Prototype of an evidence-based tool to aid individualized treatment for type 2 diabetes.

Data-driven tools are needed to inform individualized treatment decisions for people with type 2 diabetes (T2D). To show how treatment might be individualized, an interactive outline tool was developed to predict treatment outcomes. Individualized predictions were generated for change in HbA1c and body weight after initiation of newer antidiabetes drugs recommended by current guidelines. These predictions were based on data from randomized controlled trials of glucose-lowering drugs. The data included patient demographics and clinical characteristics (sex, age, body mass index, weight, diabetes duration, HbA1c level, current diabetes treatment and renal function). Predicted outcomes were determined using prespecified statistical models from original trial protocols and estimated coefficients for selected baseline characteristics. This prototype illustrates how evidence-based individualized treatment might be facilitated in the clinic for people with T2D. Further and ongoing development is required to improve the tool's prognostic value, including the addition of disease co-morbidities and patient-orientated outcomes. Patient engagement and data-sharing by sponsors of clinical trials, as well as real-world evidence, are needed to provide reliable predicted outcomes to inform shared patient-physician decision-making.

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.

BACKGROUND: Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS: We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome. RESULTS: Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups. CONCLUSIONS: Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).

Development of a hypoglycaemia risk score to identify high-risk individuals with advanced type 2 diabetes in DEVOTE.

AIMS: The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2-year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. MATERIALS AND METHODS: Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data-driven machine-learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data-driven model, included: insulin treatment regimen; diabetes duration; sex; age; and glycated haemoglobin, all at baseline. Both the data-driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE, and were validated against the external LEADER cardiovascular outcomes trial dataset. RESULTS: Both the data-driven model and the simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time-dependent area under the curve index (0.63 and 0.66, respectively) over a 2-year time horizon. CONCLUSIONS: Both the data-driven model and the simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care.

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE.

AIMS: To undertake a post-hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes. MATERIALS AND METHODS: The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all-cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all-cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all-cause mortality were investigated. RESULTS: Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all-cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all-cause mortality). CONCLUSIONS: The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all-cause mortality and that, in this high-risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality.

AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529.

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2).

AIMS/HYPOTHESIS: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c. RESULTS: Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49). CONCLUSIONS/INTERPRETATION: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial.

IMPORTANCE: Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. OBJECTIVE: To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs. INTERVENTIONS: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period. RESULTS: Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to -13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02030600.

Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: behavioural and psychometric measures of dietary response.

We previously reported results based on the examination of a gluten- and casein-free diet as an intervention for children diagnosed with an autism spectrum disorder as part of the ScanBrit collaboration. Analysis based on grouped results indicated several significant differences between dietary and non-dietary participants across various core and peripheral areas of functioning. Results also indicated some disparity in individual responses to dietary modification potentially indicative of responder and non-responder differences. Further examination of the behavioural and psychometric data garnered from participants was undertaken, with a view to determining potential factors pertinent to response to dietary intervention. Participants with clinically significant scores indicative of inattention and hyperactivity behaviours and who had a significant positive changes to said scores were defined as responders to the dietary intervention. Analyses indicated several factors to be potentially pertinent to a positive response to dietary intervention in terms of symptom presentation. Chronological age was found to be the strongest predictor of response, where those participants aged between 7 and 9 years seemed to derive most benefit from dietary intervention. Further analysis based on the criteria for original study inclusion on the presence of the urine compound, trans-indolyl-3-acryloylglycine may also merit further investigation. These preliminary observations on potential best responder characteristics to a gluten- and casein-free diet for children with autism require independent replication.

Similarities and differences in borderline and organic personality disorder.

