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OBJECTIVE Estimated time in range (eTIR) obtained from DCCT glucose profiles (pre- and postprandial and bedtime) was recently reported to be associated with microvascular outcomes and was recommended as a clinical trial outcome, but without consideration of HbA1c. RESEARCH DESIGN AND METHODS The associations of eTIR with diabetic retinopathy and microalbuminuria were assessed without and with adjustment for HbA1c and baseline covariates. RESULTS Adjusted for HbA1c and covariates, eTIR was marginally significantly associated with retinopathy in the full cohort (hazard ratio [HR] 1.12 per 10% lower eTIR [95% CI 1.0, 1.26], P = 0.042). Conversely, HbA1c was significantly associated with both outcomes (HR ≥1.19 per 0.5% higher HbA1c, P ≤ 0.0002) in five of six adjusted analyses. CONCLUSIONS The association of eTIR with complications is largely explained by its correlation with HbA1c. HbA1c, not eTIR or continuous glucose monitoring TIR, remains the preferred outcome in clinical studies of type 1 diabetes complications.

Diabetes Technology — To Pump or Not to Pump This interactive feature about a person with type 1 diabetes mellitus and impaired awareness of hypoglycemia offers a case vignette accompanied by two e...

The Diabetes Control and Complications Trial (DCCT, 1983–1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy, and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to date). Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes. The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near-normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.

The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

The lower risk of cardiovascular disease (CVD) among women compared with men in the general population may be diminished among those with diabetes.To evaluate cardiometabolic risk factors and their management in association with CVD events in women vs men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.This cohort study used data obtained during the combined DCCT (randomized clinical trial, conducted 1983-1993) and EDIC (observational study, conducted 1994 to present) studies through April 30, 2018 (mean [SD] follow-up, 28.8 [5.8] years), at 27 clinical centers in the US and Canada. Data analyses were performed between July 2021 and April 2022.During the DCCT phase, patients were randomized to intensive vs conventional diabetes therapy.Cardiometabolic risk factors and CVD events were assessed via detailed medical history and focused physical examinations. Blood and urine samples were assayed centrally. CVD events were adjudicated by a review committee. Linear mixed models and Cox proportional hazards models evaluated sex differences in cardiometabolic risk factors and CVD risk over follow-up.A total of 1441 participants with type 1 diabetes (mean [SD] age at DCCT baseline, 26.8 [7.1] years; 761 [52.8%] men; 1390 [96.5%] non-Hispanic White) were included. Over the duration of the study, compared with men, women had significantly lower body mass index (BMI, calculated as weight in kilograms divided by height in meters squared; β = -0.43 [SE, 0.16]; P = .006), waist circumference (β = -10.56 cm [SE, 0.52 cm]; P .001), blood pressure (systolic: β = -5.77 mm Hg [SE, 0.35 mm Hg]; P .001; diastolic: β = -3.23 mm Hg [SE, 0.26 mm Hg]; P .001), and triglyceride levels (β = -10.10 mg/dL [SE, 1.98 mg/dL]; P .001); higher HDL cholesterol levels (β = 9.36 mg/dL [SE, 0.57 mg/dL]; P .001); and similar LDL cholesterol levels (β = -0.76 mg/dL [SE, 1.22 mg/dL]; P = .53). Women, compared with men, achieved recommended targets more frequently for blood pressure (ie,130/80 mm Hg: 90.0% vs 77.4%; P .001) and triglycerides (ie,150 mg/dL: 97.3% vs 90.5%; P .001). However, sex-specific HDL cholesterol targets (ie, ≥50 mg/dL for women, ≥40 mg/dL for men) were achieved less often (74.3% vs 86.6%; P .001) and cardioprotective medications were used less frequently in women than men (ie, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker: 29.6% [95% CI, 25.7%-33.9%] vs 40.0% [95% CI, 36.1%-44.0%]; P = .001; lipid-lowering medication: 25.3% [95% CI, 22.1%-28.7%] vs 39.6% [95% CI, 36.1%-43.2%]; P .001). Women also had significantly higher pulse rates (mean [SD], 75.2 [6.8] beats per minute vs 71.8 [6.9] beats per minute; P .001) and hemoglobin A1c levels (mean [SD], 8.3% [1.0%] vs 8.1% [1.0%]; P = .01) and achieved targets for tighter glycemic control less often than men (ie, hemoglobin A1c7%: 11.2% [95% CI, 9.3%-13.3%] vs 14.0% [95% CI, 12.0%-16.3%]; P = .03).These findings suggest that despite a more favorable cardiometabolic risk factor profile, women with type 1 diabetes did not have a significantly lower CVD event burden than men, suggesting a greater clinical impact of cardiometabolic risk factors in women vs men with diabetes. These findings call for conscientious optimization of the control of CVD risk factors in women with type 1 diabetes.

