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Use of Losartan in Diabetic Patients in the Primary Care Setting: Review of the Results in LIFE and RENAAL

Posted on: Friday, 25 February 2005, 03:00 CST

Key words: Diabetes - End-stage renal disease - Hypertension - Primary care

SUMMARY

Objective: To review outcomes of diabetic patients treated with losartan in two recent randomized, double-blind, clinical trials and compare outcomes to similar studies in diabetics.

Methods: The Reduction in ENdpoints with the Angiotensin II Antagonist Losartan (RENAAL) study recruited 1513 patients with type 2 diabetes and nephropathy. The Losartan Intervention For Endpoint reduction (LIFE) study recruited 9193 hypertensive patients with left ventricular hypertrophy (LVH) including 1195 with diabetes mellitus. The maximum losartan dose in both studies was 100 mg daily. All study patients could receive additional antihypertensive medications, excluding angiotensin converting enzyme inhibitors (ACEIs) and other angiotensin receptor blockers (ARBs), if blood pressures (BP) < 140/90 mmHg were not achieved. In RENAAL, the control group received placebo whereas in LIFE, controls received atenolol. BP reductions were comparable in the treatment and control groups of both studies. In RENAAL, the primary outcome was the composite of doubling of serum creatinine, end-stage renal disease, or death. In LIFE, the primary composite outcome was cardiovascular death and non-fatal myocardial infarction or stroke.

Results: In RENAAL, losartan reduced the primary composite end- point 16% (p = 0.02) and the incidence of end-stage renal disease (ESRD) 28% (p = 0.002). In LIFE, the primary composite endpoint among diabetics was reduced 24% (p = 0.03), cardiovascular mortality was reduced 37% (p= 0.03) and total mortality was reduced 39% (p =0.002).

Discussion: In diabetic patients with nephropathy, losartan reduces progression to end-stage renal disease. In hypertensive diabetic patients with LVH, losartan reduces cardiovascular morbidity and mortality and total mortality. Angiotensin receptor blockade with losartan appears to confer benefits beyond BP reduction in diabetic patients at high-risk for cardiovascular and renal events.

Introduction

Type 2 diabetes, due in part to the obesity epidemic1, is a growing public health problem resulting in increased risk of cardiovascular and renal morbidity and mortality2. The UK Prospective Diabetes Study Group (UKPDS) demonstrated that antihypertensive therapy can significantly ameliorate the adverse outcomes associated with diabetes and hypertension3. As we will illustrate in this review, practitioners who treat patients with type 2 diabetes now have ample evidence to support aggressive treatment of hypertension in these patients.

Approximately 90% of patients with diabetes mellitus are treated by primary care physicians4. Appropriate management of diabetes at the primary care level is crucial, since interventions have their greatest impact if instituted early5. Early detection is important because at the time of diagnosis up to 50% of type 2 diabetics show signs of progressive renal disease and about one-third have hypertension4,5. Health care providers may not screen or counsel patients for early detection4. At an estimated $132 billion in 2002 in medical expenditures and lost productivity, diabetes is likely to remain a huge public health threat6. Thus, it is critical for primary care physicians to address current and future challenges in the medical management of patients with type 2 diabetes6.

Cardiovascular and renal complications account for the vast majority of morbidity, mortality, and costs associated with type 2 diabetes5,6. There are proven treatments the physician can employ to reduce these risks, which include control of blood pressure (BP), glucose and lipids7-11. Several studies suggest that blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are particularly useful in reducing renal and cardiovascular outcomes in addition to their antihypertensive effects7-11.

The leading cause of death among men and women in the United States is cardiovascular disease. In 2000, the cardiovascular death rate was 198.9 per 100 000(12). Almost half of men and women under age 65 who have a myocardial infarction (MI) die within 8 years12. Cardiovascular morbidity and mortality are even higher in patients with type 2 diabetes. Seventy-five percent of people with diabetes mellitus die of some form of heart or blood vessel disease12. In 55- year old adult men and women, the presence of diabetes approximately doubles their estimated 10-year coronary heart disease risk12. In women, the age-adjusted prevalence of cardiovascular disease is twice that of women without diabetes (p < 0.0001)13.

Furthermore, in type 2 diabetic patients there is a 2- to 5-fold increased risk for stroke compared with those without diabetes14. Risk factors for stroke in the type 2 diabetic population include elevated BP, smoking, age, male sex, atrial fibrillation (AF), and hyperglycemia14. Within a diabetic population, total direct costs in the first year after a stroke were $26 600(15). On a national level, the direct costs of stroke total approximately $31 billion each year with indirect costs at another $20.2 billion annually16. Indeed there are substantial other costs involved with the quality of life of patients who experience a stroke and their families who take care of them.

