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We examined the association between diabetes mellitus (DM) and longitudinal MRI biomarkers for thigh muscle degeneration in patients with knee osteoarthritis (KOA) and their mediatory role in worsening KOA-related symptoms.The Osteoarthritis Initiative (OAI) participants with radiographic KOA (Kellgren-Lawrence grade ≥ 2) were included. Thighs and corresponding knees of KOA patients with versus without self-reported DM were matched for potential confounders using propensity score (PS) matching. We developed and used a validated deep learning method for longitudinal thigh segmentation. We assessed the association of DM with 4-year longitudinal muscle degeneration in biomarkers of muscle cross-sectional area (CSA) and contractile percentage (non-fat CSA/total CSA). We further investigated whether DM is associated with 9-year risk of KOA radiographic progression, knee replacement (KR), and symptoms worsening. Finally, we evaluated whether the DM-KOA worsening association is mediated through preceding muscle degeneration.After PS matching, 698 thighs/knees were included (185:513 with:without DM; average ± SD age:64 ± 8-years; female/male:1.4). Baseline DM was associated with a decreased contractile percent of total thigh muscles and quadriceps (mean difference, 95%CI -0.16%/year, -0.25 to -0.07, and -0.21%/year, -0.33 to -0.08). DM was also associated with an increased risk of worsening KOA-related symptoms (hazard ratio, 95%CI 1.70, 1.18-2.46) but not radiographic progression or KR. The decrease in quadriceps contractile percent partially mediated the increased risk of symptoms worsening in patients with DM.Baseline DM is associated with thigh muscle degeneration and KOA-related symptoms worsening. As a potentially modifiable risk factor, DM-associated longitudinal thigh muscle degeneration may partially mediate the symptoms worsening in patients with DM and coexisting KOA.• Diabetes mellitus (DM) is associated with worsening knee osteoarthritis (KOA)-related symptoms. • As a potentially modifiable factor, DM-associated thigh muscle (quadriceps) degeneration partially mediates the worsening of KOA-related symptoms.

Background: Diabetes and prediabetes are common among African Americans (AA), but the frequency and predictors of transition between normal, impaired glucose metabolism, and diabetes are not well-described. The aim of this study was to examine glucometabolic transitions and their association with the development of type 2 diabetes (T2D).Methods: AA participants of the Jackson Heart Study who attended baseline exam (2000-2004) and at least one of two subse­quent exams (2005-2008 and 2009-2013, ~8 years) were classified according to glycemic status. Transitions were defined as progression (deterioration) or remission (im­provement) of glycemic status. Multinomial logistic regression models with repeated measures were used to estimate the odds ratios (OR) for remission and progression with adjustment for demographic, anthro­pometric, behavioral, and biochemical factors.Results: Among 3353 participants, (mean age 54.6±12.3 years), 43% were normogly­cemic, 32% were prediabetes, and 25% had diabetes at baseline. For those with normal glucose at a visit, the probability at the next visit (~4years) of having prediabetes or diabetes was 38.5% and 1.8%, respectively. For those with prediabetes, the probability was 9.9% to improve to normal and 19.9% to progress to diabetes. Progression was as­sociated with baseline BMI, diabetes status, triglycerides, family history of diabetes, and weight gain (OR 1.04 kg, 95% CI:1.03-1.06, P=

OBJECTIVES: The metabolic abnormalities that lead to diabetes mellitus (DM) following an episode of acute pancreatitis (AP) have not been extensively studied. This manuscript describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) Study. METHODS: Three months after an index episode of AP, participants without pre-existing DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three sub-cohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently-sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. CONCLUSIONS: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.

Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM following AP and understanding the underlying mechanisms. The Diabetes RElated to Acute Pancreatitis and its Mechanisms (DREAM) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM following AP. In the following article, we summarize literature regarding the epidemiology of DM following AP, and provide the rationale and an overview of the DREAM study.