OBJECTIVE The principal aim is to estimate the benefits of earlier versus later implementation of intensive therapy in type 1 diabetes with respect to the long-term risks of progression of a renal (microvascular) and cardiovascular (macrovascular) complication in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS Cox proportional hazards regression models estimated the 20-year cumulative incidence (absolute risk) and the 20-year relative risk of cardiovascular disease (CVD) and reduced estimated glomerular filtration rate (eGFR) over the first 20 years of EDIC follow-up as a function of the mean HbA1c. RESULTS A hypothetical patient treated earlier with 10 years of intensive therapy and a mean HbA1c of 7% (53 mmol/mol) followed by 10 years with a mean of 9% (75 mmol/mol) would have a 33% reduction in the risk of CVD and a 52% reduction in reduced eGFR compared with a patient with a mean HbA1c of 9% (75 mmol/mol) over the first 10 years followed by later intensive therapy over 10 years with an HbA1c of 7% (53 mmol/mol). Despite both patients having the same average glycemic exposure over the 20 years, the patient with the lower HbA1c over the first 10 years had a lower risk of progression of complications over the 20 years than the patient who had the higher value initially. CONCLUSIONS While implementation of intensive therapy at any time in type 1 diabetes will be beneficial, within the 20-year period modeled, earlier relative to later implementation is associated with a greater reduction in the risks of kidney and cardiovascular complications.

Objective The Action for Health in Diabetes (Look AHEAD) study previously reported that intensive lifestyle intervention (ILI) reduced incident depressive symptoms and improved health-related quality of life (HRQOL) over nearly 10 years of intervention compared with a control group (the diabetes support and education group [DSE]) in participants with type 2 diabetes and overweight or obesity. The present study compared incident depressive symptoms and changes in HRQOL in these groups for an additional 6 years following termination of the ILI in September 2012. Methods A total of 1,945 ILI participants and 1,900 DSE participants completed at least one of four planned postintervention assessments at which weight, mood (via the Patient Health Questionnaire-9), antidepressant medication use, and HRQOL (via the Medical Outcomes Scale, Short Form-36) were measured. Results ILI participants and DSE participants lost 3.1 (0.3) and 3.8 (0.3) kg [represented as mean (SE); p = 0.10], respectively, during the 6-year postintervention follow-up. No significant differences were observed between groups during this time in incident mild or greater symptoms of depression, antidepressant medication use, or in changes on the physical component summary or mental component summary scores of the Short Form-36. In both groups, mental component summary scores were higher than physical component summary scores. Conclusions Prior participation in the ILI, compared with the DSE group, did not appear to improve subsequent mood or HRQOL during 6 years of postintervention follow-up.

The introduction of insulin in the treatment of juvenile-onset, now type 1, diabetes mellitus transformed a rapidly fatal disease into a chronic degenerative one. During the insulin-treatment era, long-term microvascular and cardiovascular complications proved to be the bane of existence for people with type 1 diabetes, leading to blindness, kidney failure, amputations, cardiovascular disease (CVD) and premature mortality. The nascent understanding of the link between non-physiologically regulated glucose levels and these complications led to the development of new treatment tools in the 1970s and 1980s that facilitated the delivery of insulin to achieve glucose levels closer to non-diabetic levels. These therapeutic advances set the stage for definitive testing of the glucose hypothesis. The Diabetes Control and Complications Trial (DCCT), supported by the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health (NIH), definitively established the benefits and risks of intensive therapy that substantially lowered mean blood glucose levels, measured by HbA1c, over a mean 6.5 years of therapy. Intensive therapy in the DCCT, resulting in a mean HbA1c of ~7% (53 mmol/mol), reduced the development and progression of early microvascular and neurological complications associated with diabetes by 34–76% compared with the conventional-treatment group, which maintained an HbA1c of ~9% (75 mmol/mol). Intensive therapy was also associated with weight gain and a threefold increased risk for hypoglycaemia. At the end of the DCCT, a long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, commenced. Despite the convergence of HbA1c levels between the two groups during EDIC, owing to the adoption of intensive therapy by the original DCCT conventional-treatment group and the return of all participants to their own healthcare providers for diabetes care, the development and progression of complications continued to be substantially less in the original intensive-treatment group vs the conventional-treatment group; this phenomenon was termed ‘metabolic memory’. The DCCT demonstrated a major reduction in early-stage complications with intensive therapy and the metabolic memory phenomenon during EDIC contributed to a substantially lower burden of advanced complications over time. These included a 57% lower risk of CVD events and 33% lower rate of mortality in the original intensive-treatment group compared with the conventional-treatment group. DCCT/EDIC has ushered in the intensive-treatment era, which has been universally adopted and includes the goal of achieving HbA1c levels less than 7% (53 mmol/mol) for most patients. Although the challenge of making intensive therapy (with the aim of achieving normoglycaemia) as widely accessible and safe as possible remains, continuing improvements in insulin therapy 100 years after its introduction promise a brighter future for people with type 1 diabetes.

