Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in probands. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels cause gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.

BackgroundThe Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes Results (LEADER) clinical trial demonstrated that liraglutide added to standard-of-care (SoC) therapy for type 2 diabetes (T2D) with established cardiovascular disease (CVD) or elevated cardiovascular (CV) risk was associated with lower rates of death from CVD, nonfatal myocardial infarction (MI), or nonfatal stroke than SoC alone.ObjectiveThe objective of this study was to assess the cost-effectiveness (CE) and budget impact of liraglutide vs SoC in T2D patients with established CVD or elevated CV risk, over a lifetime horizon from a US managed care perspective.MethodsA cohort state-transition model (costs and benefits discounted at 3% per year) was used to predict diabetes-related complications and death (CV and all-cause). Events, treatment effects, and discontinuation rates were from LEADER trial; utility and cost data (US$, 2017) were from literature. Sensitivity analysis explored the impact of uncertainty on results. Additionally, a budget impact analysis was conducted to evaluate the financial impact of liraglutide use in this population, with displacement from dulaglutide, assuming a health care plan with 1 million members.ResultsLiraglutide patients experienced 6.3% fewer events, had event-related cost-savings of $15,182, gained additional life-years of 0.67 and quality-adjusted life-years (QALYs) of 0.57, and had additional total costs ($60,928) vs SoC. Liraglutide was cost-effective with an incremental CE ratio of $106,749/QALY which was below the willingness-to-pay threshold of $150,000/QALY accepted by the Institute of Clinical and Economic Research. Liraglutide was cost-effective across all sensitivity analyses, except when the hazard ratio for all-cause mortality varied. The budget impact was neutral, with a per-plan-per-year and per-member-per-month cost-savings of $266,334 and $0.02, respectively.ConclusionFrom a US-managed care perspective, for T2D patients with established CVD or elevated CV risk, liraglutide is a cost-effective and a budget neutral treatment option for health care plans.

OBJECTIVE | Despite the demonstrated benefits of glucagon-like peptide 1 (GLP-1) receptor agonist therapy, adherence and persistence with this therapy is often challenging. The purpose of this study was to expand current understanding of patients' experiences, motivations, and challenges relevant to their persistence with GLP-1 receptor agonist therapy.

Introduction Improving real-world medication adherence to injectable antihyperglycemics in type 2 diabetes mellitus (T2DM) is a clinical challenge. Quantification of the level of adherence required to achieve a minimal clinically important difference (MCID) in glycemic control would assist in meeting this goal. The study objective was to review the literature regarding the relationships of medication adherence and persistence with health outcomes in adult T2DM patients using injectable antihyperglycemics. Methods Systematic searches were conducted using electronic databases to identify publications over the last decade. Publications were screened against established eligibility criteria. Study data were extracted, evaluated, and used to identify strengths, limitations, and gaps in current evidence. Results Eligibility criteria were met by 38 studies, and this report analyzed 34 studies related to glycemic control ( n = 25), healthcare resource use ( n = 9), and healthcare costs ( n = 14). Eight of these studies examined adherence to glucagon-like peptide-1 receptor agonists (GLP-1 RA), including 1 study regarding adherence to GLP-1 RA or to insulin, and 1 study investigating a GLP-1 RA/insulin combination; the remaining studies involved insulin. Studies used a broad range of measures to classify adherence and persistence, and most measures were unable to reliably evaluate the complexities of patient behavior over time. Better adherence to injectable antihyperglycemic medications was generally found to be associated with improved glycemic control, although no studies attempted to identify a MCID. Although higher diabetes-related pharmacy and total healthcare costs were reported for adherent or persistent patients, these patients tended to have lower diabetes-related and all-cause medical costs. Conclusion Results of this review confirmed the effectiveness of injectable antihyperglycemic medications for glycemic control, suggesting that there are clinical and financial consequences to nonadherence. Although attempts were made to quantify the effects of nonadherence, the interpretation of study results was limited by the lack of a MCID and inadequate study design. Funding Novo Nordisk, Inc., Plainsboro Township, NJ, USA. Plain Language Summary Plain language summary available for this article. Electronic Supplementary Material The online version of this article (10.1007/s13300-019-0617-3) contains supplementary material, which is available to authorized users.

Once-daily liraglutide 1.8 mg was associated with greater clinical efficacy than once-daily lixisenatide 20 μg, which resulted in a lower annual cost of control for HbA1c-focused and composite treatment targets.