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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.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

In the management of hypertension, the goal is not to lower blood pressure (BP) per se, but to protect the kidneys, the heart and the brain against harmful outcomes caused by hypertension. No single class of drugs has yet proven to be more efficacious than any other in terms of reducing all-cause mortality, cardiovascular (CV) mortality or fatal and non-fatal myocardial infarction (MI). Nevertheless, as argued by Dr. Pierre Nantel, Co-director, Kidney Foundation of Canada (Quebec Branch) and staff nephrologist, Centre hospitalier Sorel-Tracy, Quebec, some anti-hypertensive agents offer greater end-organ protection than others at identical reductions in BP.

In RENAAL, patients with type 2 diabetes and proteinuria were randomized to an angiotensin receptor blocker (ARB)-based regimen or to conventional antihypertensive therapy. There was a 16% reduction in the primary composite end point consisting of a doubling of serum creatinine, end-stage renal disease or death in the losartan-containing arm at an average follow-up of 3.4 years over conventional therapy despite almost identical reductions in BP.

The IDNT study demonstrated very similar results where, after an average follow-up of 2.6 years, approximately 20% fewer patients treated with irbesartan reached essentially the same composite end point as in RENAAL than those receiving amlodipine.

The LIFE trial demonstrated that the ARB losartan provided more efficacious end-organ protection in hypertensive patients with left ventricular hypertrophy (LVH). In this study, significantly greater reductions in both LVH and atrial fibrillation were observed among patients receiving losartan compared with atenolol, a clear sign that an ARB offers additional protection in the heart than beta-blockade in hypertensive patients with LVH. The losartan-based regimen was associated with a significant 25% reduction in stroke compared with the beta-blocker arm, another indication that the agent offers additional end-organ protection compared with conventional antihypertensive agents, not only in the kidneys but in the heart and brain as well, Dr. Nantel noted.

As Dr. Nantel also discussed, studies indicate that elevated serum uric acid levels are associated with an increased incidence of CV mortality, stroke and peripheral vascular disease. Treatment of elevated serum uric acid levels has yet to be definitively shown to reduce CV events but suggestive evidence from the SHEP study showed that the risk of coronary events was 42% lower among participants who had a <60 µmol/L increase in serum uric acid in response to therapy than those who had a ³60 µmol/L increase in serum uric acid levels and that this effect was independent of BP.

In contrast to other ARBs, losartan is known to offset elevations in uric acid that diuretics provoke. One study, for example, showed that losartan 100 mg attenuated a 77 µmol/L increase seen with a diuretic alone to only 30 µmol/L. Researchers also calculated that 29% of the extra CV benefit seen in the losartan arm over the atenolol arm could be explained by the smaller rise in uric acid at 19 µmol/L with losartan than the 43 µmol/L rise seen with atenolol.

Post-prandial Hyperglycemia and Cardiovascular Risk

As discussed by Dr. Lawrence Leiter, Professor of Medicine and Nutritional Sciences, University of Toronto, Ontario, evidence linking post-prandial hyperglycemia (PPG) and increased CV risk is actually more robust than for either fasting glucose or HbA1c. In DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe), for example, analyses indicated that it was two-hour glucose rather than fasting sugars that predicted all-cause mortality in a large cohort of patients without known diabetes.

Indeed, DECODE investigators calculated that every 1-mmol/L increase in two-hour plasma glucose carries with it the same CV risk as a 7-mm Hg increase in systolic BP, Dr. Leiter added. As HbA1c levels approach normal, PPG contributes as much as 70% to the overall glycemic load, another indication that it should be targeted as much as fasting glucose and HbA1c. Treatment of PPG, in turn, with agents such as acarbose appears to reduce the risk of MI by as much as 50% in patients with diabetes.

Lowering PPG is also possible through low glycemic index foods and rapid-acting insulin secretagogues and rapid-acting insulin analogues. In addition, promising new incretin-based therapies, including injectable GLP-1 analogues and dipeptidyl peptidase-4 inhibitors such as sitagliptin and vildagliptin, enhance the beneficial actions of gut hormones that are altered in diabetes and improve insulin sensitivity. In studies presented earlier this year, investigators reported that the combination of sitagliptin and metformin significantly improved glycemic control in 748 patients with type 2 diabetes, decreasing HbA1c by between 0.8% and 1.4% at week 54. Treatment was well tolerated and safety data from phase IIb and III sitagliptin studies indicate that the overall adverse-event profile whether used alone or in combination with other agents is similar to that seen in patients not exposed to sitagliptin.

“The rationale is that if we can use these hormones to improve the incretin effect, will can improve insulin secretion and thereby improve glucose levels,” Dr. Leiter indicated.

Targeting Residual Risk

Clinical trials have reaffirmed that for every mmol/L an agent lowers LDL-C, there is about a 20% reduction in clinical events. However, even with high-dose statins, “remaining coronary artery disease [CAD] risk may still be as high as 60% to 80%,” Dr. Robert Hegele, Professor of Medicine and Biochemistry, University of Western Ontario, London, reminded delegates. Targeting this residual risk is challenging, as to date, it has proven difficult to raise HDL-C, which in turn could lower CV risk as well. However, as Dr. Hegele cautioned, “Not all ways of raising HDL are good.” For example, torcetrapib, the first of the CETP inhibitors, very successfully raised HDL-C but it also caused increases in BP and was not associated with improvements in carotid artery intima media thickness.

Niacin has long been known to raise HDL and lower both LDL and triglycerides. Small studies such as the FATS (Familial Atherosclerosis Treatment Study), in which niacin was used with a statin, have consistently shown significant reductions in mortality and CV events, especially when niacin is used in combination with a statin. However, the Achilles heel of crystalline niacin has long been the flushing it caused in the majority of patients, as Dr. Hegele indicated. Now, however, the flushing mechanism has been identified and that pathway can be targeted within the skin to reduce flushing. Results comparing extended-release niacin with a new formulation of extended-release niacin/laropiprant, a flushing inhibitor, showed that the combination reduced LDL levels and triglycerides by approximately 20% at the end of 24 weeks and raised HDL levels by approximately the same degree.

More importantly, “there was persistent flushing out to six months with extended-release niacin alone whereas there was virtually no flushing when niacin was given with the flushing inhibitor [at the same time point],” Dr. Hegele reported. He added, “Now the issue is how patients will react to this combination and what is the added benefit of treating patients to reduce residual risk.”

Based on the CCS/CCC-sanctioned session:

“Managing Cardiometabolic Complexities: Will New Treatment Strategies Improve Health Outcomes?” Sunday, October 21, 10:00-12:00, Room 200A, Level 2.

This symposium is accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).