Assessment of dynamic cardiac repolarization and contractility in patients with hypertrophic cardiomyopathy.

AIMS: Arrhythmia mechanisms in hypertrophic cardiomyopathy remain uncertain. Preclinical models suggest hypertrophic cardiomyopathy-linked mutations perturb sarcomere length-dependent activation, alter cardiac repolarization in rate-dependent fashion and potentiate triggered electrical activity. This study was designed to assess rate-dependence of clinical surrogates of contractility and repolarization in humans with hypertrophic cardiomyopathy. METHODS: All participants had a cardiac implantable device capable of atrial pacing. Cases had clinical diagnosis of hypertrophic cardiomyopathy, controls were age-matched. Continuous electrocardiogram and blood pressure were recorded during and immediately after 30 second pacing trains delivered at increasing rates. RESULTS: Nine hypertrophic cardiomyopathy patients and 10 controls were enrolled (47% female, median 55 years), with similar baseline QRS duration, QT interval and blood pressure. Median septal thickness in hypertrophic cardiomyopathy patients was 18mm; 33% of hypertrophic cardiomyopathy patients had peak sub-aortic velocity >50mmHg. Ventricular ectopy occurred during or immediately after pacing trains in 4/9 hypertrophic cardiomyopathy patients and 0/10 controls (P = 0.03). During delivery of steady rate pacing across a range of cycle lengths, the QT-RR relationship was not statistically different between HCM and control groups; no differences were seen in subgroup analysis of patients with or without intact AV node conduction. Similarly, there was no difference between groups in the QT interval of the first post-pause recovery beat after pacing trains. No statistically significant differences were seen in surrogate measures for cardiac contractility. CONCLUSION: Rapid pacing trains triggered ventricular ectopy in hypertrophic cardiomyopathy patients, but not controls. This finding aligns with pre-clinical descriptions of excessive cardiomyocyte calcium loading during rapid pacing, increased post-pause sarcoplasmic reticulum calcium release, and subsequent calcium-triggered activity. Normal contractility at all diastolic intervals argues against clinical significance of altered length-dependent myofilament activation.

Estimation of Annual Health Care Costs for Adults with Type 1 Diabetes in the United States.

BACKGROUND: Diabetes health care resource utilization (HCRU) studies tend to focus on patients with type 2 diabetes (T2D) or pool patients with T2D and type 1 diabetes (T1D). There is a paucity of recent data on the cost of treating patients with T1D in the United States. OBJECTIVES: To (a) estimate the per-patient per-year (PPPY) HCRU and costs, from a payer perspective, associated with treating U.S. adults with T1D and (b) compare these with the HCRU and costs for patients with T2D. METHODS: This retrospective cohort study used claims data from the Optum Clinformatics database between January 2015 and December 2017. Adults (aged ≥ 18 years) with a diagnosis of T1D were propensity score-matched to adults with T2D. Overall and nondiabetes-related HCRU and costs were assessed for T1D and T2D and compared between the 2 groups. RESULTS: Propensity scores were used to match 10,103 patient pairs from T1D and T2D cohorts (mean ages 54.4 and 56.9 years, respectively). In the T1D cohort, inpatient, emergency department (ED), outpatient, and prescription claims occurred in 14.0%, 17.3%, 85.5%, and 100% of patients, respectively, resulting in a mean total cost of U.S. $18,817 PPPY (diabetes-related = $11,002; nondiabetes-related = $7,816). The T1D cohort had significantly higher mean total costs than the T2D cohort ($18,817 vs. $14,148 PPPY; P < 0.001). When extrapolating these findings to a commercial health plan with 1 million covered lives, the estimated total direct medical costs of T1D would be $103.4 million. CONCLUSIONS: This study showed that the total annual cost of managing an adult with T1D is significantly higher than that of an adult with T2D. Nondiabetes costs accounted for 40% of the total per-patient cost, similar to patients with T2D, confirming that as patients with T1D live longer lives, they may also be at greater risk for cardiometabolic complications. DISCLOSURES: This study was funded by Sanofi U.S. and Lexicon Pharmaceuticals as part of a business partnership in a diabetes program at the time this study was conducted. Joish and Davies are employees and stockholders of Lexicon Pharmaceuticals. Zhou, Preblick, and Paranjape are employees and stockholders of Sanofi. Lin was a postdoctoral fellow at Sanofi through Rutgers University during this project. Deshpande provided consulting services through Communication Symmetry. Verma is an employee of Evidera, which was contracted by Sanofi for work on this study. Pettus is a consultant for Diasome, Insulet, Lexicon, Lilly, Mannkind, Novo Nordisk, Sanofi, and Senseonics.

Adjunct Therapy in Type 1 Diabetes: A Survey to Uncover Unmet Needs and Patient Preferences Beyond HbA1c Measures.

Background: Adjunct therapy can help patients with type 1 diabetes achieve glycemic goals while potentially mitigating some of the side effects of insulin. In this study, we used a patient survey to identify the unmet needs in type 1 diabetes therapy, patient views of treatment benefit-risk trade-offs, and patient preferences for the use of an adjunct therapy. Methods: A quantitative survey was sent to 2084 adults with type 1 diabetes in November 2017. "Jobs-to-be-done" and conjoint analyses were performed on survey responses to identify unmet needs and the importance of treatment-associated benefits and risks to patients. A 5-point Likert scale measured the importance and satisfaction with patients' current therapy, and with gaps relating to unmet needs. In the conjoint analysis, patients were asked to choose between "packages" of attributes of two doses of adjunct therapy (200 and 400 mg) and placebo, based on established benefits and side effects. Results: A total of 1313 patients (63%) responded. The greatest unmet needs identified were simplifying treatment, lowering/maintaining glycated hemoglobin (HbA1c), reducing mental effort, and increasing time in range (TIR). Conjoint analysis showed that reductions in body weight and TIR had the highest attribute importance (25% and 18%, respectively). The majority (93%) of patients had a preference for the adjunct therapy (either dose) over placebo. Conclusions: This survey highlights the importance of measures beyond HbA1c, such as treatment simplification and TIR, and patient preference for adjunct therapies that help address unmet needs in type 1 diabetes treatment.