Orthostatic hypotension (OH) based on a change from seated-to-standing blood pressure (BP) is often used interchangeably with supine-to-standing BP.The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a randomized trial of vitamin D3 supplementation and fall in adults aged ≥70 years at high risk of falls. OH was defined as a drop in systolic or diastolic BP of at least 20 or 10 mmHg, measured at pre-randomization, 3-, 12-, and 24-month visits with each of 2 protocols: seated-to-standing and supine-to-standing. Participants were asked about orthostatic symptoms, and falls were ascertained via daily fall calendar, ad hoc reporting, and scheduled interviews.Among 534 participants with 993 paired supine and seated assessments (mean age 76 ± 5 years, 42% women, 18% Black), mean baseline BP was 130 ± 19/68 ± 11 mmHg; 62% had a history of high BP or hypertension. Mean BP increased 3.5 (SE, 0.4)/2.6 (SE, 0.2) mmHg from sitting to standing, but decreased with supine to standing (mean change: -3.7 [SE, 0.5]/-0.8 [SE, 0.3] mmHg; P-value 0.001). OH was detected in 2.1% (SE, 0.5) of seated versus 15.0% (SE, 1.4) of supine assessments (P 0.001). While supine and seated OH were not associated with falls (HR: 1.55 [0.95, 2.52] vs 0.69 [0.30, 1.58]), supine systolic OH was associated with higher fall risk (HR: 1.77 [1.02, 3.05]). Supine OH was associated with self-reported fainting, blacking out, seeing spots and room spinning in the prior month (P-values 0.03), while sitting OH was not associated with any symptoms (P-values ≥ 0.40).Supine OH was more frequent, associated with orthostatic symptoms, and potentially more predictive of falls than seated OH.

Background: Females have greater relative brain volume (BV) and cerebral blood flow (CBF) compared to males. BV decreases after menopause suggesting a possible role of sex hormones. We studied the association of BV, abnormal white matter hyperintensity volumes (WMHV) and cerebral blood flow (CBF) with sex hormones in adults with type 2 diabetes (T2DM), which is associated with risk of brain atrophy. Methods: The sample was 215 participants with overweight or obesity and T2DM from the Look AHEAD Brain MRI cohort (mean age 68 years [SD: 6.3], 27% male, 73% female [all postmenopausal]; without exogenous hormones), who had brain MRIs to evaluate their total BV, WMHV and CBF. The ratio of brain measurements to intracranial volume was analyzed to account for body size. Estradiol (E2) and testosterone levels (T) were estimated with electrochemoluminescence assays. In females, who have low E2 and T levels, we compared brain measures in those with detectable (vs. undetectable) hormone levels (E2 Results: Females with detectable (vs. undetectable) T levels had higher BV (p=0.04) (Table), which was attenuated after adjustment for age and BMI. WMHV and CBF were not statistically associated with sex hormone levels in females. In males, no brain measures were significantly associated with sex hormones levels. Conclusions: In postmenopausal females with T2DM, detectable levels of T were associated greater BV, but not associated any CBF or WMHV. In males, none of the brain measures were associated with sex hormones. Our findings are limited by a small, convenient sample size and low sensitivity of hormone assays with a high proportion of undetectable levels. Our findings suggest that larger samples with high sensitivity hormone assays are needed to assess clinically important differences.

Background: Prior studies showed an association between some adverse cardiometabolic outcomes and lower testosterone in males and higher estrogen in both males and post-menopausal females. However, few studies of sex hormones focused on people with type 2 diabetes (T2DM), assessed hormone changes over time or applied highly sensitive laboratory assays. Given the importance of lifestyle modification (i.e., diet, exercise and weight loss) in preventing cardiometabolic complications in people with T2DM, we examined the impact of an Intensive Lifestyle Intervention (ILI) on sex hormones over time and differences by sex. Methods: The Look AHEAD (Action for Health in Diabetes) Study was a randomized control trial of 5,145 individuals with BMI ≥25 and T2D to evaluate the effect of ILI compared to the Diabetes Support and Education (DSE) control group on incident cardiovascular events. We selected a sample of 472 males and 426 post-menopausal female participants (mean age 60 years [SD 6.3], 20.5% Black) to examine sex hormones (estradiol - E2, total testosterone - T) and sex hormone binding globulin (SHBG) at baseline and year 1. E2 and T were measured using mass spectrometry analysis and SHBG was measured using an immunoassay. Results: In males, ILI increased SHBG by 17.3% and T by 10.6% compared to the DSE group (Table). In postmenopausal females, ILI increased SHBG by 12.0% and decreased E2 by 23.4% compared to the DSE group (Table). The change in the sex hormone levels from baseline to 1-year follow up was attenuated when adjusted for change in BMI. Conclusion: ILI resulting in weight loss increased T in males and decreased E2 in postmenopausal females and increased SHBG in both sexes. We plan further analysis with a larger sample and longer follow-up to examine the role of weight loss either as a co-occurring metabolic process or as a mediator for the change in sex hormones to better understand the impact of lifestyle changes and sex diffrences.

