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.

Diabetic Kidney Disease Prevention Care Model Development.

More than one-third of people with diabetes develop diabetic kidney disease (DKD), which substantially increases risks of kidney failure, cardiovascular disease (CVD), hypoglycemia, death, and other adverse health outcomes. A multifaceted approach incorporating self-management education, lifestyle optimization, pharmacological intervention, CVD prevention, and psychosocial support is crucial to mitigate the onset and progression of DKD. The American Diabetes Association convened an expert panel to develop the DKD Prevention Model presented herein. This model addresses prevention and treatment, including screening guidelines, diagnostic tools, and management approaches; comprehensive, holistic interventions; well-defined roles for interdisciplinary health care professionals; community engagement; and future directions for research and policy.

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.

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.

Provider Response to Critical Action Values for Hypoglycemia in the Ambulatory Setting: a Retrospective Cohort Study.

BACKGROUND: The blood glucose level triggering a critical action value (CAV) for hypoglycemia is not standardized, and associated outcomes are unknown. OBJECTIVE: To evaluate the clinical consequences of, and provider responses to, CAVs for hypoglycemia. DESIGN: Retrospective cohort study at Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center between April 1, 2013, and January 31, 2017. PARTICIPANTS: Patients with an ambulatory serum glucose < 50 mg/dL. Point-of-care capillary glucose and whole blood glucose samples were excluded. MAIN MEASURES: Electronic medical record (EMR) review for providers' documented response to CAV, associated patient symptoms, and serious adverse events. KEY RESULTS: We analyzed 209 CAVs for hypoglycemia from 154 patients. The median age (IQR) was 59 years (46, 69), 89 (57.8%) were male, and 96 (62.3%) were black. Provider-to-patient contact occurred in 128 of 209 (61.2%) episodes, among which no documented etiology was observed for 81 of 128 (63.3%), no recommendations were provided in 32 of 128 (25.0%), and no patient-reported hypoglycemic symptoms were documented in 103 of 128 (80.5%). Serious adverse events were documented in 4 of 128 episodes (3.1%), two required glucagon administration, and three required an ED visit. Provider-to-patient contact was associated with the patient having malignant neoplasm (adjusted OR 3.63, p = 0.045) or a hypoglycemic disorder (adjusted OR 7.70, p = 0.018) and inversely associated with a longer time from specimen collection to EMR result (adjusted OR 0.90 per hour, p = 0.016). CONCLUSIONS: There is inconsistent provider-to-patient contact following CAVs for hypoglycemia, and the etiology and symptoms of hypoglycemia were infrequently documented. There were few serious documented adverse events associated with hypoglycemia, although undocumented events may have occurred, and the incidence of serious adverse events in non-contacted patients remains unknown. These findings demonstrate a need to standardize provider response to CAVs for hypoglycemia. Decreasing the lag time between sample collection and laboratory result reporting may increase provider-to-patient contact.

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.

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.

Immune-Modulating Therapy for Rheumatologic Disease: Implications for Patients with Diabetes.

Immune modulators used to treat rheumatologic disease have diverse endocrine effects in patients with diabetes. Providers should be aware of these effects given that diabetes and rheumatologic disease overlap in prevalence and cardiovascular morbidity. In patients with type 1 diabetes, clinical trials have demonstrated that immune modulators used early in the disease can improve pancreatic function, though their efficacy in adults with longstanding autoimmune diabetes is unknown. In patients with type 2 diabetes, hydroxychloroquine is an effective antihyperglycemic and may be preferred for rheumatologic use in patients with difficult glycemic control. In patients without diabetes, hydroxychloroquine and tumor necrosis factor (TNF) inhibitors have been found to decrease diabetes incidence in observational studies. Additionally, dapsone and sulfasalazine alter erythrocyte survival resulting in inaccurate HbA1c values. These multifaceted effects of immune modulators create a need for coordinated care between providers treating patients with diabetes to individualize medication selection and prevent hypoglycemic events. More research is needed to determine the long-term outcomes of immune modulators in patients with diabetes.

Association of Lifestyle Intervention With Risk for Cardiovascular Events Differs by Level of Glycated Hemoglobin.

