Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity : A Randomized Controlled Trial.

BACKGROUND: Time-restricted eating (TRE) lowers body weight in many studies. Whether TRE induces weight loss independent of reductions in calorie intake, as seen in rodent studies, is unknown. OBJECTIVE: To determine the effect of TRE versus a usual eating pattern (UEP) on body weight in the setting of stable caloric intake. DESIGN: Randomized, isocaloric feeding study. (ClinicalTrials.gov: NCT03527368). SETTING: Clinical research unit. PARTICIPANTS: Adults with obesity and prediabetes or diet-controlled diabetes. INTERVENTION: Participants were randomly assigned 1:1 to TRE (10-hour eating window, 80% of calories before 1 p.m.) or UEP (≤16-hour window, ≥50% of calories after 5 p.m.) for 12 weeks. Both groups had the same nutrient content and were isocaloric with total calories determined at baseline. MEASUREMENTS: Primary outcome was change in body weight at 12 weeks. Secondary outcomes were fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), glucose area under the curve by oral glucose tolerance test, and glycated albumin. We used linear mixed models to evaluate the effect of interventions on outcomes. RESULTS: All 41 randomly assigned participants (mean age, 59 years; 93% women; 93% Black race; mean BMI, 36 kg/m2) completed the intervention. Baseline weight was 95.6 kg (95% CI, 89.6 to 101.6 kg) in the TRE group and 103.7 kg (CI, 95.3 to 112.0 kg) in the UEP group. At 12 weeks, weight decreased by 2.3 kg (CI, 1.0 to 3.5 kg) in the TRE group and by 2.6 kg (CI, 1.5 to 3.7 kg) in the UEP group (average difference TRE vs. UEP, 0.3 kg [CI, -1.2 to 1.9 kg]). Change in glycemic measures did not differ between groups. LIMITATION: Small, single-site study; baseline differences in weight by group. CONCLUSION: In the setting of isocaloric eating, TRE did not decrease weight or improve glucose homeostasis relative to a UEP, suggesting that any effects of TRE on weight in prior studies may be due to reductions in caloric intake. PRIMARY FUNDING SOURCE: American Heart Association.

A Qualitative Study of Perspectives of Older Adults on Deintensifying Diabetes Medications.

BACKGROUND: While many older adults with type 2 diabetes have tight glycemic control beyond guideline-recommended targets, deintensifying (stopping or dose-reducing) diabetes medications rarely occurs. OBJECTIVE: To explore the perspectives of older adults with type 2 diabetes around deintensifying diabetes medications. DESIGN: This qualitative study used individual semi-structured interviews, which included three clinical scenarios where deintensification may be indicated. PARTICIPANTS: Twenty-four adults aged ≥65 years with medication-treated type 2 diabetes and hemoglobin A1c <7.5% were included (to thematic saturation) using a maximal variation sampling strategy for diabetes treatment and physician specialty. APPROACH: Interviews were independently coded by two investigators and analyzed using a grounded theory approach. We identified major themes and subthemes and coded responses to the clinical scenarios as positive (in favor of deintensification), negative, or ambiguous. KEY RESULTS: Participants' mean age was 74 years, half were women, and 58% used a sulfonylurea or insulin. The first of four major themes was fear of losing control of diabetes, which participants weighed against the benefits of taking less medication (Theme 2). Few participants viewed glycemic control below target as a reason for deintensification and a majority would restart the medication if their home glucose increased. Some participants were anchored to their current diabetes treatment (Theme 3) driven by unrealistic views of medication benefits. A trusting patient-provider relationship (Theme 4) was a positive influence. In clinical scenarios, 8%, 4%, and 75% of participants viewed deintensification positively in the setting of poor health, limited life expectancy, and high hypoglycemia risk, respectively. CONCLUSIONS: Optimizing deintensification requires patient education that describes both individualized glycemic targets and how they will change over the lifespan. Deintensification is an opportunity for shared decision-making, but providers must understand patients' beliefs about their medications and address misconceptions. Hypoglycemia prevention may be a helpful framing for discussing deintensification.

Engaging Payors and Primary Care Physicians Together in Improving Diabetes Prevention.