INTRODUCTION: Previous research has shown that brain injury patients with Organic Personality Disorder (OPD) may display "borderline" traits due to prefrontal damage, and their personality structure may be unstable and close to a borderline personality organisation. They may have few general neuropsychological dysfunctions but specific executive deficits. Similar deficits have been found in patients with Borderline Personality Disorder (BPD). The objective of this study was to identify differences and similarities between the neuropsychological and personality profiles of BPD and OPD patients. METHODS: Twenty BPD patients and 24 OPD patients were assessed with the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II), the Karolinska Psychodynamic Profile (KAPP), and a comprehensive neuropsychological test battery. RESULTS: Very few neuropsychological differences were found between the two patient groups. However, the verbal fluency, verbal intelligence, verbal memory, and immediate auditory memory/attention of the BPD patients were significantly poorer than the OPD patients'. The KAPP profiles of the BPD patients showed significantly poorer functioning in three areas: frustration tolerance, the body as a factor of self-esteem, and overall personality organisation. CONCLUSIONS: These results support our clinical experience and expectations concerning the severity of symptoms of both patient groups. We suggest considering in depth assessments of both neuropsychological and personality-related problems for each of these patients in order to inform treatment.

Glucagon-like Peptide 1 Receptor Agonists and Asthma Exacerbations: Which Patients Benefit Most?

RATIONALE: While recent evidence suggested glucagon-like peptide 1 receptor agonists (GLP1RA) may reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. OBJECTIVE: To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. METHODS: We implemented an active-comparator, new-user design analysis using commercially insured patients ages 18-65 from Marketscan data 2007-2019 and identified two cohorts: GLP1RA vs thiazolidinediones and GLP1RA vs sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department (ED) visit for asthma) within 180 days after initiation. We applied iterative causal forest (iCF), a novel causal machine learning subgrouping algorithm, to assess HTE. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences (aRD) for the effect of GLP1RA relative to comparators on asthma exacerbation using inverse probability treatment weighting in propensity score trimmed subpopulation. RESULTS: Among 10,989 patients initiating GLP1RA or thiazolidinediones and 17,088 patients initiating GLP1RA vs sulfonylurea, GLP1RA initiators had fewer exacerbations with an aRD of -0.5% (95% CI -1.1% to 0.1%) and -1.6% (95% CI -2.2% to -1.1%), respectively. In the GLP1RAvsSUcohort where we observed beneficial effect, our iCF analysis identified 5 subgroups with different treatment effects, defined by number of ED visits, number of prescriptions of short-acting beta2-agonsit (SABA), number of prescriptions of inhaled steroid (ICS) and long-acting beta-agonists (LABA) (either combination therapy or concurrent use), and aged 50+. Among these, patients with 2+ ED visits during 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RA (95% CI: -4.8% to -0.9%). CONCLUSIONS: GLP1RA demonstrated beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Asthma patients with 2+ ED visits (a proxy for disease severity) benefit most from GLP1RA. ED visit frequency, and number of maintenance and reliever inhalers, and age may help individualize prediction of the short-term benefit from GLP1RA on asthma exacerbation.

Association of Premorbid GLP-1RA and SGLT-2i Prescription Alone and in Combination with COVID-19 Severity.

INTRODUCTION: People with type 2 diabetes are at heightened risk for severe outcomes related to COVID-19 infection, including hospitalization, intensive care unit admission, and mortality. This study was designed to examine the impact of premorbid use of glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy, sodium-glucose cotransporter-2 inhibitor (SGLT-2i) monotherapy, and concomitant GLP1-RA/SGLT-2i therapy on the severity of outcomes in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Utilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24 months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14 days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE). RESULTS: Use of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56-0.72) and SGLT-2i (OR 0.62, 95% CI 0.57-0.68) were associated with lower odds of 60-day mortality compared to DPP-4i use. Additionally, the OR of ER visits and hospitalizations were similarly reduced with GLP1-RA and SGLT-2i use. Concomitant GLP-1RA/SGLT-2i use showed similar odds of 60-day mortality when compared to GLP-1RA or SGLT-2i use alone (OR 0.92, 95% CI 0.81-1.05 and OR 0.88, 95% CI 0.76-1.01, respectively). However, lower OR of all secondary outcomes were associated with concomitant GLP-1RA/SGLT-2i use when compared to SGLT-2i use alone. CONCLUSION: Among adults who tested positive for SARS-CoV-2, premorbid use of either GLP-1RA or SGLT-2i is associated with lower odds of mortality compared to DPP-4i. Furthermore, concomitant use of GLP-1RA and SGLT-2i is linked to lower odds of other severe COVID-19 outcomes, including ER visits, hospitalizations, and mechanical ventilation, compared to SGLT-2i use alone. Graphical abstract available for this article.

