on the use of noninsulin pharmacological treatments for type 2 diabetes among individuals aged 35 years and older between January 1, 2015 and December 31, 2019. The main outcome was type 2 diabetes visits where a prescription drug was used ("treatment visit")., Results: Ambulatory diabetes visits decreased from 30.1 million treatment visits in 2015 to 29.5 million treatment visits in 2019. Among treatment visits where a single drug was prescribed, the use of metformin declined from 57.0% of monotherapy in 2015 to 46.0% of monotherapy in 2019, while during the same period the share of monotherapy accounted for by glucagon-like peptide-1 (GLP-1) receptor agonists increased from 4.3% to 8.5% and the share accounted for by sodium-glucose cotransporter-2 (SGLT2) inhibitors increased from 7.3% to 19.5%. Among treatment visits where metformin plus another drug was prescribed, the share of second-line therapy accounted for by dipeptidyl peptidase-4 (DPP-4) inhibitors decreased from 21.9% of treatment visits in 2015 to 20.8% of treatment visits in 2019; sulphonylurea use declined from 45.2% to 32.7%, use of SGLT2 inhibitors increased from 14.5% to 21.2% and use of GLP-1 receptor agonists increased from 9.8% to 18.2%., Conclusions: Significant changes in the landscape of ambulatory care for diabetes have taken place during the past 6 years, including moderate declines in metformin monotherapy, moderate declines in second-line sulphonylurea use, and large increases in SGLT2 use. These changes underscore the dynamic nature of drug utilization for diabetes in the United States, and reflect the effects of emerging evidence, evolving clinical guidelines and evolving regulatory and payment policies., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Importance: The net benefit of aspirin for prevention of cardiovascular disease (CVD), particularly primary prevention, remains debated in people with and without diabetes. Recent studies suggest that the benefits of preventive aspirin may be outweighed by the potential for harm in older adults; therefore, it is important to monitor current aspirin use in order to minimize risk for future harm in the oldest segment of the population., Objective: To determine the prevalence of preventive aspirin use in older US adults with and without diabetes for both primary and secondary prevention by age, sex, and CVD risk category., Design, Setting, and Participants: This cross-sectional analysis used nationally representative data from the National Health and Nutrition Examination Survey from 2011 to 2018. A total of 7103 individuals 60 years or older with and without diabetes completed a questionnaire on preventive aspirin use. Statistical analyses were performed from July 1, 2019, to April 1, 2021., Main Outcomes and Measures: Preventive aspirin use was defined as participants' self-reported use of low-dose aspirin therapy based on their physician's advice or their own decision., Results: A total of 7103 individuals (mean [SD] age, 69.6 [0.1] years; 45.2% men; 75.8% White participants) were evaluated. Overall, 61.7% of older US adults with diabetes vs 42.2% without diabetes used aspirin. Among people with diabetes, in multivariable logistic models adjusting for race, sex, education, CVD risk category, and body mass index, the likelihood of aspirin use in older vs younger age categories (reference: 60-69 years) did not differ. Among people without diabetes, aspirin use was significantly greater in older age categories vs the reference (model 3, 70-79 years, odds ratio [OR], 1.50; 95% CI, 1.23-1.83; model 3, ≥80 years, OR, 1.59; 95% CI, 1.24-2.04). An estimated 9.9 million US adults 70 years or older with or without diabetes reported taking aspirin for primary prevention. The likelihood of aspirin use for primary prevention in those at high vs low risk for CVD did not differ among older adults with diabetes (model 3, OR, 1.69; 95% CI, 0.65-4.39) but was significantly higher in those without diabetes (model 3, OR, 2.46; 95% CI, 1.63-3.71). Women vs men with diabetes were less likely to be using aspirin for primary prevention (model 3, OR, 0.63; 95% CI, 0.48-0.83)., Conclusions and Relevance: This cross-sectional study found that preventive aspirin use was higher among older adults with diabetes than in those without diabetes. Results suggest that 9.9 million older US adults who previously took aspirin for primary prevention would not be recommended for its continued use, particularly among those with diabetes.