BACKGROUND: Type 2 diabetes can be prevented through lifestyle programs like the Diabetes Prevention Programs (DPP), but few people with prediabetes participate in them, in part because their insurance does not reliably cover DPPs. Prior studies have not focused on payor-level barriers. OBJECTIVE: To understand barriers to DPP uptake that exist and intersect at different levels (patients, PCPs, and payors) to inform strategies to improve diabetes prevention in primary care settings through interviews with PCPs and payors. DESIGN: From May 2020 to October 2021, we conducted remote, semi-structured interviews with PCPs and payors. PARTICIPANTS: PCPs were from primary care practices affiliated with one mid-Atlantic academic system. Payor leaders were from regional commercial, Medicare, and Medicaid plans. APPROACH: Using a standardized interview guide focused on barriers, facilitators, and potential intervention components, interviews were audio-recorded using Zoom and professionally transcribed. Two reviewers double-coded transcripts using the framework analytic approach. KEY RESULTS: We interviewed 16 PCPs from 13 primary care clinics and 7 payor leaders representing 6 insurance plans. Two themes emerged from PCP reports of patient-level barriers: (1) lack of programs and insurance coverage of resources to address nutrition and exercise and (2) inadequate resources to address social determinants of health that impact diabetes prevention. Among barriers PCPs faced, we identified two themes: (1) low PCP knowledge about DPPs and misperceptions of insurance coverage of DPPs and (2) inadequate clinical staff to address diabetes prevention. Barriers common to PCPs and payors included (1) absence of prediabetes quality measures and (2) inadequate engagement of PCPs and patients with payors. CONCLUSIONS: Discussions with PCPs and payors revealed systemic barriers that suggest important priorities to improve prediabetes clinical care, including universal coverage of DPPs, clarity about coverage benefits, data reporting and outreach by payors to PCPs, and adoption of appropriate prediabetes quality measures.

A National Survey of Physicians' Views on the Importance and Implementation of Deintensifying Diabetes Medications.

BACKGROUND: Guidelines recommend deintensifying hypoglycemia-causing medications for older adults with diabetes whose hemoglobin A1c is below their individualized target, but this rarely occurs in practice. OBJECTIVE: To understand physicians' decision-making around deintensifying diabetes treatment. DESIGN: National physician survey. PARTICIPANTS: US physicians in general medicine, geriatrics, or endocrinology providing outpatient diabetes care. MAIN MEASURES: Physicians rated the importance of deintensifying diabetes medications for older adults with type 2 diabetes, and of switching medication classes, on 5-point Likert scales. They reported the frequency of these actions for their patients, and listed important barriers and facilitators. We evaluated the independent association between physicians' professional and practice characteristics and the importance of deintensifying and switching diabetes medications using multivariable ordered logistic regression models. KEY RESULTS: There were 445 eligible respondents (response rate 37.5%). The majority of physicians viewed deintensifying (80%) and switching (92%) diabetes medications as important or very important to the care of older adults. Despite this, one-third of physicians reported deintensifying diabetes medications rarely or never. While most physicians recognized multiple reasons to deintensify, two-thirds of physicians reported barriers of short-term hyperglycemia and patient reluctance to change medications or allow higher glucose levels. In multivariable models, geriatricians rated deintensification as more important compared to other specialties (p=0.027), and endocrinologists rated switching as more important compared to other specialties (p<0.006). Physicians with fewer years in practice rated higher importance of deintensification (p<0.001) and switching (p=0.003). CONCLUSIONS: While most US physicians viewed deintensifying and switching diabetes medications as important for the care of older adults, they deintensified infrequently. Physicians had ambivalence about the relative benefits and harms of deintensification and viewed it as a potential source of conflict with their patients. These factors likely contribute to clinical inertia, and studies focused on improving shared decision-making around deintensifying diabetes medications are needed.

Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

Clinical Care Among Individuals with Prediabetes in Primary Care: a Retrospective Cohort Study.