ImportanceA combination of diabetes, coronary heart disease (CHD), and stroke has multiplicative all-cause mortality risk compared with any individual morbidity in White populations, but there is a lack of studies in Black populations in the US.ObjectiveTo examine the association of cardiometabolic multimorbidity (diabetes, stroke, and CHD) individually and collectively with all-cause and CHD mortality.Design, Setting, and ParticipantsThis cohort study included Black adults in the Jackson Heart Study followed over a median of 15 years. Baseline examinations were performed between 2000 and 2004, with follow-up on all-cause and CHD mortality through May 31, 2018. Participants were categorized into mutually exclusive groups at baseline: (1) free of cardiometabolic morbidity, (2) diabetes, (3) CHD, (4) stroke, (5) diabetes and stroke, (6) CHD and stroke, (7) diabetes and CHD, and (8) diabetes, stroke, and CHD. Data were analyzed from 2019 to 2021.ExposureCardiometabolic disease alone or in combination.Main Outcomes and MeasuresThe main outcomes were all-cause mortality and CHD mortality. Cox models estimated hazard ratios (HRs) with 95% CIs adjusted for sociodemographic and cardiovascular risk factors.ResultsAmong 5064 participants (mean [SD] age, 55.4 [12.8] years; 3200 [63%] women) in the Jackson Heart Study, 897 (18%) had diabetes, 192 (4%) had CHD, and 104 (2%) had a history of stroke. Among participants with cardiometabolic morbidities, the crude all-cause mortality rates were lowest for diabetes alone (24.4 deaths per 1000 person-years) and highest for diabetes, CHD, and stroke combined (84.1 deaths per 1000 person-years). For people with only 1 cardiometabolic morbidity, risk for all-cause mortality was highest for people with stroke (HR, 1.74; 95% CI, 1.24-2.42), followed by CHD (HR, 1.59 (95% CI, 1.22-2.08) and diabetes (HR, 1.50; 95% CI, 1.22-1.85), compared with no cardiometabolic morbidities. There were also increased risks of mortality with combinations of diabetes and stroke (HR, 1.71; 95% CI, 1.09-2.68), CHD and stroke (HR, 2.23; 95% CI, 1.35-3.69), and diabetes and CHD (HR, 2.28; 95% CI, 1.65-3.15). The combination of diabetes, stroke, and CHD was associated with the highest all-cause mortality (HR, 3.68; 95% CI, 1.96-6.93). Findings were similar for CHD mortality, but with a larger magnitude of association (eg, diabetes, stroke, and CHD: HR, 13.52; 95% CI, 3.38-54.12).Conclusions and RelevanceIn this cohort study, an increasing number of cardiometabolic multimorbidities was associated with a multiplicative increase in risk of all-cause mortality among Black adults, with a greater magnitude of association for CHD mortality.

Key Clinical Points Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes The attainment of glycemic targets and comprehensive reduction in risk factors for cardiovascular disease...

Background Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. Objective To compare the effects of 4 doses of vitamin D3 supplements on falls. Design 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). Setting 2 community-based research units. Participants 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. Intervention 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. Measurements Time to first fall or death over 2 years (primary outcome). Results During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). Limitations The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. Conclusion In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. Primary funding source National Institute on Aging.

Background Body composition often changes with age. While body mass index (BMI) is used to define obesity, the degree to which BMI accurately or consistently reflects fatness in older versus younger adults remains unclear. Importantly, it is uncertain whether diabetes risk is similar for older versus younger adults within BMI-defined categories. Objectives We evaluated the relationship of older (≥65 years) versus younger age ( Design: Participants without diabetes at first DXA visit in the Baltimore Longitudinal Study of Aging were included. Linear regression models were used to investigate the association of age categories to body composition at baseline, and Cox proportional hazard models were used to study the relationship of age categories to incident diabetes, within BMI categories for men and women. Diabetes was defined based on self-reported history, medication use, and/or ADA diagnostic criteria (fasting or 2-hour OGTT glucose levels). Results A total of 993 men (n=463 older, n=530 younger) and 1109 women (n=385 older, n=724 younger) were examined. Comparing older versus younger participants, body weight was significantly lower across all BMI categories for both men and women (all p Conclusions In our study, sex differences were observed in the relationship of older versus younger age to several measures of body composition, suggesting greater relative fat mass with aging, particularly in men. Further, our results suggest that BMI-defined categories for overweight and obesity do not fully account for changes in fat mass with aging and that the risk for diabetes is significantly greater for older compared to younger obese men. Further studies are needed to investigate the optimal BMI thresholds that predict diabetes risk in older adults. Presentation: Sunday, June 12, 2022 12:15 p.m. - 12:30 p.m.