Objective This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. Methods Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. Results After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). Conclusions An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

OBJECTIVE: To determine whether interventions that slow or prevent the development of type 2 diabetes mellitus 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 either 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 ETDRS 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 to 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. CONCLUSION: 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.

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

Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design.TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or NaResults are expected in 2024.TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.

OBJECTIVE Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P < 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.

The Diabetes Control and Complications Trial (DCCT, 1983-1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications study (EDIC, 1994 to date). Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon, and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes. The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.

ObjectiveTo characterize the relationship between hemoglobin A1c (HbA1c) levels and glucose tolerance across pregnancy and postpartum.Design and ParticipantsIn a longitudinal study of pregnant women with gestational diabetes risk factors (N = 102), we performed oral glucose tolerance testing (OGTT) and HbA1c measurements at 10–15 weeks of gestation, 24–30 weeks of gestation (N = 73), and 6–24 weeks postpartum (N = 42). Complete blood counts were obtained from clinical records. We calculated HbA1c-estimated average glucose levels and compared them with mean OGTT glucose levels (average of fasting, 1- and 2-hour glucose levels). Linear mixed effects models were used to test for longitudinal changes in measurements.ResultsMean OGTT glucose increased between 10–15 and 24–30 weeks of gestation (β = 8.1 mg/dL, P = .001), while HbA1c decreased during the same time period (β = –0.13%, P < .001). At 10–15 weeks of gestation and postpartum the discrepancy between mean OGTT glucose and HbA1c-estimated average glucose was minimal (mean [standard deviation]: 1.2 [20.5] mg/dL and 0.16 [18.1] mg/dL). At 24–30 weeks of gestation, the discrepancy widened (13.2 [17.9] mg/dL, β = 12.7 mg/dL, P < .001, compared to 10–15 weeks of gestation, with mean OGTT glucose being higher than HbA1c-estimated average glucose). Lower hemoglobin at 24–30 weeks of gestation was associated with a greater discrepancy (β = 6.4 mg/dL per 1 g/dL lower hemoglobin, P = .03 in an age- and gestational age-adjusted linear regression model).ConclusionsHbA1c accurately reflects glycemia in the 1st trimester, but underestimates glucose intolerance in the late 2nd trimester. Lower hemoglobin level is associated with greater underestimation. Accounting for gestational age and maternal hemoglobin may improve the clinical interpretation of HbA1c levels during pregnancy.

Objective To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). Methods This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. Results Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. Conclusions Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

OBJECTIVE: Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) (control) in 5,145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause or cardiovascular mortality or morbidity during 9.6 (median) years of intervention. Participants in ILI who lost ≥10% at 1 year had lower risk of composite cardiovascular outcomes relative to DSE. Since effects of ILI may take many years to emerge, we conducted intent-to-treat analyses comparing mortality in ILI over 16.7 years (9.6 years of intervention and then observation) to DSE. In a secondary exploratory analysis, we compared mortality by magnitude of weight loss in ILI relative to DSE. RESEARCH DESIGN AND METHODS: Primary outcome was all-cause mortality from randomization to 16.7 years. Other outcomes included cause-specific mortality, interactions by subgroups (age, sex, race/ethnicity, and cardiovascular disease history), and an exploratory analysis by magnitude of weight loss in ILI versus DSE as reference. Analyses used proportional hazards regression and likelihood ratio. RESULTS: The incidence of all-cause mortality did not differ significantly in ILI and DSE (549 and 589 participants, respectively) (hazard ratio [HR] 0.91 [95% CI 0.81, 1.02]; P = 0.11). There were no significant differences between treatments in cause-specific mortality or within prespecified subgroups. ILI participants who lost ≥10% at 1 year had a 21% reduced risk of mortality (HR 0.79 [95% CI 0.67, 0.94]; P = 0.007) relative to DSE. CONCLUSIONS: ILI focused on weight loss did not significantly affect mortality risk. However, ILI participants who lost ≥10% had reduced mortality relative to DSE.

Background The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. Methods We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. Results At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. Conclusions Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.).