BACKGROUND: The incidence of diabetes in the general US population (6.7 per 1000 adults in 2018) has not changed significantly since 2000, suggesting that individuals with prediabetes are not connecting to evidence-based interventions. OBJECTIVE: We sought to describe the clinical care of individuals with prediabetes, determine patient factors associated with this care, and evaluate risk for diabetes development. DESIGN: Retrospective cohort study using linked claims and electronic health record data. PARTICIPANTS: We created a cohort of adults with prediabetes based on laboratory measures. We excluded patients with a prior history of diabetes, pregnancy in prior 6 months, or recent steroid use. MAIN MEASURES: We measured ordering and completion of clinical services targeting prediabetes management and diabetes incidence within 12 months following cohort entry. We tested the strength of the association between individuals' characteristics and outcomes of interest using bivariate and multiple logistic regression. RESULTS: Our cohort included 3888 patients with a laboratory diagnosis of prediabetes (incident or prevalent prediabetes). Within 12 months, 63.4% had repeat glycemic testing, yet only 10.4% had coded diagnoses of prediabetes, 1.0% were referred for nutrition services, and 5.4% were prescribed metformin. Most patients completed labs and nutrition visits when referred and filled metformin when prescribed. Individuals with a higher glycemic level or BMI were more likely to receive prediabetes clinical care. Six percent of individuals developed diabetes within 12 months of cohort entry and had higher glycemic levels and BMI ≥ 30 kg/m2. In the adjusted model, Black individuals had 1.4 times higher odds of developing diabetes than White individuals. CONCLUSIONS: Rates of prediabetes clinical care activities are low and have not improved. Strategies are urgently needed to improve prediabetes care delivery thereby preventing or delaying incident diabetes.

Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are a recent class of medication approved for the treatment of type 2 diabetes (T2D). Previous meta-analyses have quantified the benefits and harms of SGLT2Is; however, these analyses have been limited to specific outcomes and comparisons and included trials of short duration. We comprehensively reviewed the longer-term benefits and harms of SGLT2Is compared to placebo or other anti-hyperglycemic medications. METHODS: We searched PubMed, Scopus, and clinicaltrials.gov from inception to July 2019 for randomized controlled trials of minimum 52 weeks' duration that enrolled adults with T2D, compared an SGLT2I to either placebo or other anti-hyperglycemic medications, and reported at least one outcome of interest including cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events. We conducted random effects meta-analyses to provide summary estimates using weighted mean differences (MD) and pooled relative risks (RR). The study was registered a priori with PROSPERO (CRD42018090506). RESULTS: Fifty articles describing 39 trials (vs. placebo, n = 28; vs. other anti-hyperglycemic medication, n = 12; vs. both, n = 1) and 112,128 patients were included in our analyses. Compared to placebo, SGLT2Is reduced cardiovascular risk factors (e.g., hemoglobin A1c, MD - 0.55%, 95% CI - 0.62, - 0.49), macrovascular outcomes (e.g., hospitalization for heart failure, RR 0.70, 95% CI 0.62, 0.78), and mortality (RR 0.87, 95% CI 0.80, 0.94). Compared to other anti-hyperglycemic medications, SGLT2Is reduced cardiovascular risk factors, but insufficient data existed for other outcomes. About a fourfold increased risk of genital yeast infections for both genders was observed for comparisons vs. placebo and other anti-hyperglycemic medications. DISCUSSION: We found that SGLT2Is led to durable reductions in cardiovascular risk factors compared to both placebo and other anti-hyperglycemic medications. Reductions in macrovascular complications and mortality were only observed in comparisons with placebo, although trials comparing SGLT2Is vs. other anti-hyperglycemic medications were not designed to assess longer-term outcomes.

The Longer-Term Benefits and Harms of Glucagon-Like Peptide-1 Receptor Agonists: a Systematic Review and Meta-Analysis.

BACKGROUND: Previous meta-analyses of the benefits and harms of glucagon-like peptide-1 receptor agonists (GLP1RAs) have been limited to specific outcomes and comparisons and often included short-term results. We aimed to estimate the longer-term effects of GLP1RAs on cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events in patients with type 2 diabetes, compared to placebo and other anti-hyperglycemic medications. METHODS: We searched PubMed, Scopus, and clinicaltrials.gov (inception-July 2019) for randomized controlled trials ≥ 52 weeks' duration that compared a GLP1RA to placebo or other anti-hyperglycemic medication and included at least one outcome of interest. Outcomes included cardiovascular risk factors, microvascular and macrovascular complications, all-cause mortality, and treatment-related adverse events. We performed random effects meta-analyses to give summary estimates using weighted mean differences (MD) and pooled relative risks (RR). Risk of bias was assessed using the Cochrane Collaboration risk of bias in randomized trials tool. Quality of evidence was summarized using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The study was registered a priori with PROSPERO (CRD42018090506). RESULTS: Forty-five trials with a mean duration of 1.7 years comprising 71,517 patients were included. Compared to placebo, GLP1RAs reduced cardiovascular risk factors, microvascular complications (including renal events, RR 0.85, 0.80-0.90), macrovascular complications (including stroke, RR 0.86, 0.78-0.95), and mortality (RR 0.89, 0.84-0.94). Compared to other anti-hyperglycemic medications, GLP1RAs only reduced cardiovascular risk factors. Increased gastrointestinal events causing treatment discontinuation were observed in both comparisons. DISCUSSION: GLP1RAs reduced cardiovascular risk factors and increased gastrointestinal events compared to placebo and other anti-hyperglycemic medications. GLP1RAs also reduced MACE, stroke, renal events, and mortality in comparisons with placebo; however, analyses were inconclusive for comparisons with other anti-hyperglycemic medications. Given the high costs of GLP1RAs, the lack of long-term evidence comparing GLP1RAs to other anti-hyperglycemic medications has significant policy and clinical practice implications.