Diabetes is the single leading cause of end-stage renal disease (ESRD) in the United States and accounts for ~40% of new cases5. The annual incidence of ESRD is projected to rise to 172 667 with a prevalence of more than 660 000 in 2010(17). In 1997, the cost for treating diabetic patients with ESRD exceeded $15.6 billion5. Medicare payment for each patient with ESRD averages $63 100 annually15. Total Medicare expenditures for ESRD more than doubled from $5 billion in 1991 to $12 billion in 1998(18). Medicare ESRD cost is projected to more than double again by 2010 to $28 billion18. Education of healthcare professionals working with patients with and at-risk for ESRD represents one of the keys to progress19.

In addition to UKPDS3, several studies have underlined the importance of active medical intervention for reducing the risk of diabetic complications7-11,20,21. This review discusses clinical outcomes in patients with type 2 diabetes in RENAAL and LIFE in light of the results of other studies in patients with diabetes and treated with either ARBs or ACEIs.

Methods

The Reduction in Endpoints in Non-insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study recruited a total of 1513 patients with type 2 diabetes and nephropathy22. This multinational, randomized, double-blind study compared losartan with placebo, both taken in addition to conventional antihypertensive treatment. The RENAAL study enrolled men and women 31 to 70 years old with a diagnosis of type 2 diabetes and nephropathy defined by a urinary albumin/creatinine of > 300 mg/ g of creatinme or more than 500 mg/24 hours and serum creatinine of 1.3-3.0mg/dL.

Determined by their baseline level of proteinuria, defined as a urinary albumin-to-creatinine ratio < 2000 or ≥ 2000, patients were stratified and randomly assigned to receive either losartan (50 mg) or placebo once daily, along with conventional anti- hypertensive therapy7. After four weeks, if trough sitting systolic BP was above the target of less than 140 mmHg or less than 90mmHg trough sitting diastolic BP, the dose of losartan or placebo was increased to 100 mg or the placebo equivalent. To achieve the target BP after an additional eight weeks, anti-hypertensive agents excluding ACEIs or ARBs, were added7.

The primary efficacy measure in RENAAL was the time to the first event of the composite end point of a doubling of the serum creatinine, ESRD, or death7. ESRD was defined by the need for long- term dialysis or renal transplantation7. Three pre-specified secondary end points were; (a) morbidity and mortality from cardiovascular causes, as a composite of myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, or death from cardiovascular causes; (b) progression of renal disease and; (c) changes in the level of proteinuria7. All analyses were prespecified and were performed according to the intention-to-treat (ITT) principle7.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study recruited 9193 patients with essential hypertension, of whom 1195 had diabetes at the start of the study8. This study was a double-blind, prospective, multi-center, parallel group study designed to compare the effects of losartan with those of the β- blocker atenolol, with additional hydrochlorothiazide (HCTZ)8. In LIFE, patients were male or female 55 to 80 years old with previously untreated or treated hypertension and electrocardiographically documented LVH23.

After one and two weeks on single-blind placebo, patients had to have trough sitting diastolic BP mean readings of 95 to 115 mmHg or sitting systolic BP mean readings of 160 to 200 mmHg to be included23. Patients were then randomized to either losartan or atenolol, both 50 mg daily, with 12.5 mg HCTZ added after two months if goal BP was not attained. Those who had still not reached the goal after two more months received an additional 50 mg o\f atenolol or losartan with additional HCTZ, 12.5 mg, or another open-label antihypertensive agent (excluding ACEIs, ARBs, or β- blockers)23.

The primary composite endpoints in LIFE were cardiovascular mortality, stroke, and myocardial infarction8. Other prespecified endpoints included total mortality, hospital admission for angina pectoris or heart failure, and revascularization8. All endpoints were assessed using an ITT analysis, and the level of two-sided significance was 5%8. In both studies, patients were treated with a minimum dose of losartan 50 mg to a maximum dose of losartan 100 mg, if goal BP of less than 140 mmHg systolic and 90 mmHg diastolic were not met.

Results

A total of 1513 patients were enrolled in the RENAAL study with the greatest number of patients in North America (45.5%), followed by approximately equal numbers in Asia, Europe, and Latin America22. The study population included 48.6% Caucasians, 18.2% Hispanic, 16.7% Asian, 15.2% Black, and 0.2% Native American22. Retinopathy (62%), lipid disorders (53.7%), neuropathy (49.2%), and cataracts (25%), represented the most common concurrent conditions observed at baseline22. A history of stroke occurred in 152 patients and accounted for 10.1% of the baseline concurrent conditions. The daily dose of losartan ranged from 50 to 100 mg, with 71% of the patients receiving 100 mg. More patients discontinued the study in the placebo (53.5%) than losartan group (46.5%)7.