BackgroundHeterogeneity in the long-term metabolic response to dietary macronutrient composition can be partially explained by genetic factors. However, few studies have demonstrated reproducible gene-diet interactions (GDIs), likely due in part to measurement error in dietary intake estimation as well as insufficient capture of rare genetic variation. Discovery analyses in ancestry-diverse cohorts that include rare genetic variants from whole-genome sequencing (WGS) could help identify genetic variants modifying the effects of dietary macronutrient composition on glycemic phenotypes.ObjectiveWe aimed to identify macronutrient GDIs across the genetic frequency spectrum associated with continuous glycemic traits in genetically and culturally diverse cohorts.MethodsWe analyzed N=33,187 diabetes-free participants from 10 cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program with WGS, self-reported diet, and glycemic traits (fasting glucose [FG], insulin [FI], and hemoglobin A1c [HbA1c]). We fit multivariable-adjusted linear mixed models for the main effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and for its interactions with genetic variants genome-wide. Tests were performed for both common variants and gene-based rare variant sets in each cohort followed by a combined cohort meta-analysis.ResultsIn main effect models, participants consuming more calories from carbohydrate at the expense of fat had modestly lower glycemic trait values (β per 250 kcal substitution for FG: −0.030 mmol/L, p=2.7×10−6; lnFI: −0.008 log(pmol/L), p=0.17; HbA1c: −0.013 %, p=0.025). In GDI analyses, a common African ancestry-enriched variant (rs79762542; 78 kb upstream of the FRAS1 gene) reached study-wide significance (p = 1.14×10−8) indicating a higher HbA1c with greater proportion of calories from carbohydrate vs. fat among minor allele carriers only. This interaction was replicated in the UK Biobank cohort. Simulations revealed that there is (1) a substantial impact of measurement error on statistical power for GDI discovery at these sample sizes, especially for rare genetic variants, and (2) over 150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error.ConclusionsOur analysis identified a potential genetic interaction modifying the dietary macronutrient-HbA1c association while highlighting the importance of precise exposure measurement and significantly increased sample size to identify additional similar effects.

Ty J. Gluckman, MD, FACC, Chair Niti R. Aggarwal, MD, FACC Nicole M. Bhave, MD, FACC Gregory J. Dehmer, MD, MACC Olivia N. Gilbert, MD, MSc, FACC Chayakrit Krittanawong, MD Dharam J. Kumbhani, MD, SM, FACC Andrea L. Price, CPHQ, RCIS, AACC Javier A. Sala-Mercado, MD, PhD David E.

Reduced pancreatic volume, often referred to as atrophy, is a commonly reported imaging feature of chronic pancreatitis (CP). This study evaluated whether there is an association between pancreatic volume and fibrosis, the criterion standard of CP, in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for recurrent acute pancreatitis (RAP) and CP.All adult patients who underwent TPIAT between 2010 and 2019 were categorized into 3 groups: RAP, definite CP and indeterminate CP. Pancreatic volume was calculated by summing up the areas from each thin section of the pancreas on 3D CT imaging. Excisional biopsies of the pancreatic head as well as body/tail region were obtained at the time of TPIAT. Two different fibrosis scores were used for histologic assessment.A total of 16, 29 and 15 patients underwent TPIAT for RAP, definite CP and indeterminate CP, respectively. The mean pancreatic volumes for patients with RAP, definite CP and indeterminate CP were 65.7 ± 28.5 cc, 54.9 ± 22.9 cc and 61.8 ± 23.6 cc, respectively (p = 0.3). The mean fibrosis scores were significantly higher in patients with definite CP compared to RAP (p 0.001) and indeterminate CP (p 0.001). Pancreatic volume was not associated with either fibrosis score after adjusting for age, gender, duration of disease, BMI and diabetes in the multivariable analysis.While the fibrosis scores were higher in definite CP compared to both RAP and indeterminate CP, there was no correlation between pancreatic volume and fibrosis. This suggests that atrophy alone cannot be used to diagnose CP.

ObjectiveTo determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived β-amyloid42 (Aβ42) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia.MethodsThis was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level–dependent per 1 mm Hg Etco2) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aβ42 and tau.ResultsWhole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (β = −0.02%/mm Hg; 95% confidence interval [CI] −0.038 to −0.001). After adjustment for CSF Aβ42 and tau, higher whole-brain CVR was associated with better performance on the MoCA (β = 29.64, 95% CI 9.94–49.34) and with a global composite cognitive score (β = 4.32, 95% CI 0.05–8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (β = 28.09, 95% CI 6.14–50.04), while the other 2 measures were not significant.ConclusionsCVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals.Classification of evidenceThis study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.