Hypoglycemia Communication in Primary Care Visits for Patients with Diabetes.

BACKGROUND: Hypoglycemia is a common and serious adverse effect of diabetes treatment, especially for patients using insulin or insulin secretagogues. Guidelines recommend that these patients be assessed for interval hypoglycemic events at each clinical encounter and be provided anticipatory guidance for hypoglycemia prevention. OBJECTIVE: To determine the frequency and content of hypoglycemia communication in primary care visits. DESIGN: Qualitative study PARTICIPANTS: We examined 83 primary care visits from one urban health practice representing 8 clinicians and 33 patients using insulin or insulin secretagogues. APPROACH: Using a directed content analysis approach, we analyzed audio-recorded primary care visits collected as part of the Achieving Blood Pressure Control Together study, a randomized trial of behavioral interventions for hypertension. The coding framework included communication about interval hypoglycemia, defined as discussion of hypoglycemic events or symptoms; the components of hypoglycemia anticipatory guidance in diabetes guidelines; and hypoglycemia unawareness. Hypoglycemia documentation in visit notes was compared to visit transcripts. KEY RESULTS: Communication about interval hypoglycemia occurred in 24% of visits, and hypoglycemic events were reported in 16%. Despite patients voicing fear of hypoglycemia, clinicians rarely assessed hypoglycemia frequency, severity, or its impact on quality of life. Hypoglycemia anticipatory guidance was provided in 21% of visits which focused on diet and behavior change; clinicians rarely counseled on hypoglycemia treatment or avoidance of driving. Limited discussions of hypoglycemia unawareness occurred in 8% of visits. Documentation in visit notes had low sensitivity but high specificity for ascertaining interval hypoglycemia communication or hypoglycemic events, compared to visit transcripts. CONCLUSIONS: In this high hypoglycemia risk population, communication about interval hypoglycemia and counseling for hypoglycemia prevention occurred in a minority of visits. There is a need to support clinicians to more regularly assess their patients' hypoglycemia burden and enhance counseling practices in order to optimize hypoglycemia prevention in primary care.

Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Programme.

AIM: To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. MATERIALS AND METHODS: We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. RESULTS: A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. CONCLUSIONS: Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.

National Survey of Primary Care Physicians' Knowledge, Practices, and Perceptions of Prediabetes.

BACKGROUND: Despite strong evidence and national policy supporting type 2 diabetes prevention, little is known about type 2 diabetes prevention in the primary care setting. OBJECTIVE: Our objective was to assess primary care physicians' knowledge and practice regarding perceived barriers and potential interventions to improving management of prediabetes. DESIGN: Cross-sectional mailed survey. PARTICIPANTS: Nationally representative random sample of US primary care physicians (PCPs) identified from the American Medical Association Physician Masterfile. MAIN MEASURES: We assessed PCP knowledge, practice behaviors, and perceptions related to prediabetes. We performed chi-square and Fisher's exact tests to evaluate the association between PCP characteristics and the main survey outcomes. KEY RESULTS: In total, 298 (33%) eligible participants returned the survey. PCPs had limited knowledge of risk factors for prediabetes screening, laboratory diagnostic criteria for prediabetes, and management recommendations for patients with prediabetes. Only 36% of PCPs refer patients to a diabetes prevention lifestyle change program as their initial management approach, while 43% discuss starting metformin for prediabetes. PCPs believed that barriers to type 2 diabetes prevention are both at the individual level (e.g., patients' lack of motivation) and at the system level (e.g., lack of weight loss resources). PCPs reported that increased access to and insurance coverage of type 2 diabetes prevention programs and coordination of referral of patients to these resources would facilitate type 2 diabetes preventive efforts. CONCLUSIONS: Addressing gaps in PCP knowledge may improve the identification and management of people with prediabetes, but system-level changes are necessary to support type 2 diabetes prevention in the primary care setting.