Examining patients with diabetes at baseline (n = 1195) in approximately 830 centers, the LIFE investigators found that 767 (64%) of the patients came from the Nordic countries, 365 (31%) from the US, and 63 (5%) from the UK8. In the LIFE diabetic population, 85% were Caucasian, 11% Black, 2% Hispanic, 0.8% Asian, and 0.2% Other8. At baseline, 35% of the patients had some form of vascular disease, 24% had coronary heart disease, 20% had isolated systolic hypertension (ISH), 12% had cerebrovascular disease, 7% had peripheral vascular disease and another 7% had atrial fibrillation8. At the end of the trial, the daily dose of losartan ranged from 50 to 100 mg with 8% of patients receiving 50 mg alone, 14% with 50 mg plus additional drugs and 51% with 100 mg with or without additional drugs. Similarly, at the end of the trial, the daily dose of atenolol ranged from 50 to 100 mg with 5% of patients receiving 50 mg alone, 16% with 50 mg plus additional drugs and 47% with 100 mg with or without additional drugs. (The additional drugs included HCTZ.) The average dosage of losartan during the study was 82 mg daily, and the average dosage for atenolol was 79 mg daily8.

Mean follow-up was 4.8 years in LIFE and 3.2 years in RENAAL. Diabetic patients in the intervention and control groups of LIFE and RENAAL were comparable in regard to BMI, pulse rate, total cholesterol, and serum glucose at baseline (Table 1). By study design, diabetic patients in RENAAL had worse renal function than those in LIFE based on serum creatinine levels and the degree of proteinuria. BP reductions were also comparable in the treatment and control groups of both studies. In RENAAL, the trough BP at the end of the study averaged 140/74 mmHg in the losartan group and 142/74 mmHg in the placebo group7. In the LIFE study, mean BP at the end of follow-up was 146/79 ( 17/11) and 148/79 mmHg ( 19/11) in the losartan and atenolol groups8.

Primary Outcome Measures

The primary composite endpoint and its components for RENAAL are shown in Table 2. According to the ITT analysis, the primary composite endpoint of a doubling of the serum creatinine concentration, ESRD, or death was reached in 327 patients in the losartan group (43.5%), as compared with 359 in the placebo group (47.1 %)7. Treatment with losartan resulted in a 16% reduction in the risk of the primary composite end point (p = 0.02). The decrease in risk remained unchanged (15%) after adjustment for BP (p = 0.03). Losartan also reduced the risk of ESRD by 28% (p = 0.002). There was no significant difference between the losartan group and the placebo group in the composite end point of morbidity and mortality from cardiovascular causes7.

Table 1. Baseline characteristics of diabetic patients in LIFE and RENAAL

Table 2. Incidence of primary end-points: RENAAL

Within the diabetic population of the LIFE study, participants were closely matched and the incidences of their end points are shown in Table 3. The primary composite endpoint (first occurrence of cardiovascular death, fatal and non-fatal stroke and MI) occurred in 242 (20%) participants during 5596 patient-years: 103 in losartan group (39.2 per 1000 patient years) and 139 in the atenolol group (53.6), relative risk 0.76, p = 0.031(8). There was also a significant difference in the number of participants who died from cardiovascular disease (p = 0.028), 38 (13.6 per 1000 patient- years) and 61 participants (21.8) in the losartan and atenolol groups, respectively. Stroke occurred in 51 losartan and 65 atenolol patients (p = 0.205), and myocardial infarction in 41 and 50 participants, respectively (p = 0.373).

Table 3. Incidence of primary endpoints: LIFE (diabetic population)

Secondary Outcome Measures

In RENAAL, the prespecified secondary end point, morbidity and mortality from cardiovascular causes, was a composite of myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, or death from cardiovascular causes. In the composite of morbidity and mortality from cardiovascular causes, there was no significant difference between the losartan group (32.9%) and the placebo group (35.2%) in RENAAL (p = 0.26)7. In most of the other cardiovascular end points, there were also no significant differences, except the first hospitalization with heart failure (11.9% in the losartan group and 16.7% in the placebo group, p = 0.05). The difference in the number of myocardial infarctions (6.7% in the losartan group and 8.9% in the placebo group, p = 0.08) was not statistically significant7.

In the LIFE diabetic population, other prespecified end points included: total mortality, admission to the hospital for angina pectoris or heart failure, and revascularization. A statistically significant difference was attained for only two of these in total mortality (p = 0.002) and heart failure (p = 0.019), both favoring treatment with losartan8.

