Reports

Invasive Fungal Infections in Severely Immunocompromised Patients: Strategies to Improve Overall Survival
Examining New Treatment Options for Overactive Bladder Syndrome

Optimizing Hypertension Treatment to Improve Renal Outcomes in Patients with Diabetes

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 22nd Scientific Meeting of the European Society of Hypertension

London, UK / April 26-29, 2012

London - The first-line antihypertensive agent in patients with diabetes and either one additional cardiovascular (CV) risk factor, evidence of renal dysfunction, such as microalbuminuria, or both, is an ACE inhibitor or an angiotensin receptor blocker, according to most major guidelines. However, the majority of hypertensive patients with diabetes will require a second antihypertensive agent to reach treatment goals. Currently, most renin-angiotensin system inhibitors are combined with a diuretic because of the synergy provided by combination of these agents, but experts at the 2012 annual ESH meeting noted that new guidelines, driven by evidence that the specific diuretic matters, are specifying preferred agents. The evidence that diuretics are not interchangeable for optimal reduction of CV and renal events is producing a modest but important shift in definitions of optimal hypertension management.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The renin-angiotensin system (RAS) participates in driving progressive cardiovascular (CV) disease, such as cardiac remodelling and renal damage, including proteinuria. ACE inhibitors and angiotensin receptor blockers (ARBs) both inhibit the RAS; they are identified as first-line antihypertensive agents in patients with diabetes by the US Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) and the UK’s National Institute for Health and Clinical Excellence (NICE). The rigorous treatment goal for hypertension in diabetes (<130/80 mm Hg) generally requires at least two antihypertensive drugs. While diuretics are recommended with RAS inhibitors, a recent change in the NICE guidelines emphasizes the choice of diuretic.

New Guidelines for Diuretics

According to the new NICE guidelines, cited by Dr. Franz H. Messerli, Director, Hypertension Program, St. Luke’s-Roosevelt Hospital Center, New York City, a “thiazide-like diuretic such as chlorthalidone [12.5-25 mg once daily] or indapamide [1.5 mg modified-release or 2.5 mg once daily]” should be used “in preference to a conventional thiazide diuretic such as bendroflumethiazide (BFTZ) or hydrochlorothiazide (HCTZ).” Providing the data that led to this change in August 2011, Dr. Messerli suggested that other guidelines, including the next iteration of the JNC guidelines, would contain similar language.

The reason for the change is the lack of evidence that thiazide diuretics, such as HCTZ, provide a significant reduction in CV and renal events despite blood pressure (BP) control. In contrast, both indapamide and chlorthalidone in combination with ACE inhibitors or ARBs have been associated with an important reduction in events, not just control of hypertension. The reason for the greater benefit of indapamide and chlorthalidone is that they appear to exert a greater effect on the underlying pathophysiologic processes, such as worsening nephropathy. When these agents are introduced before significant end-organ damage, the potential for serious events is reduced.

Specifically, reducing mortality in the CV-renal continuum can be attained by preventing microalbuminuria, regressing macroalbuminuria and retarding worsening nephropathy, according to Dr. Pavel Hamet, Centre hospitalier de l’Université de Montréal, Quebec. “Ultimately, physicians should intervene very early to prevent the onset of renal disease,” he remarked.

The ADVANCE (Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation) study was a real-world trial with no HbA1c or BP inclusion criteria and a study population very representative of diabetic patients in the community. Dr. Hamet reported that a fixed-dose combination of the ACE inhibitor perindopril and indapamide reduced new-onset microalbuminuria by 21% relative to placebo (Lancet 2007; 370:829-40). Active treatment also reduced the risk for progression of ≥1 albuminuria stage by 22% and regression of ≥1 albuminuria stage by 16% (J Am Soc Nephrol 2009;20:883-92). Overall the study associated the combination with an 18% reduction in CV deaths, 21% reduction in total renal events and a 14% reduction in all-cause mortality relative to placebo.

“The capacity to regress is very important for practicing physicians treating patients with diabetes,” emphasized Dr. Hamet. “Fifty percent of disease can be regressed over 5 years, and this is even further enhanced by 16% just by adding one fixed-dose combination.”