Background: Cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) in patients without cardiovascular or renal disease, a majority of newly diagnosed patients with type 2 diabetes often excluded from clinical trials on this association, is poorly understood. Thus, we investigate the risk of major adverse cardiovascular events (MACE) associated with DPP-4i in low-risk patients with diabetes., Methods: Using a new-user retrospective cohort derived from IBM MarketScan Commercial Claims and Encounters (2010-2015), we identified patients aged 35-65 with type 2 diabetes, without cardiovascular or renal disease, initiating DPP-4i, sulfonylureas, or metformin. Primary composite outcome of time to first MACE was defined as the first of any of the following: myocardial infarction, cardiac arrest, coronary artery bypass graft, coronary angioplasty, heart failure, and stroke. Secondary outcomes were time to first heart failure, acute myocardial infarction, and stroke. We compared outcomes for DPP-4i versus sulfonylurea and DPP-4i versus metformin using propensity score weighted Cox proportional hazards, adjusting for demographics, baseline comorbidities, concomitant medications, and cumulative exposure., Results: Of 445,701 individuals, 236,431 (53.0%) were male, median age was 51 (interquartile range: [44, 57]), 30,267 (6.79%) initiated DPP-4i, 52,138 (11.70%) initiated sulfonylureas, and 367,908 (82.55%) initiated metformin. After adjustment, DPP-4i was associated with lower risk of MACE than sulfonylurea (adjusted hazard ratio (aHR) = 0.87; 95% confidence interval (CI): 0.78-0.98), and similar risk to metformin (aHR = 1.07; 95% CI: 0.97-1.18). Risk for acute myocardial infarction (aHR = 0.70; 95% CI: 0.51-0.96), stroke (aHR = 0.57; 95% CI: 0.41-0.79), and heart failure (aHR = 0.57; 95% CI: 0.41-0.79) with DPP-4i was lower compared to sulfonylureas., Conclusion: Our findings show that for this cohort of low-risk patients newly treated for type 2 diabetes, DPP-4i exhibited 13% lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin, suggesting DPP-4i is a low cardiovascular risk option for low-risk patients initiating antihyperglycemic treatment., Competing Interests: Dr. Alexander is Chair of FDA’s Peripheral and Central Nervous System Advisory Committee, has served as a paid advisor to IQVIA, is a co-founding Principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, and serves on OptumRx’s National P&T Committee. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: Type 2 diabetes (T2DM) in a first-degree relative is a risk factor for incident diabetes. Americans of African ancestry (AA) have higher rates of T2DM than Americans of European ancestry (EA). Thus, we aimed to determine whether the presence, number and kinship of affected relatives are associated with race-specific T2DM incidence in a prospective study of participants from the Genetic Study of Atherosclerosis Risk (GeneSTAR), who underwent baseline screening including a detailed family history., Methods: Nondiabetic healthy siblings (n=1405) of patients with early-onset coronary artery disease (18-59 years) were enrolled (861 EA and 544 AA) and followed for incident T2DM (mean 14±6 years)., Results: Baseline age was 46.2±7.3 years and 56% were female. T2DM occurred in 12.3% of EA and 19.1% of AA. Among EA, 32.6% had ≥1 affected first-degree relatives versus 53.1% in AA, P<0.0001. In fully adjusted Cox proportional hazard analyses, any family history was related to incident T2DM in EA (HR=2.53, 95% CI: 1.58-4.06) but not in AA (HR=1.01, 0.67-1.53). The number of affected relatives conferred incremental risk of T2DM in EA with HR=1.82 (1.08-3.06), 4.83 (2.15-10.85) and 8.46 (3.09-23.91) for 1, 2, and ≥3 affected, respectively. In AA only ≥3 affected increased risk (HR=2.45, 1.44-4.19). Specific kinship patterns were associated with incident T2DM in EA but not in AA., Conclusions: The presence of any first-degree relative with T2DM does not discriminate risk in AA given the high race-specific prevalence of diabetes. Accounting for the number of affected relatives may more appropriately estimate risk for incident diabetes in both races., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Identifying reliable predictors of long-term weight loss (LTWL) could lead to improved weight management., Objective: To identify some predictors of LTWL., Design: The DPP (Diabetes Prevention Program) was a randomized controlled trial that compared weight loss with metformin, intensive lifestyle intervention (ILS), or placebo. Its Outcomes Study (DPPOS) observed patients after the masked treatment phase