Context The Study to Understand Fall Reduction and Vitamin D in You (STURDY), a randomized trial enrolling older adults with low 25-hydroxyvitamin D [25(OH)D], demonstrated vitamin D supplementation ≥ 1000 IU/day did not prevent falls compared with 200 IU/day, with doses ≥ 2000 IU/day potentially showing safety concerns. Objective To examine associations of achieved and change in 25(OH)D concentrations after 3 months of vitamin D supplementation with fall risk. Design Observational analysis of trial data. Setting General community. Participants A total of 637 adults aged ≥ 70 with baseline 25(OH)D concentrations 10 to 29 ng/mL and elevated fall risk. Three-month on-treatment absolute 25(OH)D; absolute and relative changes from baseline. Main Outcome Measures Incident first fall (primary) and first consequential fall (injury or sought medical care) up to 24 months. Cox models were adjusted for sociodemographics, season, Short Physical Performance Battery, and body mass index. Results At baseline, mean (SD) age was 77.1 (5.4) years and 25(OH)D was 22.1 (5.1) ng/mL; 43.0% were women and 21.5% non-White. A total of 395 participants experienced ≥ 1 fall; 294 experienced ≥ 1 consequential fall. There was no association between absolute achieved 25(OH)D and incident first fall (30-39 vs Conclusion Achieved 25(OH)D concentration after supplementation was not associated with reduction in falls. Risk of consequential falls may be increased with achieved concentrations ≥ 40 ng/mL. Trial Registration ClinicalTrials.gov: NCT02166333

Background Low serum 25-hydroxyvitamin D [25(OH)D] level is associated with a greater risk of frailty, but the effects of daily vitamin D supplementation on frailty are uncertain. This secondary analysis aimed to examine the effects of vitamin D supplementation on frailty using data from the Study To Understand Fall Reduction and Vitamin D in You (STURDY). Methods The STURDY trial, a two-stage Bayesian, response-adaptive, randomized controlled trial, enrolled 688 community-dwelling adults aged ≥ 70 years with a low serum 25(OH)D level (10–29 ng/mL) and elevated fall risk. Participants were initially randomized to 200 IU/d (control dose; n = 339) or a higher dose (1000 IU/d, 2000 IU/d, or 4000 IU/d; n = 349) of vitamin D3. Once the 1000 IU/d was selected as the best higher dose, other higher dose groups were reassigned to the 1000 IU/d group and new enrollees were randomized 1:1 to 1000 IU/d or control group. Data were collected at baseline, 3, 12, and 24 months. Frailty phenotype was based on number of the following conditions: unintentional weight loss, exhaustion, slowness, low activity, and weakness (≥ 3 conditions as frail, 1 or 2 as pre-frail, and 0 as robust). Cox proportional hazard models estimated the risk of developing frailty, or improving or worsening frailty status at follow-up. All models were adjusted for demographics, health conditions, and further stratified by baseline serum 25(OH)D level (insufficiency (20–29 ng/mL) vs. deficiency (10–19 ng/mL)). Results Among 687 participants (mean age 77.1 ± 5.4, 44% women) with frailty assessment at baseline, 208 (30%) were robust, 402 (59%) were pre-frail, and 77 (11%) were frail. Overall, there was no significant difference in risk of frailty outcomes comparing the pooled higher doses (PHD; ≥ 1000 IU/d) vs. 200 IU/d. When comparing each higher dose vs. 200 IU/d, the 2000 IU/d group had nearly double the risk of worsening frailty status (HR = 1.89, 95% CI: 1.13–3.16), while the 4000 IU/d group had a lower risk of developing frailty (HR = 0.22, 95% CI: 0.05–0.97). There were no significant associations between vitamin D doses and frailty status in the analyses stratified by baseline serum 25(OH)D level. Conclusions High dose vitamin D supplementation did not prevent frailty. Significant subgroup findings might be the results of type 1 error. Trial registration ClinicalTrials.gov: NCT02166333.

Context Multiple studies suggest that adults who were normal weight at diabetes diagnosis are at higher risk for all-cause mortality than those who had overweight or obesity at diagnosis. Objective While obesity is a known risk factor for cardiometabolic disease, differences in body fat distribution in those without obesity are understudied, especially in African Americans. Methods In 1005 participants of the Jackson Heart Study, without cardiovascular disease at baseline, we used logistic regression to investigate the longitudinal association of body fat distribution by CT scan with metabolic syndrome (MetS) or type 2 diabetes (T2D). We used the harmonized International Diabetes Federation criteria to define MetS. We included only normal weight or overweight participants (BMI: 18.5 to < 30.0 kg/m2). We created separate models for MetS and T2D adjusted for a standard set of covariates. We excluded participants with prevalent MetS or T2D, respectively in sensitivity. Results Higher visceral fat, subcutaneous fat, BMI, and insulin resistance (HOMA-IR) were significantly associated with MetS and T2D after adjustment. Visceral fat was strongly associated with both outcomes (MetS OR = 2.07 [1.66-2.68]; T2D OR = 1.51 [1.21-1.88]), and the association for MetS persisted in the normal weight only group. Estimates were robust to sensitivity analysis and were only modestly mediated by insulin resistance. Physical activity was not associated with MetS or T2D. Conclusion Visceral fat is strongly associated with developing MetS, even in normal weight individuals, suggesting that excess visceral fat plays a role in cardiometabolic risk beyond that of overall adiposity and obesity in African Americans.