New NIKA Results Presented

Similar benefit on renal function with this same combination was derived from a subanalysis of the NIKA study presented at the 2012 ESH meeting. In this study of 445 diabetic patients, of which 77 had microalbuminuria at baseline, patients received the combination perindopril 5 mg (corresponding dosage in Canada is 4 mg) with indapamide 1.25 mg for 6 months (abstract 596). Regression of microalbuminuria was observed in 80% of patients with a mean decrease from 48 µg/min to 30 µg/min (P=0.034) and 36% attaining normoalbuminuria at study end (Table 1). Notably, 63% of patients achieved target systolic BP <130 mm Hg. This subanalysis supports ADVANCE data that the combination treatment contributes to achieve optimal BP reduction and regression of nephropathy in patients with diabetes, including those with microalbuminuria.

Table 1.

Combinations with ACE Inhibitors

Awareness of the importance that kidney damage is associated with major adverse CV and renal events in patients with diabetes and hypertension has increased over the past decade. Approximately 75% of patients with diabetes will have a renal event, including microalbuminuria, decreased creatinine clearance, macroalbuminuria or doubling of serum creatinine. Individuals with diabetes are at threefold higher risk of death from renal disease in addition to a twofold higher risk of death from vascular causes (N Engl J Med 2011;364:829-41). Importantly, it is estimated that >75% of hypertensive patients with type 2 diabetes require a combination therapy.

As demonstrated in ADVANCE, both albuminuria and kidney function independently predicted CV and renal outcomes (J Am Soc Nephrol 2009;20:1813-21). “In the future, we will probably have to distinguish these 2 components and treat them in different targeted ways,” Dr. Hamet predicted. Importantly, active treatment reduced total mortality by 14%. “For me, this is a clear benefit which is significant for clinicians,” he stated. “There are few data on kidney protection that translate into mortality reduction other than from the ADVANCE trial,” he stressed.

Microvascular Complications

A new analysis of ADVANCE data presented here at ESH shows that every increase in heart rate of 10 bpm was associated with a 13% increase in the risk of major microvascular outcomes (P<0.001) (abstract 1333). Prof. John Chalmers, Emeritus Professor of Medicine, The George Institute for International Health, University of Sydney, Australia, reported that among the 11,140 patients, the highest resting heart rate (84-140 bpm) was associated with a 60% increased risk. The increased risk was present for the development of new or worsening retinopathy (16%) and for new or worsening nephropathy (11%). This effect did not vary by sex, prior macrovascular disease, atrial fibrillation treatment with b-blockers, randomized BP or glucose treatments.

“It is not clear whether higher heart rate directly mediates the increase in risk, or whether it is a marker for underlying conditions that determine a poor prognosis such as poor physical fitness, obesity, high BP and an adverse lipid profile, each of which is strongly associated with increased risk of microvascular disease in diabetes,” Prof. Chalmers explained. One plausible mechanism is the possibility that autonomic dysfunction in diabetes leads to sympathetic overactivity and impaired baroreflexes, he suggested.

Type of Diuretic Appears Important

Although not conducted in patients with diabetes, Dr. Messerli cited several other studies suggesting that the diuretic can make a difference in outcome. These included the HYVET (Hypertension in the Very Elderly trial), which also compared the perindopril/indapamide combination against placebo and demonstrated large benefits in events, including a 21% reduction in all-cause mortality (N Engl J Med 2008;358:1887-98); and PATS (Post-Stroke Hypertension Study), which associated indapamide alone with a 29% reduction in stroke relative to placebo (Chin Med J 1995;108:710-7). While no such data are available for BFTZ and HCTZ, he cited data from the MRFIT trial which associated chlorthalidone but not HCTZ with highly significant reductions in myocardial infarction, stroke and revascularization.

“The antihypertensive effect of diuretics is not directly mediated by diuresis,” noted Dr. Messerli, explaining why antihypertensive agents in the diuretic class differ. Consequently, HCTZ should no longer be used. Rather, “if a diuretic is indicated in the treatment of hypertension, chlorthalidone or indapamide are the agents of choice.” He emphasized that this is not solely his opinion but will be increasingly reflected in formal guidelines as it is now in NICE.   

 

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.