Protection of Cardiovascular System and Kidney Beyond Glucose Control in Diabetes

SD-3-1

New Therapies for Diabetes and Protection of Diabetic Kidney Disease Beyond Blood Glucose

HIroFuMI MaKIno

Okayama University Hospital, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan

The most problematic issue in clinical nephrology is relentless and progressive increase in the patients with end-stage renal disease (ESRD) in worldwide. Among various kidney diseases, the impact of diabetic nephropathy on the increasing population with chronic kidney disease (CKD) and ESRD is enormous. Diabetic nephropathy is characterized by accumulation of extracellular matrix in glomeruli, called exudative, diffuse and nodular lesions. They are finally followed by glomerulosclerosis and interstitial fibrosis, and in such situation, the patients inevitably undergo dialysis therapies and renal transplantation to survive.

We have been emphasizing the importance of chronic inflammation and oxidative stress in the progression of diabetic nephropathy and the identification of key molecules would facilitate to the development of new therapeutic strategies. We focused and emphasized on the anti-inflammatory and anti-oxidative effects of glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidaSE-4 (DPP4) inhibitors, which ameliorated the progression of diabetic nephropathy in rodent models. We also recently investigated the beneficial role of sodium glucose cotransporter-2 (SGLT2) inhibitors on the progression of diabetic nephropathy using various animal models and reported SGLT2 inhibitors primarily ameliorates oxidative stress and inflammation in proximal tubular cells. New therapies such as incretin-related drugs and SGLT2 inhibitors would have the additional benefit in the protection of diabetic nephropathy beyond blood glucose control.

SD-3-2

Do We Need a New ARB, Azilsartan M for Better BP Control and beyond glucose control in Diabetes?

roberT J. CHILTon

Department of Medicine, Division of Cardiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Hypertension affects an estimated 25 - 30% of the adult population of the world.

Despite the availability of antihypertensive treatments, hypertension remains inadequately controlled, with slightly less than half of patients who receive treatment successfully achieving blood pressure (BP) goals. While there are many drug classes available to reduce BP, drugs that modulate the renin-angiotensin-aldosterone system (RAAS) are more commonly used because of their efficacy, coupled with one of the lowest side effect profiles. Moreover, within the RAAS classes, those that inhibit the action of angiotensin II by binding directly to the angiotensin type 1 (AT1) receptor (ie, angiotensin receptor blockers [ARBs]) are the best tolerated of all antihypertensive drug classes. Some ARBs have shown efficacy in reducing mortality in patients with heart failure and post–myocardial infarction as well as slowing progression of diabetic nephropathy.

Azilsartan medoxomil (AZL-M) is an ARB in development for the treatment of hypertension. It is a prodrug that is rapidly hydrolyzed to its active moiety, azilsartan. The current study assesses the antihypertensive efficacy and safety of the angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL-M), compared with placebo and the ARB olmesartan medoxomil (OLM-M).

This randomized, double-blind, placebo controlled, multicenter study assessed change from baseline in mean 24-hour ambulatory systolic blood pressure (SBP) following 6 weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24-hour mean ambulatory systolic pressure ³130 mmHg and £170 mmHg were studied; 142 received placebo and the remainder received 20mg, 40mg, or 80mg AZL-M or 40mg OLM-M. Mean age of participants was 58±11 years, baseline mean 24-hour SBP was 146 mmHg. DoSE-dependent reductions in 24-hour mean SBP at study end occurred in all AZL-M groups. Reduction in 24-hour mean SBP was greater with AZL-M 80 mg than OLM-M 40 mg by 2.1 mmHg (95% confidence interval, -4.0 to -0.1; P=.038), while AZL-M 40mg was non inferior to OLM-M 40mg. The side effect profiles of both ARBs were similar to placebo. AZL-M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM-M.

Data from this study suggest that AZL-M (Edarbi) 80 mg is more effective in reducing SBP than the highest approved dose of OLM-M, which is considered to be more effective than others in the ARB class.

Moreover, the data from the current study have been validated internally by consistency of clinic and ABPM measurements. Outcome studies are needed to assess whether these differences in BP efficacy will be borne out in reduction of cardiovascular events.