Approaches to Risk Assessment Among Older Patients With Diabetes.

PURPOSE OF REVIEW: A patient's prognosis and risk of adverse drug effects are important considerations for individualizing care of older patients with diabetes. This review summarizes the evidence for risk assessment and proposes approaches for clinicians in the context of current clinical guidelines. RECENT FINDINGS: Diabetes guidelines vary in their recommendations for how life expectancy should be estimated and used to inform the selection of glycemic targets. Readily available prognostic tools may improve estimation of life expectancy but require validation among patients with diabetes. Treatment decisions based on prognosis are difficult for clinicians to communicate and for patients to understand. Determining hypoglycemia risk involves assessing major risk factors; models to synthesize these factors have been developed. Applying risk assessment to individualize diabetes care is complex and currently relies heavily on clinician judgment. More research is need to validate structured approaches to risk assessment and determine how to incorporate them into patient-centered diabetes care.

Predictors of Insulin Initiation in Patients with Type 2 Diabetes: An Analysis of the Look AHEAD Randomized Trial.

BACKGROUND: The decision to initiate insulin in patients with type 2 diabetes is a challenging escalation of care that requires an individualized approach. However, the sociodemographic and clinical factors affecting insulin initiation are not well understood. OBJECTIVE: We sought to identify patient factors that were independent predictors of insulin initiation among participants in the Look AHEAD (Action for Health in Diabetes) clinical trial. DESIGN: Retrospective analysis of a randomized clinical trial. PARTICIPANTS: Beginning in 2001, Look AHEAD enrolled ambulatory U.S. adults with type 2 diabetes who were overweight or obese and had a primary healthcare provider. Participants were randomized (1:1) to an intensive lifestyle intervention, or diabetes support and education. This study examined 3913 participants across the two trial arms who were not using insulin at baseline. MAIN MEASURES: We used Cox proportional hazards models to estimate the association between participant characteristics and time to insulin initiation. We performed time-varying adjustment for HbA1c measured eight times over the 10-year study period, as well as for multiple clinical and socioeconomic factors. KEY RESULTS: A total of 1087 participants (27.8%) initiated insulin during a median follow-up of 8.0 years. Age was inversely associated with insulin initiation (adjusted hazard ratio [aHR] 0.88 per 10 years, P = 0.025). The risk of insulin initiation was greater with a higher number of diabetes complications (P < 0.001 for trend); chronic kidney disease and cardiovascular disease were independently associated with insulin initiation. There was a lower risk of insulin initiation in black (aHR 0.77, P = 0.008) and Hispanic participants (aHR 0.66, P < 0.001) relative to white participants. Socioeconomic factors were not associated with insulin initiation. CONCLUSIONS: Patient age, race/ethnicity, and diabetes complications may influence insulin initiation in type 2 diabetes, independent of glycemic control. Future work is needed to understand the drivers of racial differences in antihyperglycemic treatment, and to identify patients who benefit most from insulin.

Team-Based Health Information Exchange Use Increased Mammography Documentation and Referral in an Academic Primary Care Practice: An Interrupted Time Series.