ended. (ClinicalTrials.gov: NCT00004992 and NCT00038727)., Setting: 27 DPP and DPPOS clinics., Participants: Of the 3234 randomly assigned participants, 1066 lost at least 5% of baseline weight in the first year and were followed for 15 years., Measurements: Treatment assignment, personal characteristics, and weight., Results: After 1 year, 289 (28.5%) participants in the metformin group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the placebo group had lost at least 5% of their weight. After the masked treatment phase ended, the mean weight loss relative to baseline that was maintained between years 6 and 15 was 6.2% (95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI, 3.1% to 4.4%) in the ILS group, and 2.8% (CI, 1.3% to 4.4%) in the placebo group. Independent predictors of LTWL included greater weight loss in the first year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and higher fasting plasma glucose levels at baseline in the placebo group., Limitation: Post hoc analysis; examination of nonrandomized subsets of randomized groups after year 1., Conclusion: Among persons with weight loss of at least 5% after 1 year, those originally randomly assigned to metformin had the greatest loss during years 6 to 15. Older age and the amount of weight initially lost were the most consistent predictors of LTWL maintenance., Primary Funding Source: National Institutes of Health.

Background: Debate over the cardiometabolic risk associated with metabolically healthy obesity (MHO) continues. Many studies have investigated this relationship by examining MHO at baseline with longitudinal follow-up, with inconsistent results., Objectives: The authors hypothesized that MHO at baseline is transient and that transition to metabolic syndrome (MetS) and duration of MetS explains heterogeneity in incident cardiovascular disease (CVD) and all-cause mortality., Methods: Among 6,809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) the authors used Cox proportional hazards and logistic regression models to investigate the joint association of obesity (≥30 kg/m 2 ) and MetS (International Diabetes Federation consensus definition) with CVD and mortality across a median of 12.2 years. We tested for interaction and conducted sensitivity analyses for a number of conditions., Results: Compared with metabolically healthy normal weight, baseline MHO was not significantly associated with incident CVD; however, almost one-half of those participants developed MetS during follow-up (unstable MHO). Those who had unstable MHO had increased odds of CVD (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.14 to 2.25), compared with those with stable MHO or healthy normal weight. Dose response for duration of MetS was significantly and linearly associated with CVD (1 visit with MetS OR: 1.62; 95% CI: 1.27 to 2.07; 2 visits, OR: 1.92; 95% CI: 1.48 to 2.49; 3+ visits, OR: 2.33; 95% CI: 1.89 to 2.87; p value for trend <0.001) and MetS mediated approximately 62% (44% to 100%) of the relationship between obesity at any point during follow-up and CVD., Conclusions: Metabolically healthy obesity is not a stable or reliable indicator of future risk for CVD. Weight loss and lifestyle management for CVD risk factors should be recommended to all individuals with obesity., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Frailty assessment provides a means of identifying older adults most vulnerable to adverse outcomes. Attention to frailty in clinical practice is more likely with better understanding of its prevalence and associations with patient characteristics. We sought to provide national estimates of frailty in older people., Methods: A popular, validated frailty phenotype proposed by Fried and colleagues was applied to 7,439 participants in the 2011 baseline of the National Health and Aging Trends Study, a national longitudinal study of persons aged 65 and older. All measures drew on a 2-hour in-person interview. Weighted estimates of frailty prevalence were obtained., Results: Fifteen percent (95% CI: 14%, 16%) of the older non-nursing home population is frail, and 45% is prefrail (95% CI: 44%, 47%). Frailty is more prevalent at older ages, among women, racial and ethnic minorities, those in supportive residential settings, and persons of lower income. Independently of these characteristics, frailty prevalence varies substantially across geographic regions. Chronic disease and disability prevalence increase steeply with frailty. Among the frail, 42% were hospitalized in the previous year, compared to 22% of the prefrail and 11% of persons considered robust. Hip, back, and heart surgery