Novel blood pressure lowering agent shows promise in resistant hypertension

Novel blood pressure lowering agent shows promise in resistant hypertension

Darusentan is a novel endothelin antagonist designed for the treatment of hypertension; raised levels of endothelin 1 have been reported both in patients with hypertension and those with diabetes.


Weber et al. conducted a randomised, multicentre, double-blind study on the use of darusentan for resistant hypertension.  379 patients with a systolic blood pressure of 140 mmHg or more who were receiving at least three blood-pressure-lowering drugs were randomly assigned to 14 weeks’ treatment with placebo (n=132) or darusentan 50mg (n=81), 100mg (n=81), or 300mg (n=85) once a day.  The primary endpoints were changes in systolic sitting and diastolic blood pressures.
The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mmHg with placebo, 17/10 mmHg with darusentan 50mg, 18/10 mmHg with darusentan 100mg, and 18/11 mmHg with darusentan 300mg (p<0.0001 for all effects, see figure).  However, oedema or fluid retention occurred in 67(27%) of patients treated with darusentan, compared to only 19 (14%) of those given placebo.

Conclusions:
Darusentan is a promising new anti-hypertensive agents, however diuretic therapy may be needed to treat any associated fluid retention.  A further phase III trial, using an active comparator, is currently underway.

•    Weber MA, Black H, Bakris G, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomized, double-blind, placebo-controlled trial. Lancet 2009; 374, 1423-1431.
•    Williams B. Resistant hypertension: an unmet need. Lancet 2009; DOI:10.1016/S0140-6736(09)61600-7.

Life-style modifications can prevent diabetes in the long term

The Diabetes Prevention Program (DPP) was a randomized clinical trial that showed that the incidence of diabetes in high-risk adults could be reduced by 58% with lifestyle interventions (physical activity and weight loss goals), and by 31% with metformin, when compared to placebo.  The initial trial ran for a mean follow-up period of 2.8 years; in this analysis long-term follow-up outcomes were examined.
2766 of 3150 (88%) of patients enrolled for a median additional follow-up of 5.7 years (910 from the lifestyle intervention group, 924 from the metformin group, and 932 from the original placebo groups).  All three groups were offered group-implemented lifestyle intervention, including the original lifestyle group who were offered additional support.  Patients originally on metformin were continued on the treatment at a dose of 850mg twice daily.  The primary outcome was the development of diabetes according to the American Diabetes Association Criteria.
Over the 10.0 year (IQR 9.0-10.5) follow-up since randomization to the original DPP trial, the modest weight loss seen with metformin was maintained, whereas the original lifestyle group lost, then partly regained, weight.  As a result, diabetes incidence rates during the long-term follow-up study (i.e. since the original trial report) in the lifestyle group were higher at 5.9 per 100 person-years for the lifestyle group, compared to 4.9 per 100 person-years for metformin, and 5.6 per 100 person-years for placebo.  Nonetheless, over the entire ten year period of the trial this translated into a 34% reduction in the incidence of diabetes in the lifestyle group, and an 18% reduction in the metformin group, when compared to placebo.

Conclusions:
The cumulative incidence of diabetes in this ten year prevention study was lowest in individuals who took active lifestyle interventions.  However, more than half these high-risk individuals developed diabetes over the ten year period of the study, highlighting that further preventative strategies are urgently needed.

•    Diabetes Prevention Program Research Group.  10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcome Study.  Lancet, published online before print October 29, 2009.  DOI: 10.1016/S0140-6736(09)61457-4

Noncardiovascular mortality risk rises in dialysis patients

Cardiovascular disease is the most common cause of death amongst patients with chronic kidney disease, accounting for 40-50% of deaths in patients with end-stage renal disase.  Cardiovascular morbidity is exceptionally high in patients receiving dialysis, and the prevalence of coronary artery disease or congestive heart failure in this subgroup is approximately 40%.  The authors determined to investigate whether this leads to increased cardiovascular mortality, or whether noncardiovascular mortality is equally increased.
Using data from the European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] registry, the authors compared mortality rates of adults starting dialysis with general European population.  Cause of death was known for 90% of the 123,407 patients examined in the registry data, and 99% of the control European population.  Cardiovascular and noncardiovascular mortality rates in patients were 38.1 per 100 person years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2), respectively, both of which were higher than in the general population.  On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population.  Although the relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis, compared with the general population, was 1.09 (95% CI, 1.06-1.12), this ratio dropped to 0.9 (95% CI, 0.88-0.93) when unknown or missing causes of death were accounted for.

Conclusions:

This study contradicts the popular belief that the increased risk amongst people starting dialysis can be attributed to an excess risk of cardiovascular mortality.  Physicians treating dialysis patients should be aware that the risk of death from both cardiovascular and noncardiovascular causes is increased in this cohort.

•    de Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 2009; 302:1782-1789.

Journals scanned:
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

Reviewers:
Dr Alistair C. Lindsay, Dr Katie Qureshi, Dr Jon Spiro, Dr Hussain Contractor

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