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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.

PHYSICIAN PERSPECTIVE Viewpoint based on the following article: Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes Sep 2008;32(suppl 1).

December 2008

Reviewed by:

Richard Lewanczuk, MD, PhD

Professor, Department of Medicine, University of Alberta, Edmonton, Alberta

The new treatment guidelines from the Canadian Diabetes Association (CDA) attempt to provide a state-of-the-art approach to mortality and morbidity reductions.¹ Since 2003, the year in which the previous guidelines were published,² the prevalence of diabetes in Canada has climbed from 4.7% to 5.5% of the population.³ Due to increasing rates of obesity and a rise in the median age of the Canadian population, the proportion of Canadians with diabetes is expected to grow substantially in coming years.⁴ While new strategies are needed to reverse this trend, better strategies are also necessary to improve outcomes in those who already have diabetes. Vascular protection is perhaps the single most important concept for reducing morbidity and mortality due to the important relationship between vascular dysfunction and vulnerability to myocardial infarction (MI) and stroke. Cardiovascular (CV) disease and stroke account for almost 85% of all deaths in patients with diabetes.⁵

Vascular Protection Through RAAS Inhibition

In the CDA guidelines, the importance of vascular protection is reflected by the decision to devote a specific section to this topic. In this section, renin-angiotensin-aldosterone system (RAAS) inhibition is identified as an essential component of CV risk management. A great deal of new information has become available since completion of the previous guidelines. While HOPE (Heart Outcomes Prevention Evaluation), a placebo-controlled trial with ramipril, was the first study to demonstrate blood pressure (BP)-independent protection against CV events from a RAAS inhibitor,⁶ the more recently completed ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) demonstrated comparable benefit when the angiotensin receptor blocker (ARB) telmisartan was directly compared to ramipril.⁷ The major difference between these strategies was better tolerability for telmisartan. Prior to ONTARGET, it had been unclear whether any ARB was capable of offering better, similar, or less protection against CV events. Telmisartan is the only ARB to demonstrate equivalence in the high-risk patients randomized in HOPE and ONTARGET.

Prior to ONTARGET, studies of RAAS inhibition for vascular protection were largely placebo-controlled. By the time ONTARGET was initiated, the benefits of ACE inhibitors had been sufficiently well established that a placebo arm for the high-risk patients would have been unethical. In HOPE, ramipril provided a 22% reduction (P<0.001) in the composite end point of MI, stroke, and CV death relative to placebo. In EUROPA (European Trial on Reduction of Cardiac Events), a trial conducted in a slightly different population of patients with stable coronary artery disease (CAD), perindopril was associated with a comparable 20% reduction (P<0.0003) in MI, resuscitated cardiac arrest, and CV mortality.⁸ Both studies included substantial numbers of patients with diabetes and both appeared to demonstrate vascular protection independent of BP reductions.

The ONTARGET study had two goals. One was to determine whether 80 mg of telmisartan, an ARB with a long half-life, could offer protection comparable to 10 mg ramipril, the proven ACE inhibitor in HOPE, when both were administered once daily. The second was to determine whether a combination of telmisartan and ramipril at the same doses as those employed in the single-drug arms provided any additional advantage. The study, which randomized 25,620 patients into the three arms, was one of the largest studies of RAAS inhibition and the largest ARB study ever conducted. For entry, patients were required to be at least 55 years of age with coronary, peripheral or cerebral vascular disease, or diabetes with end-organ damage. Approximately 38% of the population, or more than 9500 patients, had diabetes at entry. A substantial proportion of these had no prior CV event.

After a median follow-up of 56 months, the rate of the primary composite outcome of MI, stroke, hospitalization for heart failure, and CV death were nearly identical in the three study arms (16.7%, 16.5% and 16.3% for the ARB, ACE inhibitor and combination, respectively). When compared for the HOPE composite outcome of MI, stroke and CV death, the rates were again nearly identical (13.9%, 14.1% and 14.1%, respectively)(Figure 1). The authors of the CDA guidelines cited these data in concluding that 80 mg of telmisartan is non-inferior to 10 mg ramipril for CV protection.

Figure 1.

Tolerability

When the three treatment strategies were compared for tolerability, the discontinuation rate was greatest on the combination, approaching 30%. While this was significantly greater than the 24.5% rate of discontinuation on ramipril (P<0.001), the rate of discontinuation of the ACE inhibitor was significantly greater than the rate of discontinuation on telmisartan (23%; P=0.02, Figure 2), despite a run-in period prior to randomization in which patients intolerant or non-compliant to either ramipril or telmisartan were excluded from the trial. The characteristic cough of ACE inhibitors accounted for 4.2% of these discontinuations (vs. 1.1% for telmisartan; P<0.001), suggesting that the study was not a good reflection on real-world practice. In ACE inhibitor trials without run-ins, discontinuation rates for cough have been as high as 35%.⁹ Although hypotensive symptoms occurred more frequently on telmisartan than ramipril (2.7% vs. 1.7%; P<0.001), there was no difference in the rate of syncope (0.2% vs. 0.2%), which is the most feared consequence of hypotension. Conversely, angioedema, a potentially life-threatening adverse effect, was significantly more common on ramipril
.01).

Figure 2.