Increased Derived Time in Range Is Associated with Reduced Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and Microvascular Events in Type 2 Diabetes: A Post Hoc Analysis of DEVOTE.

Time spent in glycemic target range (time in range [TIR]; plasma glucose 70-180 mg/dL [3.9-10.0 mmol/L]) as a surrogate endpoint for long-term diabetes-related outcomes requires validation. This post hoc analysis investigated the association between TIR, derived from 8-point glucose profiles (derived TIR [dTIR]) at 12 months, and time to cardiovascular or severe hypoglycemic episodes in people with type 2 diabetes in the DEVOTE trial. At 12 months, dTIR was significantly negatively associated with time to first major adverse cardiovascular event (P = 0.0087), severe hypoglycemic episode (P < 0.0001), or microvascular event (P = 0.024). A nonsignificant trend was seen toward association between 12-month hemoglobin A1c (HbA1c) and these outcomes, but this was no longer seen after addition of dTIR to the model. The results support targeting TIR >70% and suggest dTIR could be used in addition to, or in some instances in place of, HbA1c as a clinical biomarker. Trial registration details: ClinicalTrials.gov, NCT01959529.

Case study of semaglutide and cardiovascular outcomes: An application of the Causal Roadmap to a hybrid design for augmenting an RCT control arm with real-world data.

Introduction: Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study. Methods: The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. Results: In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). Conclusions: The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.

A causal roadmap for generating high-quality real-world evidence.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers.

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP-1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long-term follow-up: pooled data from three randomized double-blind placebo-controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry-based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP-1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25-0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86-0.93 with yearly increased exposure to GLP-1 RAs). DISCUSSION: Treatment with GLP-1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes.

Hemoglobin glycation index, calculated from a single fasting glucose value, as a prediction tool for severe hypoglycemia and major adverse cardiovascular events in DEVOTE.

INTRODUCTION: Hemoglobin glycation index (HGI) is the difference between observed and predicted glycated hemoglobin A1c (HbA1c), derived from mean or fasting plasma glucose (FPG). In this secondary, exploratory analysis of data from DEVOTE, we examined: whether insulin initiation/titration affected the HGI; the relationship between baseline HGI tertile and cardiovascular and hypoglycemia risk; and the relative strengths of HGI and HbA1c in predicting these risks. RESEARCH DESIGN AND METHODS: In DEVOTE, a randomized, double-blind, cardiovascular outcomes trial, people with type 2 diabetes received once per day insulin degludec or insulin glargine 100 units/mL. The primary outcome was time to first occurrence of a major adverse cardiovascular event (MACE), comprising cardiovascular death, myocardial infarction or stroke; severe hypoglycemia was a secondary outcome. In these analyses, predicted HbA1c was calculated using a linear regression equation based on DEVOTE data (HbA1c=0.01313 FPG (mg/dL) (single value)+6.17514), and the population data were grouped into HGI tertiles based on the calculated HGI values. The distributions of time to first event were compared using Kaplan-Meier curves; HRs and 95% CIs were determined by Cox regression models comparing risk of MACE and severe hypoglycemia between tertiles. RESULTS: Changes in HGI were observed at 12 months after insulin initiation and stabilized by 24 months for the whole cohort and insulin-naive patients. There were significant differences in MACE risk between baseline HGI tertiles; participants with high HGI were at highest risk (low vs high, HR: 0.73 (0.61 to 0.87)95% CI; moderate vs high, HR: 0.67 (0.56 to 0.81)95% CI; p<0.0001). No significant differences between HGI tertiles were observed in the risk of severe hypoglycemia (p=0.0911). With HbA1c included within the model, HGI no longer significantly predicted MACE. CONCLUSIONS: High HGI was associated with a higher risk of MACE; this finding is of uncertain significance given the association of HGI with insulin initiation and HbA1c. TRIAL REGISTRATION NUMBER: NCT01959529.