OBJECTIVETo conduct post hoc secondary analysis examining the association between change in physical activity. Measured with self-report and accelerometry, from baseline to 1 and 4 years and cardiovascular disease (CVD) outcomes in the Look AHEAD Trial.RESEARCH DESIGN AND METHODSParticipants were adults with overweight/obesity and type 2 diabetes with physical activity. Data at baseline and year 1 or 4 (n = 1,978). Participants were randomized to diabetes support and education or intensive lifestyle intervention. Measures included accelerometry-measured moderate-to-vigorous physical activity (MVPA), self-reported physical activity, and composite (morbidity and mortality) CVD outcomes.RESULTSIn pooled analyses of all participants, using Cox proportional hazards models, each 100 MET-min/week increase in accelerometry-measured MVPA from baseline to 4 years was associated with decreased risk of the subsequent primary composite outcome of CVD. Results were consistent for changes in total MVPA (hazard ratio 0.97 [95% CI 0.95, 0.99]) and MVPA accumulated in ≥10-min bouts (hazard ratio 0.95 [95% CI 0.91, 0.98]), with a similar pattern for secondary CVD outcomes. Change in accelerometry-measured MVPA at 1 year and self-reported change in physical activity at 1 and 4 years were not associated with CVD outcomes.CONCLUSIONSIncreased accelerometry-measured MVPA from baseline to year 4 is associated with decreased risk of CVD outcomes. This suggests the need for long-term engagement in MVPA to reduce the risk of CVD in adults with overweight/obesity and type 2 diabetes.

Background: Young adults with diabetes face transitions in health care (provider, insurance, costs) and commonly have suboptimal glycemic control. We explored healthcare coverage and access to care and their associations with HbA1c, by diabetes type. Methods: In the SEARCH (T1D and T2D) and TODAY (T2D) studies, interviewer-administered surveys collected data on health care coverage at study visits (2017-2019). The associations between healthcare coverage or access and HbA1c were examined separately in T1D and T2D. Results: A total of 1374 participants, mean age 25 years, completed the survey. Mean HbA1c was similar in T1D and T2D for those with public insurance, but higher in T1D with no insurance. Having health insurance and a usual place for diabetes care were associated with lower HbA1c for T1D participants but not for those with T2D (Table). Participants from states with Medicaid eligibility expansion were more likely to have health insurance for T1D: 99% with vs. 91% without expansion; and T2D: 93% with vs. 75% without expansion. Conclusion: Having healthcare coverage and access was associated with better glycemic control for young adults with T1D, but not T2D. Medicaid eligibility expansion was associated with having health insurance. Examining how healthcare access factors affect self-care differently in T1D and T2D is essential. Disclosure C. Pihoker: None. J. Divers: None. P. Zhang: None. D. M. Nathan: None. K. Drews: None. D. Dabelea: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Janssen Research & Development, LLC, Merck & Co., Inc. B. H. Braffett: None. T. Songer: Employee; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc. W. H. Herman: Advisory Panel; Spouse/Partner; Rhythm Pharmaceuticals, Inc., Consultant; Self; RTI International, Other Relationship; Self; American Diabetes Association, American Diabetes Association, American Diabetes Association, International Diabetes Federation, Merck Sharp & Dohme Corp., National Committee for Quality Assurance, National Institute of Diabetes and Digestive and Kidney Diseases, Special Government Employee, Research Support; Spouse/Partner; Nestle. M. Tung: None. S. Kuo: None. A. Bellatorre: None. E. M. Isganaitis: None. E. T. Jensen: None.

Background The role of genetic factors on the risk of cardiovascular disease (CVD) risk in type 1 diabetes remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Methods Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD when adjusted for other factors (including age, lipids, blood pressure and glycemia). Results CAD PRS was strongly associated with the subsequent risk of any-CVD (42% and 38% higher risk per 1 standard deviation (SD) increase in unadjusted and fully adjusted models, respectively, p Conclusions Genetic factors are associated with the risk of subsequent cardiovascular disease in individuals with type 1 diabetes, above and beyond the effect of established risk factors such as age, lipids, blood pressure and glycemia.