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare variants’ (RVs) associations with complex human traits. Variant set analysis is a powerful approach to study RV association, and a key component of it is constructing RV sets for analysis. However, existing methods have limited ability to define analysis units in the noncoding genome. Furthermore, there is a lack of robust pipelines for comprehensive and scalable noncoding RV association analysis. Here we propose a computationally-efficient noncoding RV association-detection framework that uses STAAR (variant-set test for association using annotation information) to group noncoding variants in gene-centric analysis based on functional categories. We also propose SCANG (scan the genome)-STAAR, which uses dynamic window sizes and incorporates multiple functional annotations, in a non-gene-centric analysis. We furthermore develop STAARpipeline to perform flexible noncoding RV association analysis, including gene-centric analysis as well as fixed-window-based and dynamic-window-based non-gene-centric analysis. We apply STAARpipeline to identify noncoding RV sets associated with four quantitative lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several noncoding RV associations in an additional 9,123 TOPMed samples.

Cardiovascular disease (CVD) complications constitute about 50-70% of mortality in people with diabetes. However, there remains a persistently greater relative increase in CVD morbidity and mortality in women with diabetes than in their male counterparts. This review presents recent evidence for the risks, outcomes, and management implications for women with diabetes.Compared to men, women have higher BMI and more adverse cardiovascular risk profile at time of diabetes diagnosis with greater risk for coronary heart disease, stroke, vascular dementia, and heart failure. Pregnancy-specific risk factors of gestational diabetes and pre-eclampsia are associated with future type 2 diabetes (T2D) and CVD. Women with T2D may experience greater benefits than men from GLP-1 receptor agonists. Women with diabetes are at greater relative risk for CVD complications than men, with poorer outcomes, superimposed on preexisting gender disparities in social determinants of health, lower likelihood of being offered cardioprotective interventions, and enrollment in trials. Further research and the utilization of SGLT-2 inhibitors, GLP-1 receptor agonists, and other CVD prevention strategies will help reduce morbidity and mortality.

Key Points Question What are the trends in ambulatory insulin use among adults with type 2 diabetes in the United States between 2016 and 2020? Findings In this cross-sectional study of 27.9 million ambulatory insulin treatment visits, the use of insulin analogs and insulin glargine predominated, while the use of insulin pens and newer insulins increased during the 5 year study period. Meaning These findings suggest that even with increased costs and scrutiny for insulin products, ambulatory use remains dominated by the use of insulin analogs and insulin pen delivery devices, with persistent uptake of newer products as they are approved., This cross-sectional study characterizes trends in ambulatory insulin use, overall and based on insulin characteristics, among adults with type 2 diabetes in the United States from 2016 to 2020., 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.

Background Vitamin D3 supplementation is considered a potential intervention to prevent orthostatic hypotension (OH) based on observational evidence that vitamin D levels are inversely associated with OH. With data from The Study to Understand Fall Reduction and Vitamin D in You (STURDY), a double-blind, randomized, response-adaptive trial, we determined if higher doses of vitamin D3 reduced risk of OH. Methods STURDY tested the effects of higher (1,000+ IU/day, i.e., 1,000, 2,000, and 4,000 IU/day combined) vs. lower-dose vitamin D3 (200 IU/day, comparison) on fall risk in adults ages 70 years and older with low serum 25-hydroxyvitamin D (25(OH)D, 10–29 ng/ml). OH was determined at baseline, 3, 12, and 24 months by taking the difference between seated and standing blood pressure (BP). OH was defined as a drop in systolic or diastolic BP of at least 20 or 10 mm Hg after 1 minute of standing. Participants were also asked about OH symptoms during the assessment and the preceding month. Results Among 688 participants (mean age 77 [SD, 5] years; 44% women; 18% Black), the mean baseline systolic/diastolic BP was 130 (19)/67 (11) mm Hg, serum 25(OH)D was 22.1 (5.1) ng/ml, and 2.8% had OH. There were 2,136 OH assessments over the maximum 2-year follow-up period. Compared with 200 IU/day, 1,000+ IU/day was not associated with seated, standing, or orthostatic BP, and it did not lower risk of OH or orthostatic symptoms. Conclusions These findings do not support use of higher doses of vitamin D3 supplementation as an intervention to prevent OH. Clinical trials registration Trial Number NCT02166333.

