Prevalence of Genetically Associated Dilated Cardiomyopathy: A Systematic Literature Review and Meta-Analysis.

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation globally. Disease-associated genetic variants play a significant role in the development of DCM. Accurately determining the prevalence of genetically associated DCM (genetic DCM) is important for developing targeted prevention strategies. This review synthesized published literature on the global prevalence of genetic DCM across various populations, focusing on two of the most common variants: titin (TTN) and myosin heavy chain 7 (MYH7). Methods: MEDLINE® and Embase were searched from database inception to September 19, 2022 for English-language studies reporting the prevalence of genetic DCM within any population. Studies using family history as a proxy for genetic DCM were excluded. Results: Of 2,736 abstracts, 57 studies were included. Among the global adult or mixed (mostly adults with few pediatric patients) DCM population, median prevalence was 20.2% (interquartile range (IQR): 16.3-36.0%) for overall genetic DCM, 11.4% (IQR: 8.2-17.8%) for TTN-associated DCM, and 3.2% (IQR: 1.8-5.2%) for MYH7-associated DCM. Global prevalence of overall pediatric genetic DCM within the DCM population was similar (weighted mean: 21.3%). Few studies reported data on the prevalence of genetic DCM within the general population. Conclusions: Our study identified variable prevalence estimates of genetic DCM across different populations and geographic locations. The current evidence may underestimate the genetic contributions due to limited screening and detection of potential DCM patients. Epidemiological studies using long-read whole genome sequencing to identify structural variants or non-coding variants are needed, as well as large cohort datasets with genotype-phenotype correlation analyses.

The role of early-phase trials and real-world evidence in drug development.

Phase 3 randomized controlled trials (RCTs), while the gold standard for treatment efficacy and safety, are not always feasible, are expensive, can be prolonged and can be limited in generalizability. Other under-recognized sources of evidence can also help advance drug development. Basic science, proof-of-concept studies and early-phase RCTs can provide evidence regarding the potential for clinical benefit. Real-world evidence generated from registries or observational datasets can provide insights into the treatment of rare diseases that often pose a challenge for trial recruitment. Pragmatic trials embedded in healthcare systems can assess the treatment effects in clinical settings among patient populations sometimes excluded from trials. This Perspective discusses potential sources of evidence that may be used to complement explanatory phase 3 RCTs and to speed the development of new cardiovascular medications. Content is derived from the 19th Global Cardiovascular Clinical Trialists meeting (December 2022), involving clinical trialists, patients, clinicians, regulators, funders and industry representatives.

Diverse Concepts in Definitions of Dilated Cardiomyopathy: Theory and Practice.

Our understanding of dilated cardiomyopathy (DCM) is evolving as new insights into the underlying pathophysiology become available. Professional organizations and clinical experts are improving definitions of DCM, allowing for more accurate treatment recommendations. This review summarized key published literature describing definitions and/or diagnostic criteria for DCM. Embase was searched from database inception to September 19, 2022 for 1) publications reporting definitions of DCM by major professional organizations and related opinion papers, and 2) clinical studies in DCM and heart failure with reduced ejection fraction. Sixty-eight records were included in this review. Definitions of DCM provided by two major professional organizations (American Heart Association (AHA) and European Society of Cardiology (ESC)) agreed on the clinical presentation of DCM; however, they differed in the classification of DCM within the larger context of cardiomyopathy taxonomies. Both organizations agreed that DCM could be clinically defined by the presence of left ventricular dilation and contractile dysfunction in the absence of abnormal loading conditions and severe coronary artery disease. AHA guidelines divided cardiomyopathies into two major groups (primary and secondary) based on predominant organ involvement. DCM was classified as primary cardiomyopathy with mixed (genetic and/or acquired) etiology. Conversely, ESC published a clinically oriented taxonomy in which cardiomyopathies were grouped into specific morphological and functional phenotypes; each was subclassified into familial or non-familial forms. Opinion papers further elaborated on the complex interplay between genetics and environment in the etiology of DCM. Several articles summarized the importance of the new and updated diagnostic tools, such as cardiac magnetic resonance imaging, electrocardiogram, and other biomarkers, in correctly identifying the etiology of DCM. Within clinical studies, most inclusion criteria used standard definitions proposed by leading professional associations (AHA and ESC). Clinical study investigators sometimes used a narrower definition of DCM using additional criteria for the left ventricular ejection fraction threshold value and left ventricular dilatation. Current efforts in cardiology research are focused on a more granular understanding of DCM etiology and the natural history of the disease. Definitions of DCM found in clinical studies mainly rely on published guidelines, with some studies adding idiosyncratic inclusion criteria refining the broad definitions of DCM.

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces renal glucose reabsorption in an insulin-independent manner. We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin. METHODS: In this phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial, 546 adults with type 2 diabetes who were receiving daily metformin (>/=1500 mg per day) and had inadequate glycaemic control were randomly assigned to receive one of three doses of dapagliflozin (2.5 mg, n=137; 5 mg, n=137; or 10 mg, n=135) or placebo (n=137) orally once daily. Randomisation was computer generated and stratified by site, implemented with a central, telephone-based interactive voice response system. Patients continued to receive their pre-study metformin dosing. The primary outcome was change from baseline in haemoglobin A(1c)(HbA(1c)) at 24 weeks. All randomised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement (last observation carried forward) were included in the analysis. Data were analysed by use of ANCOVA models. This trial is registered with ClinicalTrials.gov, number NCT00528879. FINDINGS: 534 patients were included in analysis of the primary endpoint (dapagliflozin 2.5 mg, n=135; dapagliflozin 5 mg, n=133; dapagliflozin 10 mg, n=132; placebo, n=134). At week 24, mean HbA(1c) had decreased by -0.30% (95% CI -0.44 to -0.16) in the placebo group, compared with -0.67% (-0.81 to -0.53, p=0.0002) in the dapagliflozin 2.5 mg group, -0.70% (-0.85 to -0.56, p<0.0001) in the dapagliflozin 5 mg group, and -0.84% (-0.98 to -0.70, p<0.0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2-4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2.5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group). INTERPRETATION: Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone. FUNDING: Bristol-Myers Squibb and AstraZeneca.