While chronic neurological effects from concussion have been studied widely, little is known about possible links between concussion and long-term medical and behavioral comorbidities. We performed a retrospective cohort study of 9205 adult patients with concussion, matched to non-concussion controls from a hospital-based electronic medical registry. Patients with comorbidities before the index visit were excluded. Behavioral and medical comorbidities were defined by International Classification of Diseases, Ninth and Tenth Revision codes. Groups were followed for up to 10 years to identify comorbidity incidence after a concussion. Cox proportional hazards models were used to calculate associations between concussion and comorbidities after multi-variable adjustment. Patients with concussion were 57% male (median age: 31; interquartile range [IQR] = 23–48 years) at enrollment with a median follow-up time of 6.1 years (IQR = 4.2–9.1) and well-matched to healthy controls. Most (83%) concussions were evaluated in outpatient settings (5% inpatient). During follow-up, we found significantly higher risks of cardiovascular risks developing including hypertension (hazard ratio [HR] = 1.7, 95% confidence interval [CI]: 1.5–1.9), obesity (HR = 1.7, 95% CI: 1.3–2.0), and diabetes mellitus (HR = 1.8, 95% CI: 1.4–2.3) in the concussion group compared with controls. Similarly, psychiatric and neurological disorders such as depression (HR = 3.0, 95% CI: 2.6–3.5), psychosis (HR = 6.0, 95% CI: 4.2–8.6), stroke (HR = 2.1 95% CI: 1.5–2.9), and epilepsy (HR = 4.4, 95% CI: 3.2–5.9) were higher in the concussion group. Most comorbidities developed less than five years post-concussion. The risks for post-concussion comorbidities were also higher in patients under 40 years old compared with controls. Patients with concussion demonstrated an increased risk of development of medical and behavioral health comorbidities. Prospective studies are warranted to better describe the burden of long-term comorbidities in patients with concussion.

The introduction of insulin in the treatment of juvenile-onset, now type 1, diabetes mellitus transformed a rapidly fatal disease into a chronic degenerative one. During the insulin-treatment era, long-term microvascular and cardiovascular complications proved to be the bane of existence for people with type 1 diabetes, leading to blindness, kidney failure, amputations, cardiovascular disease (CVD) and premature mortality. The nascent understanding of the link between non-physiologically regulated glucose levels and these complications led to the development of new treatment tools in the 1970s and 1980s that facilitated the delivery of insulin to achieve glucose levels closer to non-diabetic levels. These therapeutic advances set the stage for definitive testing of the glucose hypothesis. The Diabetes Control and Complications Trial (DCCT), supported by the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health (NIH), definitively established the benefits and risks of intensive therapy that substantially lowered mean blood glucose levels, measured by HbA

Older adults with diabetes are heterogeneous in their medical, functional, and cognitive status, and require careful individualisation of their treatment regimens. However, in the absence of detailed information from clinical trials involving older people with varying characteristics, there is little evidence-based guidance, which is a notable limitation of current approaches to care. It is important to recognise that older people with diabetes might vary in their profiles according to age category, functional health, presence of frailty, and comorbidity profiles. In addition, all older adults with diabetes require an individualised approach to care, ranging from robust individuals to those residing in care homes with a short life expectancy, those requiring palliative care, or those requiring end-of-life management. In this Review, our multidisciplinary team of experts describes the current evidence in several important areas in geriatric diabetes, and outlines key research gaps and research questions in each of these areas with the aim to develop evidence-based recommendations to improve the outcomes of interest in older adults.

OBJECTIVE The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia). RESULTS CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE. CONCLUSIONS Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.