PURPOSE: We reevaluated the Action for Health in Diabetes (Look AHEAD) intensive lifestyle intervention (ILI) to assess whether the effect of ILI on cardiovascular disease (CVD) prevention differed by baseline glycated hemoglobin (HbA1c). METHODS: Look AHEAD randomized 5145 adults, aged 45 to 76 years with type 2 diabetes and overweight/obesity to ILI or a diabetes support and education (DSE) control group for a median of 9.6 years. ILI focused on achieving weight loss through decreased caloric intake and increased physical activity. We assessed the parent trial's primary composite CVD outcome. We evaluated additive and multiplicative heterogeneity of the intervention on CVD risk by baseline HbA1c. RESULTS: Mean baseline HbA1c was 7.3% (SD 1.2) and ranged from 4.4% (quintile 1) to 14.5% (quintile 5). We observed additive and multiplicative heterogeneity of the association between ILI and CVD (all P < .001) by baseline HbA1c. Randomization to ILI was associated with lower CVD risk for HbA1c quintiles 1 [hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.53, 0.88] and 2 (HR: 0.80, 95% CI: 0.66, 0.96) and associated with higher CVD risk for HbA1c quintile 5 (HR: 1.27, 95% CI: 1.02, 1.58), compared to DSE. CONCLUSION: Among adults with type 2 diabetes and overweight/obesity, randomization to a lifestyle intervention was differentially associated with CVD risk by baseline HbA1c such that it was associated with lower risk at lower HbA1c levels and higher risk at higher HbA1c levels. There is a critical need to develop and tailor lifestyle interventions to be successful for individuals with type 2 diabetes and high HbA1c.

Within and post-trial effects of an intensive lifestyle intervention on kidney disease in adults with overweight or obesity and type 2 diabetes mellitus: a secondary analysis of the Look AHEAD clinical trial.

INTRODUCTION: The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45-76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial's secondary outcome of kidney disease. RESEARCH DESIGN AND METHODS: We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m2 or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall). RESULTS: Incidence of eGFR <45 mL/min/1.73 m2 was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m2 and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m2; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m2 by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits. CONCLUSIONS: ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.

A National Physician Survey of Deintensifying Diabetes Medications for Older Adults With Type 2 Diabetes.

OBJECTIVE: To determine physicians' approach to deintensifying (reducing/stopping) or switching hypoglycemia-causing medications for older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this national survey, U.S. physicians in general medicine, geriatrics, or endocrinology reported changes they would make to hypoglycemia-causing medications for older adults in three scenarios: good health, HbA1c of 6.3%; complex health, HbA1c of 7.3%; and poor health, HbA1c of 7.7%. RESULTS: There were 445 eligible respondents (response rate 37.5%). In patient scenarios, 48%, 4%, and 20% of physicians deintensified hypoglycemia-causing medications for patients with good, complex, and poor health, respectively. Overall, 17% of physicians switched medications without significant differences by patient health. One-half of physicians selected HbA1c targets below guideline recommendations for older adults with complex or poor health. CONCLUSIONS: Most U.S. physicians would not deintensify or switch hypoglycemia-causing medications within guideline-recommended HbA1c targets. Physician preference for lower HbA1c targets than guidelines needs to be addressed to optimize deintensification decisions.

An Examination of Whether Diabetes Control and Treatments Are Associated With Change in Frailty Index Across 8 Years: An Ancillary Exploratory Study From the Action for Health in Diabetes (Look AHEAD) Trial.

OBJECTIVE: The aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging. RESEARCH DESIGN AND METHODS: We conducted exploratory analyses from 4,169 participants, aged 45-76 years, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up. RESULTS: Baseline and average HbA1c levels over time of <7%, as compared with ≥8%, were associated with less increase in FI scores over 8 years (both P ≤ 0.002). After adjustment for HbA1c, use of metformin and weight loss >5% were independently associated with slower increases in frailty. CONCLUSIONS: Lower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

Design and Implementation of a Time-Restricted Eating Intervention in a Randomized, Controlled Eating Study.

The efficacy of time-restricted eating for weight loss has not been established, as prior studies were limited by a lack of controlled isocaloric designs. This study describes the design and implementation of interventions in a controlled eating study evaluating time-restricted eating. We designed a randomized, controlled, parallel-arm eating study comparing time-restricted eating (TRE) to a usual eating pattern (UEP) for the primary outcome of weight change. Participants were aged 21-69 years with prediabetes and obesity. TRE consumed 80% of calories by 1300 h (military time), and UEP consumed ≥ 50% of calories after 1700 h (military time). Both arms consumed identical macro- and micro-nutrients based on a healthy, palatable diet. We calculated individual calorie requirements, which were maintained throughout the intervention. The desired distribution of calories across eating windows in both arms was achieved, as were the weekly averages for macronutrients and micronutrients. We actively monitored participants and adapted diets to facilitate adherence. We provide the first report, to our knowledge, on the design and implementation of eating study interventions that isolated the effect of meal timing on weight while maintaining constant caloric intake and identical diets during the study period.