Management of high blood pressure in clinical practice: perceptible qualitative differences in approaches utilized by clinicians.

The authors recruited a group of physicians from among the investigators participating in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with a greater (more successful) or lesser (less successful) proportion of trial patients meeting blood pressure (BP) control goals. The authors utilized qualitative focus group methods to identify similarities and differences in practice behaviors. Successful and less successful physicians had similarities in knowledge and practice behaviors regarding awareness of treatment guidelines, approaches to diagnosis, use of pharmacologic management, and the opinion that systolic BP guidelines should consider a patient's age. However, there were discernible differences between the two physician groups in their views on doctor-patient relationships: physicians from the less successful group were more paternalistic with their patients, while physicians from the more successful group were more likely to use a patient-centered clinical approach to BP awareness and management.

Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Recruitment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter clinical trial using a double 2 x 2 factorial design in 10,251 participants with type 2 diabetes mellitus at high risk for cardiovascular disease (CVD) events. ACCORD is testing 3 complementary medical treatment strategies that may reduce high rates of major CVD morbidity and mortality in patients with type 2 diabetes. The ACCORD vanguard phase, conducted at 59 clinics in the United States and Canada, recruited 1,174 participants in 20 weeks from January through June 1, 2001, with a recruitment efficiency (R-factor) of 0.65. The recruitment strategies used in this vanguard phase were almost exclusively chart and database review within clinical practices and institutions. Recruitment for the main trial began in February 2003, involved 77 clinics, and resulted in an additional 9,077 participants by October 29, 2005 (total, 10,251). The R-factor during main trial recruitment was 0.96. Although new and refined recruitment strategies were formulated from the vanguard experience, the most powerful determinant of improved recruitment efficiency was the immediate start of enrollment by most clinics at the beginning of the main trial. Recruitment in the main trial required only a brief extension of 3 months and facilitated the nearly complete capture of the expected number of person-years of observation. Described herein are vanguard and main trial recruitment activities, including strategy implementation, screening procedures, randomization results, problems encountered, and lessons learned.

Health-related quality of life and cost-effectiveness components of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: rationale and design.

Diabetes mellitus affects not only life expectancy but also quality of life. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial's health-related quality of life (HRQOL) and cost-effectiveness components will enable the assessment of the relative importance of the various outcomes from the point of view of patients, provide an understanding of the balance between the burdens and benefits of the intervention strategies, and offer valuable insights into adherence. The HRQOL measures used include the Diabetes Symptoms Distress Checklist; the 36-Item Short Form Health Survey, Version 2 (SF-36) (RAND Corporation, Santa Monica, CA); the Patient Health Questionnaire (PHQ) depression measure (Pfizer Inc, New York, NY); the World Health Organization (WHO) Diabetes Treatment Satisfaction Questionnaire (DTSQ); and the EuroQol Feeling Thermometer (EuroQol Group, Rotterdam, Netherlands). The cost-effectiveness analysis (CEA) in ACCORD will provide information about the relative economic efficiency of the different interventions being compared in the trial. Effectiveness will be measured in terms of cardiovascular event-free years gained and quality-adjusted life-years gained (using the Health Utilities Index Mark 3 [HUI-3] [Health Utilities Inc., Dundas, Ontario, Canada] to measure health-state utility). Costs will be direct medical costs assessed from the perspective of a single-payer health system collected by means of patient and clinic cost forms and hospital discharge summaries. The primary HRQOL and CEA hypotheses mirror those in the main ACCORD trial, addressing the effects of the 3 main ACCORD interventions considered separately. There are also secondary (pairwise reference case) comparisons that do not assume independence of treatment effects on HRQOL. CEA will be done on a subsample of 4,311 ACCORD participants and HRQOL on a subsample of 2,053 nested within the CEA subsample. Most assessments will occur through questionnaires at baseline and at 12, 36, and 48 months.

Development of the sodium-glucose co-transporter 2 inhibitor dapagliflozin for the treatment of patients with type 2 diabetes mellitus.

Dapagliflozin is a highly selective sodium-glucose co-transporter 2 inhibitor developed for the treatment of Type 2 diabetes mellitus. Its inhibition of sodium-glucose co-transporter 2 blocks glucose reabsorption in the proximal tubule of the kidney, increasing renal glucose excretion via the urine, resulting in reduction of glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose in patients with Type 2 diabetes mellitus. The pharmacokinetics and pharmacodynamics of dapagliflozin are suitable for once-daily dosing. Dapagliflozin improves glycemic control when used as monotherapy and when used in combination with other antidiabetic treatments. Throughout all phases of clinical studies, dapagliflozin was generally well tolerated. Increased events suggestive of urinary tract and genital infections have been reported; most resolved with conventional treatment. Unexpected numerical imbalances between dapagliflozin and comparator were noted for breast and bladder cancers. The potential for increased cancer risk with dapagliflozin needs to be further assessed.

A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment.

OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.