Increased risk of neurological and psychiatric conditions after traumatic brain injury (TBI) is well-defined. However, cardiovascular and endocrine comorbidity risk after TBI in individuals without these comorbidities and associations with post-TBI mortality have received little attention.To assess the incidence of cardiovascular, endocrine, neurological, and psychiatric comorbidities in patients with mild TBI (mTBI) or moderate to severe TBI (msTBI) and analyze associations between post-TBI comorbidities and mortality.This prospective longitudinal cohort study used hospital-based patient registry data from a tertiary academic medical center to select patients without any prior clinical comorbidities who experienced TBI from 2000 to 2015. Using the same data registry, individuals without head injuries, the unexposed group, and without target comorbidities were selected and age-, sex-, and race-frequency-matched to TBI subgroups. Patients were followed-up for up to 10 years. Data were analyzed in 2021.Mild or moderate to severe head trauma.Cardiovascular, endocrine, neurologic, and psychiatric conditions were defined based on International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Associations between TBI and comorbidities, as well as associations between the comorbidities and mortality, were analyzed.A total of 4351 patients with mTBI (median [IQR] age, 45 [29-57] years), 4351 patients with msTBI (median [IQR] age, 47 [30-58] years), and 4351 unexposed individuals (median [IQR] age, 46 [30-58] years) were included in analyses. In each group, 45% of participants were women. mTBI and msTBI were significantly associated with higher risks of cardiovascular, endocrine, neurologic, and psychiatric disorders compared with unexposed individuals. In particular, hypertension risk was increased in both mTBI (HR, 2.5; 95% CI, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9) groups. Diabetes risk was increased in both mTBI (HR, 1.9; 95% CI, 1.4-2.7) and msTBI (HR, 1.9; 95% CI, 1.4-2.6) groups, and risk of ischemic stroke or transient ischemic attack was also increased in mTBI (HR, 2.2; 95% CI, 1.4-3.3) and msTBI (HR, 3.6; 95% CI, 2.4-5.3) groups. All comorbidities in the TBI subgroups emerged within a median (IQR) of 3.49 (1.76-5.96) years after injury. Risks for post-TBI comorbidities were also higher in patients aged 18 to 40 years compared with age-matched unexposed individuals: hypertension risk was increased in the mTBI (HR, 5.9; 95% CI, 3.9-9.1) and msTBI (HR, 3.9; 95% CI, 2.5-6.1) groups, while hyperlipidemia (HR, 2.3; 95% CI, 1.5-3.4) and diabetes (HR, 4.6; 95% CI, 2.1-9.9) were increased in the mTBI group. Individuals with msTBI, compared with unexposed patients, had higher risk of mortality (432 deaths [9.9%] vs 250 deaths [5.7%]; P .001); postinjury hypertension (HR, 1.3; 95% CI, 1.1-1.7), coronary artery disease (HR, 2.2; 95% CI, 1.6-3.0), and adrenal insufficiency (HR, 6.2; 95% CI, 2.8-13.0) were also associated with higher mortality.These findings suggest that TBI of any severity was associated with a higher risk of chronic cardiovascular, endocrine, and neurological comorbidities in patients without baseline diagnoses. Medical comorbidities were observed in relatively young patients with TBI. Comorbidities occurring after TBI were associated with higher mortality. These findings suggest the need for a targeted screening program for multisystem diseases after TBI, particularly chronic cardiometabolic diseases.

Aims To analyze mathematical relationships between timed Self-Monitored Blood Glucose (SMBG) and HbA1c, and to identify the SMBG values that correlate most strongly with HbA1c. Methods We utilized the average premeal (Pre) and 90-min postmeal (Post) SMBG results from 547 A1c-Derived Average Glucose (ADAG) study participants (285 type 1, 178 type 2 and 84 non-diabetic) to analyze the mathematical relationships with HbA1c levels. Specific times of daily SMBG that best correlate with HbA1c were identified. Results Linear regression analyses showed the following correlations for Pre and Post, Pre only and Post only, respectively: HbA1c = 2.488 + 0.018 × Premg/dl + 0.012 × Postmg/dl, R2 = 0.741, P Among patients with type 2 diabetes mellitus (DM), of the 6 individual timepoints, pre-dinner SMBG had the strongest correlation with HbA1c (R2 = 0.577). This was followed by pre-breakfast (R2 = 0.562). Examining combinations of timepoints revealed that pre-breakfast + pre-dinner (R2 = 0.666) performed similarly to the full 6-timepoints (pre-meals + post-meals, R2 = 0.712). Conclusions We have established mathematical relationships between HbA1c and timed SMBG values and identified pre-dinner and pre-breakfast as the two SMBG timepoints that best correlate with HbA1c in patients with type 2 DM.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of ‘brain insulin resistance’ and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

Intentional weight loss is an important treatment option for overweight persons with type 2 diabetes mellitus (DM), but the effects on long term fracture risk are not known. The purpose of this Look AHEAD analysis was to evaluate whether long term intentional weight loss would increase fracture risk in overweight or obese persons with DM. Look AHEAD is a multicenter, randomized clinical trial. Recruitment began in August 2001 and follow-up continued for a median of 11.3 years at 16 academic centers. 5145 persons aged 45 – 76 with DM were randomized to either an intensive lifestyle intervention (ILI) with reduced calorie consumption and increased physical activity designed to achieve and maintain ≥7% weight loss or to diabetes support and education intervention (DSE). Incident fractures were ascertained every 6 months by self-report and confirmed with central adjudication of medical records. The baseline mean age of participants was 59 years, 60% were women, 63% were Caucasian, and the mean BMI was 36 kg/m2. Weight loss over the intervention period (median 9.6 years) was 6.0% in ILI and 3.5% in DSE. 731 participants had a confirmed incident fracture (358 in DSE v. 373 in ILI). There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR = 1.39, 95% CI 1.02, 1.89). An intensive lifestyle intervention resulting in long term weight loss in overweight/obese adults with DM was not associated with an overall increased risk of incident fracture but may be associated with an increased risk of frailty fracture. When intentional weight loss is planned, consideration of bone preservation and fracture prevention is warranted.