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Targeting Other Risk Factors

In the new CDA guidelines on vascular protection, RAAS inhibition is identified as a strategy independent of BP control, but the guidelines emphasize that this strategy should be combined with a comprehensive, multifaceted approach that addresses other modifiable risk factors, including both hypertension and hyperlipidemia. Although patients with diabetes in need of vascular protection should receive the 80-mg dose of telmisartan, the 10-mg dose of ramipril, or the 8-mg dose of perindopril regardless of BP, these agents may also serve a dual role in BP control. In ONTARGET, patients randomized to 80 mg telmisartan had a slightly but potentially clinically significant 2.4/1.4 mm Hg greater reduction in BP relative to 10 mg ramipril. In the large proportion of patients who require at least two antihypertensive agents to reach the current goal of <130/80 mm Hg, as recommended in the CDA guidelines, the combination of telmisartan and a low dose of a thiazide diuretic produces an especially effective combination with a very low risk of adverse events.¹⁰ However, it is important to emphasize that a RAAS inhibitor at doses associated with vascular protection are required
regardless of antihypertensive treatment (Table 1).

Table 1.

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The relative efficacy of an ARB other than 80 mg telmisartan for achieving vascular protection comparable to 10 mg ramipril is unknown. At 25 hours, the half-life of telmisartan is substantially longer than all other available ARBs.¹¹ In many cases, the duration of action is twice as long. Of particular interest in patients with diabetes, there have been several recent studies suggesting that telmisartan, unlike other RAAS inhibitors, improves insulin resistance.^12,13 The importance of evidence-based medicine and the multiple potential differences between ARBs suggest that vascular protection should be sought with the proven ARB in the proven dose. A similar statement is appropriate for employing the proven ACE inhibitors in their proven doses. The guidelines point out that trandolapril at a dose of 4 mg once daily did not reduce the composite end point of CV events in the placebo-controlled PEACE (Prevention of Events with the Angiotensin Converting Enzyme inhibitor) study, which, like EUROPA, randomized patients with stable CAD.¹⁴

The importance of using proven RAAS inhibitors at their proven doses is inherent to the concept of vascular protection, which is based on tissue-specific effects, including preserved endothelial function that reduces the risk of atherosclerotic plaque formation and growth. RAAS inhibition is one of the pharmacologic strategies emphasized in the CDA guidelines, but other risk reduction strategies participate in maintaining vascular health. This is why the CDA recommendations list a multifaceted approach to modifiable risk reduction as the first priority for all patients with diabetes in the section on vascular protection. This includes lifestyle modification that emphasizes smoking cessation, a healthy weight, a healthy diet, and regular physical exercise. It also includes optimal BP control and optimal glycemic control.

Vascular protection strategies that include RAAS inhibition with the proven agents are recommended for patients with diabetes who are at a high risk of a CV event, defined as any male 45 years or older and any female 50 years or older as well as anyone with multiple risk factors, anyone with an extreme level of a single risk factor, anyone with micro- or macrovascular disease, and anyone with diabetes for 15 or more years. The guidelines also recommend antiplatelet therapy as a component of vascular protection in high-risk patients, but the authors cautioned that the vascular protection from antiplatelet drugs may be weaker in patients with diabetes than in those without, and that antiplatelet therapy must be considered only after considering the individual patient’s risk for bleeding.

Summary

In the new CDA guidelines, a section devoted to vascular protection has recommended RAAS inhibition as a strategy independent of BP control to reduce the risk of CV events among aging patients or those who already have signs of micro- or macrovascular disease. Based on the recently completed ONTARGET study, 80 mg of the ARB telmisartan is considered equivalent to 10 mg of ramipril for this goal. Lifestyle modifications, such as healthy weight, healthy diet, and exercise, are also strategies for vascular protection that should be implemented in all patients with diabetes.

References

1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008;32(suppl 1):S1-S201.

2. Meltzer S, Leiter L, Daneman D, et al. CMAJ 1998;159(suppl 9):S1-S29.

3. National Diabetes Fact Sheet, Canada 2007. Public Health Agency of Canada website. Available at www.phac-aspc.gc.ca/ ccdpc-cpcmc/diabetes-diabete/english/pubs/ndfs-fnrd07-eng.html. Accessed December 1, 2008.

4. Ohinmaa A, Jacobs P, Simpson S, et al. Can J Diabetes 2004;28:116-23.

5. U.S. National Institutes of Health. Death among people with diabetes, United States, 2006. NIDDK website. Available at http://diabetes.niddk.nih.gov/ dm/pubs/statistics/#deaths. Accessed December 1, 2008.

6. Yusuf S, Sleight P, Pogue J, et al. N Engl J Med 2000;342:145-53.

7. ONTARGET investigators. N Engl J Med 2008;358:1547-59.

8. Fox KM and EUROPA investigators. Lancet 2003;362:782-8.

9. Dicpinigaitis PV. Chest 2006;129:S169-S173.

10. Fogari R, Preti P, Zoppi A, et al. Am J Hypertens 2005;18:577-83.

11. Israili ZH. J Human Hypertens 2000;14(suppl 1):S73-S86.

12. Yamana A, Arita M, Furuta M, et al. Diabetes Res Clin Pract 2008;82:127-31.

13. Sanchez RA, Masnatta LD, Pesiney C, et al. J Hypertens 2008;26:2393-8.

14. Braunwald E, Domanski W, Fowler SE, et al. N Engl J Med 2004;351:2058-68.