Discussion

Hypertension is the most common chronic medical problem triggering visits to primary health care providers16. Data from a representative national survey of adults with type 2 diabetes showed that of those patients with hypertension, 82% were diagnosed and treated with antihypertensive agents24. However, in patients who were diagnosed before the survey, 59% were not controlled to < 140/ 90 mmHg. Once combined with newly diagnosed type 2 diabetics with hypertension, 40% of all patients had uncontrolled hypertension, at the time the survey was administered24. BP levels achieved with losartan compared to the control group (placebo) in RENAAL, and the control groups in LIFE (atenolol) were similar. The benefits with losartan in RENAAL and LIFE suggest that angiotensin receptor blockade confers benefits beyond BP reduction in diabetic patients with nephropathy and with hypertension and LVH, but precise mechanisms behind that benefit are unknown. Current Joint National Committee (JNC 7) guidelines state that in participants with hypertension and diabetes mellitus the BP target goal should be < 130/80 mmHg25. Perhaps this lower BP goal would have further reduced outcomes in both studies.

Losartan has documented efficacy in improving renal outcomes and decreasing hospitalizations due to heart failure in diabetic patients with overt nephropathy. Although RENAAL included only participants with proteinuria, LIFE included a prespecified subgroup of diabetics without proteinuria. Losartan demonstrated effectiveness as an appropriate evidence-based agent for substantially reducing CV morbidity and mortality among diabetic patients in LIFE. The primary composite outcome of cardiovascular death, fatal and non-fatal stroke, and MI was reduced in the losartan treated participants of LIFE by comparison to those treated with atenolol.

Several other studies have provided data on similar primary and secondary outcome measures comparing irbesartan, amlodipine, or ramipril with placebo (Table 4). In a study done by Parving et al., irbesartan, an ARB, reduced the rate of progression to clinical albuminuria, and its renoprotective nature was also found to be independent of its BP lowering effect3. The interruption of the RAS with irbesartan may induce the same degree of renoprotection as the use of an agent such as losartan, although a significant decline in ESRD was not noted in the Irbesartan Diabetic Nephropathy Trial (IDNT)21. Whether this observation was not made in IDNT because of molecule specific differences or differences in the length of follow- up is not known. However, losartan has documented efficacy in improving renal and cardiovascular outcomes for diabetic patients with nephropathy (heart failure) and with hypertension and LVH (primary composite endpoint).

Table 4. Outcomes in recent studies of angiotensin receptor blockers in diabetic patients with renal disease

Table 4. Outcomes in recent studies of angiotensin receptor blockers in diabetic patients with renal disease

Importantly, when it comes to the treatment of patients with diabetic nephropathy some believe that ACEIs ought to be used in type 1 diabetics and ARBs in type 2 diabetics26 based on the strength of available evidence. However, the American Diabetes Association recommendations indicate that in type 2 patients with diabetes and macroalbuminuria, nephropathy or renal insufficiency, an ARB should be strongly considered and that in patients without macroalbuminuria or renal insufficiency, ACE inhibitors and ARBs have beenshown to delay the progression of nephropathy27.

Meta-analysis in non-diabetic patients with protein excretion greater than 1.0g/day indicates that a systolic blood pressure goal between 110 and 129 is optimal28. For diabetic patients with hypertension, lowering BP to the more stringent goal of < 130/ 80mmHg27, while very important in reducing complications, may not provide optimal protection from adverse cardiovascular and renal events16. The study to examine the feasibility of lowering blood pressures to truly normotensive (i.e. < 120/80) levels in diabetic patients with hypertension, on renal and cardiovascular outcomes, has yet to be completed (ACCORD). Therefore, it is crucial for the medical community to recognize and use treatments that offer benefits that go beyond the BP reductions observed in clinical trials. Despite comparable attained blood pressures, drugs targeting the RAS are repeatedly winners in clinical trials. Losartan is unique among these drugs in having demonstrated cardiovascular protection compared to beta-blockade in diabetic patients in LIFE and delaying ESRD in comparison to conventional, non-RAS modifying, blood pressure treatment in RENAAL.

Diabetic patients are at very high risk for cardiovascular and renal morbidity and mortality. A coordinated and integrated effort by health care providers to prescribe effective, evidence-based therapies and to enhance patient adherence with recommended therapy is vital in addressing the epidemic of diabetes-related disease.

Acknowledgments

The publication of this article was supported by Merck & Co., Inc. Dr. Gilbert Gleim is an employee and Ms. Jessica Panish was a former employee of Merck & Co., Inc.

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29. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002:359;995-1003

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2788_5, Accepted for publication: 08 October 2004

Published Online: 10 November 2004

doi: 10.1185/030079904X13040

Brent Egan1, Gilbert Gleim2 and Jessica Panish2

1 Medical University of South Carolina, Charleston, SC, USA

2 Merck Research Laboratories, West Point, PA, USA

Address for Correspondence: Brent M. Egan MD, Professor of Pharmacology and Medicine, Medical University of South Carolina, 171 Ashley Avenue CSB 826 H, Charleston, SC, 29425, USA. Tel.: +1-843- 792-1715; email: eganbm@musc.edu

Copyright Librapharm Dec 2004

Source: Current Medical Research and Opinion

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