in the last year were associated with frailty. Over half of frail persons had a fall in the previous year., Conclusions: Our findings support the importance of frailty in late-life health etiology and potential value of frailty as a marker of risk for adverse health outcomes and as a means of identifying opportunities for intervention in clinical practice and public health policy., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The presence of diabetes is associated with increased odds of difficulties in functional tasks but it remains unclear if the burden is similar by race., Methods: Our study included 122,004 non-Hispanic Black (NHB) and non-Hispanic White (NHW) adults ≥50 years from the U.S. National Health Interview Survey (2001-2012). Diabetes was defined as self-reported diagnosis or medication use. Functional limitations were defined as any self-reported difficulty in performing mobility tasks, general physical activities (GPA), or leisure and social activities (LSA). Logistic regression models were created to investigate the relationship of race with functional limitations accounting for key covariates, among men and women, by diabetes status., Results: Among older U.S. adults, NHB versus NHW women without diabetes had a higher odds of limitations in mobility (OR=1.39, 1.30-1.49) and LSA (OR=1.13, 1.05-1.23) without diabetes but a similar odds of these limitations with diabetes by race, after adjusting for age, income, education, obesity, arthritis, heart disease, stroke, COPD, and cancer. Interestingly, NHB versus NHW women had significantly lower odds of GPA, irrespective of diabetes status. However, NHB versus NHW men with diabetes had a persistently higher odds for mobility and LSA limitations with diabetes as follows: mobility (OR=1.30, 1.12-1.51) and LSA limitations (OR=1.07, 1.06-1.34). The interaction of race and diabetes was significant among women for mobility limitations (p<0.01), but not men., Conclusions: The burden of functional limitations differs by race among both men and women with diabetes. Future studies should examine mechanisms underlying these differences to prevent progression to disability in older adults with diabetes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To examine the independent association between diabetes mellitus (and its duration and severity) and quadriceps strength, quadriceps power, and gait speed in a national population of older adults., Design: Cross-sectional nationally representative survey., Setting: United States., Participants: Two thousand five hundred seventy-three adults aged 50 and older in the National Health and Nutrition Examination Survey 1999-2002 who had assessment of quadriceps strength., Methods: Diabetes mellitus was ascertained according to questionnaire. Measurement of isokinetic knee extensor (quadriceps) strength was performed at 60º/s. Gait speed was assessed using a 20-foot walk test. Multiple linear regression analyses were used to assess the association between diabetes mellitus status and outcomes, adjusting for potential confounders or mediators., Results: Older U.S. adults with diabetes mellitus had significantly slower gait speed (0.96 ± 0.02 m/s) than those without (1.08 ± 0.01 m/s; P < .001). After adjusting for demographic characteristics, weight, and height, diabetes mellitus was also associated with significantly lower quadriceps strength (-4.6 ± 1.9 Nm; P = .02) and power (-4.9 ± 2.0 W; P = .02) and slower gait speed (-0.05 ± 0.02 m/s; P = .002). Associations remained significant after adjusting for physical activity and C-reactive protein. After accounting for comorbidities (cardiovascular disease, peripheral neuropathy, amputation, cancer, arthritis, fracture, chronic obstructive pulmonary disease), diabetes mellitus was independently associated only with gait speed (-0.04 ± 0.02 m/s; P = .02). Diabetes mellitus duration in men and women was negatively associated with age-adjusted quadriceps strength (-5.7 and -3.5 Nm/decade of diabetes mellitus, respectively) and power (-6.1 and -3.8 W/decade of diabetes mellitus, respectively) (all P ≤ .001, no significant interactions according to sex). Glycosylated hemoglobin was not associated with outcomes after accounting for body weight., Conclusion: Older U.S. adults with diabetes mellitus have lower quadriceps strength and quadriceps power that is related to the presence of comorbidities and walk slower than those without diabetes mellitus. Future studies should investigate the relationship between hyperglycemia and subsequent declines in leg muscle function., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)