Assessment and prevention of hypoglycaemia in primary care among U.S. Veterans: a mixed methods study.

Background: Hypoglycaemia from diabetes treatment causes morbidity and lower quality of life, and prevention should be routinely addressed in clinical visits. Methods: This mixed methods study evaluated how primary care providers (PCPs) assess for and prevent hypoglycaemia by analyzing audio-recorded visits from five Veterans Affairs medical centres in the US. Two investigators independently coded visit dialogue to classify discussions of hypoglycaemia history, anticipatory guidance, and adjustments to hypoglycaemia-causing medications according to diabetes guidelines. Findings: There were 242 patients (one PCP visit per patient) and 49 PCPs. Two thirds of patients were treated with insulin and 40% with sulfonylureas. Hypoglycaemia history was discussed in 78/242 visits (32%). PCPs provided hypoglycaemia anticipatory guidance in 50 visits (21%) that focused on holding diabetes medications while fasting and carrying glucose tabs; avoiding driving and glucagon were not discussed. Hypoglycaemia-causing medications were de-intensified or adjusted more often (p < 0.001) when the patient reported a history of hypoglycaemia (15/51 visits, 29%) than when the patient reported no hypoglycaemia or it was not discussed (6/191 visits, 3%). Haemoglobin A1c (HbA1c) was not associated with diabetes medication adjustment, and only 5/12 patients (42%) who reported hypoglycaemia with HbA1c <7.0% had medications de-intensified or adjusted. Interpretation: PCPs discussed hypoglycaemia in one-third of visits for at-risk patients and provided limited hypoglycaemia anticipatory guidance. De-intensifying or adjusting hypoglycaemia-causing medications did not occur routinely after reported hypoglycaemia with HbA1c <7.0%. Routine hypoglycaemia assessment and provision of diabetes self-management education are needed to achieve guideline-concordant hypoglycaemia prevention. Funding: U.S. Department of Veterans Affairs and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review.

BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. METHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. RESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes. CONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

This study reviews the available evidence on which patient features (such as age, sex, and blood test results) are associated with different outcomes for two recently introduced type 2 diabetes medications: SGLT2-inhibitors and GLP1-receptor agonists. Understanding what individual characteristics are associated with different response patterns may help clinical providers and people living with diabetes make more informed decisions about which type 2 diabetes treatments will work best for an individual. We focus on three outcomes: blood glucose levels (raised blood glucose is the primary symptom of diabetes and a primary aim of diabetes treatment is to lower this), heart disease, and kidney disease. We identified some potential factors that reduce effects on blood glucose levels, including poorer kidney function for SGLT2-inhibitors and lower production of the glucose-lowering hormone insulin for GLP1-receptor agonists. We did not identify clear factors that alter heart and kidney disease outcomes for either medication. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes.

Precision medicine in type 2 diabetes: A systematic review of treatment effect heterogeneity for GLP1-receptor agonists and SGLT2-inhibitors.

Background: A precision medicine approach in type 2 diabetes requires identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. Results: After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. The majority of papers had methodological limitations precluding robust assessment of treatment effect heterogeneity. For glycaemic outcomes, most cohorts were observational, with multiple analyses identifying lower renal function as a predictor of lesser glycaemic response with SGLT2-inhibitors and markers of reduced insulin secretion as predictors of lesser response with GLP1-receptor agonists. For cardiovascular and renal outcomes, the majority of included studies were post-hoc analyses of randomized control trials (including meta-analysis studies) which identified limited clinically relevant treatment effect heterogeneity. Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care. Plain language summary: This review identifies research that helps understand which clinical and biological factors that are associated with different outcomes for specific type 2 diabetes treatments. This information could help clinical providers and patients make better informed personalized decisions about type 2 diabetes treatments. We focused on two common type 2 diabetes treatments: SGLT2-inhibitors and GLP1-receptor agonists, and three outcomes: blood glucose control, heart disease, and kidney disease. We identified some potential factors that are likely to lessen blood glucose control including lower kidney function for SGLT2-inhibitors and lower insulin secretion for GLP1-receptor agonists. We did not identify clear factors that alter heart and renal disease outcomes for either treatment. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.