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.

OBJECTIVE: To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESEARCH DESIGN AND METHODS: We analyzed observational data from SARS-CoV-2-positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018-February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics. RESULTS: The study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 [95% CI 0.37-0.80] and 0.66 [0.50-0.86], respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations. CONCLUSIONS: Among SARS-CoV-2-positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.

Event dependent sampling of recurrent events.

The effect of event-dependent sampling of processes consisting of recurrent events is investigated when analyzing whether the risk of recurrence increases with event count. We study the situation where processes are selected for study if an event occurs in a certain selection interval. Motivation comes from psychiatric epidemiology where repeated hospital admissions are studied for patients with affective disease, as seen in Kessing et al. (Acta Psychiatr Scand 109:339-344, 2004b). For the selected processes, either only disease course from selection and onwards is used in the analysis, or, both retrospective and prospective disease course histories are used. We examine two methods to correct for the selection depending on which data are used in the analysis. In the first case, the conditional distribution of the process given the pre-selection history is determined. In the second case, an inverse-probability-of-selection weighting scheme is suggested. The ability of the methods to correct for the bias due to selection is investigated with simulations. Furthermore, the methods are applied to affective disease data from a register-based study (Kessing et al. Br J Psychiatry 185:372-377, 2004a) and from a long-term clinical study (Kessing et al. Acta Psychiatr Scand 109:339-344, 2004b).

Suicide risk in patients treated with lithium.

CONTEXT: Prior observational studies suggest that treatment with lithium may be associated with reduced risk of suicide in bipolar disorder. However, these studies are biased toward patients with the most severe disorders, and the relation to sex and age has seldom been investigated. OBJECTIVE: To investigate whether treatment with lithium reduces the risk of suicide in a nationwide study. DESIGN: An observational cohort study with linkage of registers of all prescribed lithium and recorded suicides in Denmark during a period from January 1, 1995, to December 31, 1999. SETTING: All patients treated with lithium in Denmark, ie, within community psychiatry, private specialist practice settings, and general practice. PARTICIPANTS: A total of 13 186 patients who purchased at least 1 prescription of lithium and 1.2 million subjects from the general population. MAIN OUTCOME MEASURE: All suicides identified on the basis of death certificates completed by doctors at the time of death. RESULTS: Patients who purchased lithium had a higher rate of suicide than persons who did not purchase lithium. Purchasing lithium at least twice was associated with a 0.44 reduced rate of suicide (95% confidence interval, 0.28-0.70) compared with the rate when purchasing lithium only once. Further, the rate of suicide decreased with the number of prescriptions of lithium. There was no significant interaction between continued lithium treatment and sex and age regarding the suicide rate. CONCLUSION: In a nationwide study including all patients treated with lithium, it was found that continued lithium treatment was associated with reduced suicide risk regardless of sex and age.

Do antidepressants prevent suicide?

As in many developed countries, the use of antidepressants in Denmark has been substantially increasing during recent years, coinciding with a decreasing suicide rate. We aimed to investigate the relationship between treatment with antidepressants and suicide on individualized data from a nationwide study comprising an observational cohort study with linkage of registers of all prescribed antidepressants and recorded suicides in Denmark during the period 1995-99. A total of 438 625 patients who purchased at least one prescription of antidepressants and 1073 862 individuals from the general population were included in the study. Patients who continued treatment with selective serotonin reuptake inhibitors (SSRIs) (i.e. who purchased SSRIs twice or more) had a decreased rate of suicide compared with patients who purchased SSRIs once only [rate ratio (RR)=0.63; 95% confidence interval (CI)=0.56-0.71]. Furthermore, the rate of suicide decreased consistently with the number of prescriptions. Similarly, among patients treated with newer antidepressants other than SSRIs, the rate of suicide was decreased compared with the rate for patients who purchased other newer antidepressants once only (RR=0.70; 95% CI=0.52-0.94). Continued antidepressant treatment with SSRIs or other newer antidepressants is found to be associated with a reduced risk of suicide.