In “Understanding Metabolic Memory: A Tale of Two Studies,” Miller and Orchard (1) purportedly disprove “metabolic memory.” However, their analyses do not directly address metabolic memory and their interpretations are flawed. The Diabetes Control and Complications Trial (DCCT) (2) demonstrated that randomly assigned intensive therapy, with mean HbA1c of ∼7%, dramatically reduced microvascular complications compared with conventional therapy, with mean HbA1c of ∼9%, an effect entirely attributable to the separation in HbA1c levels between the two groups (3). Afterward, all participants were taught intensive therapy and referred to their physicians for care, resulting in similar HbA1c levels of ∼8% in the two original groups. This would have been predicted to narrow the rate of complications between the original groups. However, with …

OBJECTIVE To assess the cost-effectiveness (CE) of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, as implemented in the Action for Health in Diabetes study. RESEARCH DESIGN AND METHODS Data were from 4,827 participants during their first 9 years of study participation from 2001 to 2012. Information on Health Utilities Index Mark 2 (HUI-2) and HUI-3, Short-Form 6D (SF-6D), and Feeling Thermometer (FT), cost of delivering the interventions, and health expenditures was collected during the study. CE was measured by incremental CE ratios (ICERs) in costs per quality-adjusted life year (QALY). Future costs and QALYs were discounted at 3% annually. Costs were in 2012 U.S. dollars. RESULTS Over the 9 years studied, the mean cumulative intervention costs and mean cumulative health care expenditures were $11,275 and $64,453 per person for ILI and $887 and $68,174 for DSE. Thus, ILI cost $6,666 more per person than DSE. Additional QALYs gained by ILI were not statistically significant measured by the HUIs and were 0.07 and 0.15, respectively, measured by SF-6D and FT. The ICERs ranged from no health benefit with a higher cost based on HUIs to $96,458/QALY and $43,169/QALY, respectively, based on SF-6D and FT. CONCLUSIONS Whether ILI was cost-effective over the 9-year period is unclear because different health utility measures led to different conclusions.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.

Importance Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown. Objective To explore the associations between concussion symptom history and participant-reported indicators of low testosterone levels and ED. Design, Setting, and Participants This cross-sectional study of former professional US-style football players was conducted in Boston, Massachusetts, from January 2015 to March 2017. Surveys on past football exposures, demographic factors, and current health conditions were sent via electronic and postal mail to participants within and outside of the United States. Analyses were conducted in Boston, Massachusetts; the data analysis began in March 2018 and additional analyses were performed through June 2019. Of the 13 720 male former players eligible to enroll who were contacted, 3506 (25.6%) responded. Exposures Concussion symptom score was calculated by summing the frequency with which participants reported 10 symptoms, such as loss of consciousness, disorientation, nausea, memory problems, and dizziness, at the time of football-related head injury. Main Outcomes and Measures Self-reported recommendations or prescriptions for low testosterone or ED medication served as indicators for testosterone insufficiency and ED. Results In 3409 former players (mean [SD] age, 52.5 [14.1] years), the prevalence of indicators of low testosterone levels and ED was 18.3% and 22.7%, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for previously established risk factors (eg, diabetes, sleep apnea, and mood disorders). Models adjusted for demographic characteristics, football exposures, and current health factors showed a significant monotonically increasing association of concussion symptom score with the odds of reporting the low testosterone indicator (highest vs lowest quartile, odds ratio, 2.39; 95% CI, 1.79-3.19;P Conclusions and Relevance Concussion symptoms at the time of injury among former football players were associated with current participant-reported low testosterone levels and ED indicators. These findings suggest that men with a history of head injury may benefit from discussions with their health care clinicians regarding testosterone deficiency and sexual dysfunction.

Point-of-care test (POCT) HbA1c assays provide rapidly available results for clinical decision-making. Accuracy and precision must be established. Venous blood samples from 300 patients were assayed for HbA1c by a laboratory technician (“laboratory assessment”) with the POCT Alere Afinion™ assay and a laboratory (Premier AffinityTM) assay. POCT results from 402 patients’ fingerstick samples assayed by nine nontechnician staff (“clinical assessment”) were compared with the laboratory assay. The laboratory assessment showed tight correlation ( r2= .977, P < .001) between the assays. Mean absolute and relative differences were 0.01 percentage points and 2.1%, respectively. CVs for the POCT and laboratory assays were 2= .978, P < .001), with mean absolute and relative differences of 0.2 percentage points and 3.41%, respectively. CV for the POCT assay was