Background The prognostic value of anthropometric, adipokine, and computed tomography measures of adiposity to predict diabetes in Black, specifically by normoglycemia versus prediabetes, remains incompletely understood. Methods and Results Among Black participants without diabetes in the JHS (Jackson Heart Study), waist circumference [WC], body mass index, adiponectin, leptin, and leptin:adiponectin ratio were standardized in sample 1 (2422 participants at baseline [2000–2004]) and WC, body mass index, visceral adipose tissue (VAT), subcutaneous adipose tissue, and liver attenuation in 1537 participants at examination 2 (2005–2008) (sample 2). Hazard ratios (HRs) for diabetes were estimated using interval‐censored Cox modeling adjusting for traditional risk factors and validated with the C index. Over 5 years, 300 and 122 incident diabetes cases occurred in sample 1 and sample 2, respectively. In sample 1 and sample 2, a 1‐SD higher log‐leptin:adiponectin ratio and VAT had the strongest associations (HR, 1.95 [95% CI, 1.67–2.27] and 1.76 [95% CI, 1.52–2.04]) and discriminatory power (C index 0.68 [95% CI, 0.64–0.71] and C index 0.67 [95% CI, 0.61–0.74]) with diabetes. The normoglycemic compared with the prediabetes group had a 1.3 to 1.9 times greater magnitude of associations with diabetes for WC, liver attenuation, and VAT ( P interaction 1c (HR, 0.74; 95% CI, 0.57–0.90) in normoglycemia, whereas HbA 1c was best in prediabetes (HR, 0.72; 95% CI, 0.66–0.78). Conclusions Overall, among Black adults, multiple measures of adiposity were associated with incident diabetes with modest predictive ability. In Black patients with normoglycemia, WC, liver attenuation, and VAT may appropriately identify those at high risk for diabetes, whereas HbA 1c was the best predictor in individuals with prediabetes.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

Background/aim:Cost-efficient methods are essential for successful participant recruitment in clinical trials. Patient portal messages are an emerging means of recruiting potentially eligible patients into trials. We assessed the response rate and complaint rate from direct-to-patient, targeted recruitment through patient portals of an electronic medical record for a clinical trial, and compared response rates by differences in message content.Methods:The Study to Understand Fall Reduction and Vitamin D in You (STURDY) trial is a National Institutes of Health–sponsored, community-based study of vitamin D supplementation for fall prevention in older adults conducted at Johns Hopkins. Potential participants were identified using the Epic electronic medical record at the Johns Hopkins Health System based on age (≥70 years), ZIP code (30-mile radius of study site), and prior activation of a patient portal account. We prepared a shorter message and a longer message. Both had basic information about study participation, but the longer message also contained information about the significance of the study and a personal invitation from the STURDY principal investigator. The Hopkins Institutional Review Board did not require prior consent from the patient or their providers. We calculated the response rate and tracked the number of complaints and requests for removal from future messages. We also determined response rate according to message content.Results:Of the 5.5 million individuals receiving care at the Johns Hopkins Health System, a sample of 6896 met our inclusion criteria and were sent one patient portal recruitment message between 6 April 2017 and 3 August 2017. Assessment of enrollment by this method ended on 1 December 2017. There were 116 patients who expressed interest in the study (response rate: 1.7%). Twelve (0.2%) recipients were randomized. There were two complaints (0.03%) and one request to unsubscribe from future recruitment messages (0.01%). Response rate was higher with the longer message than the shorter message (2.1% vs 1.2%; p = 0.005).Conclusion:Patient portal messages inviting seniors to participate in a randomized controlled trial resulted in a response rate similar to commercial email marketing and resulted in very few complaints or opt-out requests. Furthermore, a longer message with more content enhanced response rate. Recruitment through patient portals might be an effective strategy to enroll trial participants.

Total pancreatectomy with islet autotransplantation can relieve pain associated with chronic pancreatitis while preserving islet function. Islet preparations are often contaminated by enteric flora. We assessed the impact of contaminated islet preparations on the prevalence of postoperative infection.Electronic health records for patients who underwent total pancreatectomy with islet autotransplantation from August 1, 2011, to November 15, 2017 were retrospectively reviewed to compare the prevalence of postoperative infection in patients with a positive islet culture and islet culture negative patients.Sixty-one patients were included. Twenty-nine patients (47.5%) had a positive islet culture, and 23 (79.3%) of these patients received antimicrobial prophylaxis. The prevalence of postoperative infection did not differ between the islet culture positive and islet culture negative groups (41% vs 34%, P = 0.57). No infections occurred in the 6 islet culture positive patients who did not receive prophylaxis. No difference in intensive care unit or hospital length of stay or in 30-day or 90-day readmission rates were observed.Despite the common use of postoperative systemic antimicrobials, we observed no difference in the prevalence of postoperative infection, length of stay, or hospital readmission in patients receiving a contaminated islet preparation. If prophylactic antimicrobials are used, the duration should be minimized.