BACKGROUND: Few studies have examined the impact of health information exchanges (HIE) on quality in ambulatory settings. METHODS: From September 29, 2014, to September 4, 2015, we conducted an interrupted time series analysis of query-based use of the state HIE as part of team-based care to improve mammography screening in an academic primary care practice. Women aged 50-74 years with a practice visit and who were eligible for mammography were included. We conducted non-parametric data analysis using LOESS, followed by ARIMA analysis. RESULTS: During the study period, there were 2020 visits among 904 eligible patients, including 648 visits among 485 patients during 16 baseline weeks, and 1372 visits by 755 patients during 33 intervention weeks. During the intervention period, 16.0% of eligible women who were not up to date in our EHR had a mammogram in the HIE. Of eligible women, the proportion who had a documented up-to-date mammogram at the time of their visit increased by 11.3%, from 73.4% at baseline to 84.7% (p < 0.0001), the proportion who had mammography addressed at the time of their visit increased by 42.7%, from 32.7% at baseline to 75.4% (p < 0.0001), and the proportion who were up to date at 8 weeks post-visit increased by 11.7%, from 76.3% at baseline to 88.0% (p < 0.0001). DISCUSSION: Query-based use of the state HIE as part of team-based care improved documentation of mammography and led to an increase in the proportion of eligible women who received counseling on mammography screening in one primary care practice. These results suggest that HIE use in primary care could lead to improved delivery of other preventive services.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Survey of primary care providers' knowledge of screening for, diagnosing and managing prediabetes.

BACKGROUND: Prediabetes affects 86 million US adults, but primary care providers' (PCPs') knowledge, practices, attitudes and beliefs toward prediabetes are unclear. OBJECTIVE: Assess PCPs' (1) knowledge of risk factors that should prompt prediabetes screening, laboratory criteria for diagnosing prediabetes and guidelines for management of prediabetes; (2) management practices around prediabetes; (3) attitudes and beliefs about prediabetes. DESIGN: Self-administered written survey of PCPs. PARTICIPANTS: One hundred forty of 155 PCPs (90%) attending an annual provider retreat for academically affiliated multispecialty practices in the mid-Atlantic region. MAIN MEASURES: Descriptive analyses of survey questions on knowledge, management, and attitudes and beliefs related to prediabetes. Multivariate logistic regression was used to determine the association between provider characteristics (gender, race/ethnicity, years since training, specialty and provider type) and knowledge, management, and attitudes and beliefs about prediabetes. KEY RESULTS: Six percent of PCPs correctly identified all of the risk factors that should prompt prediabetes screening. Only 17% of PCPs correctly identified the laboratory parameters for diagnosing prediabetes based on both fasting glucose and hemoglobin A1c. Nearly 90% of PCPs reported close follow-up (within 6 months) of patients with prediabetes. Few PCPs (11%) selected referral to a behavioral weight loss program as the recommended initial management approach to prediabetes. PCPs agreed that patient-related factors are important barriers to lifestyle change and metformin use. Provider characteristics were generally not associated with knowledge, management, attitudes and beliefs about prediabetes in multivariate analyses. CONCLUSIONS: Addressing gaps in knowledge and the underutilization of behavioral weight loss programs in prediabetes are two essential areas where PCPs could take a lead in curbing the diabetes epidemic.

Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices. PURPOSE: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes. DATA SOURCES: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015). STUDY SELECTION: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. DATA EXTRACTION: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. DATA SYNTHESIS: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. LIMITATION: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes. CONCLUSION: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Implementing the Comprehensive Unit-Based Safety Program (CUSP) to Improve Patient Safety in an Academic Primary Care Practice.

BACKGROUND: While there is growing awareness of the risk of harm in ambulatory health care, most patient safety efforts have focused on the inpatient setting. The Comprehensive Unit-based Safety Program (CUSP) has been an integral part of highly successful safety efforts in inpatient settings. In 2014 CUSP was implemented in an academic primary care practice. METHODS: As part of CUSP implementation, staff and clinicians underwent training on the science of safety and completed a two-question safety assessment survey to identify safety concerns in the practice. The concerns identified by team members were used to select two initial safety priorities. The impact of CUSP on safety climate and teamwork was assessed through a pre-post comparison of results on the validated Safety Attitudes Questionnaire. RESULTS: Ninety-six percent of staff completed science of safety training as part of CUSP implementation, and 100% of staff completed the two-question safety assessment. The most frequently identified safety concerns were related to medications (n = 11, 28.2), diagnostic testing (n = 9, 25), and communication (n = 5, 14). The CUSP team initially prioritized communication and infection control, which led to standardization of work flows within the practice. Six months following CUSP implementation, large but nonstatistically significant increases were found for the percentage of survey respondents who reported knowledge of the proper channels for questions about patient safety, felt encouraged to report safety concerns, and believed that the work setting made it easy to learn from the errors of others. CONCLUSION: CUSP is a promising tool to improve safety climate and to identify and address safety concerns within ambulatory health care.

Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity.

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.