Context For decades, there has been epidemiologic evidence linking chronic toxic metal exposure with cardiovascular disease, suggesting a therapeutic role for metal chelation. Given the lack of compelling scientific evidence, however, the indications for metal chelation were never clearly defined. To determine the safety and efficacy of chelation therapy, the National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT). TACT was the first double-blind, randomized, controlled trial to demonstrate an improvement in cardiovascular outcomes with edetate disodium therapy in patients with prior myocardial infarction. The therapeutic benefit was striking among the prespecified subgroup of patients with diabetes. Design We review the published literature focusing on the atherogenic nature of diabetes, as well as available evidence from clinical trials, complete and in progress, of metal chelation with edetate disodium therapy in patients with diabetes. Results The TACT results support the concept that ubiquitous toxic metals such as lead and cadmium may be modifiable risk factors for cardiovascular disease, particularly in patients with diabetes. Conclusions The purpose of this review is to discuss the potential mechanisms unifying the pathogenesis of atherogenic factors in diabetes with toxic metal exposure, and the potential role of metal chelation.

Understanding of the long-term clinical outcomes associated with bariatric surgery has recently been advanced. Research related to the sequelae of diabetes—in particular, long-term microvascular and macrovascular complications—in patients who undergo weight-loss surgery is imperative to this pursuit. While numerous randomized control trials have assessed glucose control with bariatric surgery compared with intensive medical therapy, bariatric surgery outcome data relating to microvascular and macrovascular complications have been limited to observational studies and nonrandomized clinical trials. As a result, whether bariatric surgery is associated with a long-term reduction in microvascular and macrovascular complications when compared with current intensive glycemic control therapy cannot be determined because the evidence is insufficient. However, the consistent salutary effects of bariatric surgery on diabetes remission and glycemic improvement support the opportunity (and need) to conduct high-quality studies of bariatric surgery versus intensive glucose control. This review provides relevant background information related to the treatment of diabetes, hyperglycemia, and long-term complications; reports clinical findings (to date) with bariatric surgery; and identifies ongoing research focusing on long-term vascular outcomes associated with bariatric surgery.

AIMS: We assessed whether and to what extent established cardiovascular disease (CVD) risk factors moderate (enhance/reduce) the effect of hyperglycemia on CVD outcomes in the long-term follow-up of the Diabetes Control and Complications Trial type 1 diabetes (T1D) cohort (N=1441). METHODS: Moderation of the effect of glycemia on subsequent risk of major adverse cardiovascular events (MACE: fatal or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure) was assessed separately using interaction terms between HbA1c and other risk factors in Cox proportional hazards models. RESULTS: Over a median follow-up of 29 years, there were 120 MACE cases and 239 any-CVD cases. Higher pulse, higher triglycerides, use of calcium channel blockers, and presence of neuropathy individually enhanced (p

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

Islet autoantibodies are typically associated with type 1 diabetes, but have been found in patients diagnosed with type 2 diabetes in whom they are associated with lower adiposity. The significance of autoantibody positivity in overweight and obese patients is not well understood. The aim of this study was to determine the prevalence and clinical significance of islet autoantibodies in overweight/obese adults diagnosed with type 2 diabetes. This study includes 204 participants at one site of the multicenter Look AHEAD (Action for Health in Diabetes) trial (ClinicalTrials.gov identifier: NCT00017953) which randomized overweight/obese adults diagnosed with type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. We measured antibodies to glutamic acid decarboxylase, insulinoma antigen-2, and zinc transporter 8. Participants with and without autoantibodies were compared with respect to baseline clinical features, and longitudinal changes in weight, hemoglobin A1c, and antihyperglycemic medications. We found that 13 participants (6.4%) were autoantibody positive, including six of 47 participants (12.8%) with BMI ≥40 kg/m2. At baseline, autoantibody positive participants had higher HDL cholesterol (1.27 vs. 1.09 mmol/L, p = .034) and lower fasting C-peptide (0.32 vs. 0.57 nmol/L, p = .049). Over four years, autoantibody positive participants lost 5.1 kg more weight than autoantibody negative participants (p = .056). Longitudinal changes in hemoglobin A1c did not differ by autoantibody status, though autoantibody positive participants were more likely to increase the number of antihyperglycemic medications or initiate insulin (p = .011). In conclusion, islet autoantibodies were present in 6.4% of overweight/obese adults with type 2 diabetes including those with severe obesity, and were associated with distinct clinical features. The effect of autoantibody positivity on weight loss interventions requires further study.

Expert clinicians counter some of the recommendations regarding hemoglobin A1c targets for type 2 diabetes that were proposed in a recent American College of Physicians guideline.