OBJECTIVE Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD). RESEARCH DESIGN AND METHODS Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up. RESULTS Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65–0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78–1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75–1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. CONCLUSIONS Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range.

ObjectiveTo develop clinical practice guidelines for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM) in individuals at metabolic risk for developing these conditions.ConclusionsHealth care providers should incorporate regular screening and identification of individuals at metabolic risk (at higher risk for ASCVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and blood glucose. Individuals identified at metabolic risk should undergo 10-year global risk assessment for ASCVD or coronary heart disease to determine targets of therapy for reduction of apolipoprotein B–containing lipoproteins. Hypertension should be treated to targets outlined in this guideline. Individuals with prediabetes should be tested at least annually for progression to diabetes and referred to intensive diet and physical activity behavioral counseling programs. For the primary prevention of ASCVD and T2DM, the Writing Committee recommends lifestyle management be the first priority. Behavioral programs should include a heart-healthy dietary pattern and sodium restriction, as well as an active lifestyle with daily walking, limited sedentary time, and a structured program of physical activity, if appropriate. Individuals with excess weight should aim for loss of ≥5% of initial body weight in the first year. Behavior changes should be supported by a comprehensive program led by trained interventionists and reinforced by primary care providers. Pharmacological and medical therapy can be used in addition to lifestyle modification when recommended goals are not achieved.

Introduction “Frailty” has attracted attention for its promise of identifying vulnerable older adults, hence its potential use to better tailor geriatric health care. There remains substantial controversy, however, regarding its nature and ascertainment. Recent years have seen a proliferation of frailty assessment methods. We argue that the development of frailty assessments should be grounded in “validation”—the process of substantiating that a measurement accurately and precisely measures what it intends, identify unresolved measurement issues, and highlight measurement-related considerations for clinical practice. Methods Principles for validating frailty measures are elucidated. We follow principles—articulated, for example, by Borsboom—in which a construct must be clearly defined and then analyses undertaken to substantiate that a measurement accurately and precisely measures what it intends. Key elements are content validity, criterion validity, and construct validity, with an emphasis on the latter. Results We illustrate the principles for a physical frailty phenotype construct. Conclusions Unresolved conceptual issues include the roles of intersecting concepts such as cognition, disease severity, and disability in frailty measurement, conceptualization of frailty as a state versus a continuum, and the potential need for dynamic measures and systems concepts in furthering understanding of frailty. Clinical considerations include needs to distinguish interventions designed to address frailty “symptoms” versus underlying physiology, improve “prefrailty” measures intended to screen individuals early in their frailty progression, address feasibility demands, and further visioning followed by rigorous efficacy research to address the landscape of potential uses of frailty assessment in clinical practice.

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.

Importance Tens of millions of individuals in the United States have Type 2 diabetes, and most require treatment with glucose-lowering medications to manage the disease. Objective To examine trends in non-insulin drug treatment of Type 2 diabetes, including first-line and second-line therapies on top of metformin, from 2015 to 2019. Design, setting and participants We conducted a descriptive analysis of cross-sectional data using the IQVIA National Disease and Therapeutic Index (NDTI), a nationally representative audit of ambulatory physician practices in the United States. We focused on the use of non-insulin pharmacologic treatments for Type 2 diabetes among individuals age 35 years and older between January 1st 2015 and December 31st 2019. Main outcome and measures Type 2 diabetes visits where a prescription drug was used ("treatment visit"). Results Ambulatory diabetes visits decreased from 30.1 million (M) treatment visits in 2015 to 29.5 M treatment visits in 2019. Among treatment visits where a single drug was prescribed, 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) agonists increased from 4.3% to 8.5% and the share accounted for by sodium-glucose cotransporter-2 (SGLT-2) 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; sulfonylurea use declined from 45.2% to 32.7%, use of SGLT-2 inhibitors increased from 14.5% to 21.2% and use of GLP-1 agonists increased from 9.8% to 18.2%. Conclusions and relevance Significant changes in the landscape of ambulatory care for diabetes have taken place during the past six years, including moderate declines in metformin monotherapy, moderate declines in second-line sulfonylurea use, and large increases in SGLT-2 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. This article is protected by copyright. All rights reserved.