Cardiovascular and Renal Protection in Patients with Diabetes and Metabolic Syndrome

Introduction

What percentage of patients with diabetes achieve the combined goals of HbA1c level less than 7.0%, blood pressure less than 130/80 mm Hg, and total cholesterol level less than 200 mg/dL (5.18 mmol/L)?

  1. 45%-55%
  2. 35%-45%
  3. 25%-35%
  4. 15%-25%
  5. Less than 10%

Individuals with diabetes and the metabolic syndrome are among those at greatest risk for developing cardiovascular disease (CVD).6-9 Adults with diabetes have a two- to fourfold increased death rate from heart disease and risk for stroke as compared to adults without diabetes, whereas adults with the metabolic syndrome have a threefold increased risk for heart disease and stroke.1,8 In addition, approximately one-third of patients with diabetes develop diabetic nephropathy, many of whom subsequently progress to end-stage renal disease (ESRD). Diabetes is the leading cause of ESRD, accounting for nearly half of all new cases.1,6,10

Control of blood glucose levels, blood pressure (BP), and cholesterol levels has been proven to reduce the risk of CVD in patients with diabetes by up to 40%, 50%, and 50%, respectively, while glycemic and BP control have also been shown to reduce the risk of kidney disease by up to 40% and 33%, respectively.1,7,11-28 Yet, despite the overwhelming evidence to support aggressive risk management, data from the Third National Health and Nutrition Examination Survey (NHANES III), revealed that only 7.3% of adults with diabetes attained the combined targets of HbA1c level less than 7.0%, BP less than 130/80 mm Hg, and total cholesterol (TC) level less than 200 mg/dL (5.18 mmol/L). The percentage of patients achieving individual HbA1c, BP, and TC goals was 37.0%, 35.8%, and 51.8%, respectively. Compared with data from NHANES III, these percentages have either remained unchanged or worsened (see Figure 1).2

Given the global efforts to promote disease prevention and treatment and the widespread availability of evidence-based treatment guidelines and effective therapies, the NHANES data reflect multiple deficiencies in patient care that will likely be compounded by the growing prevalence of diabetes and the metabolic syndrome. This monograph focuses on critical issues in HTN management that contribute to the development of micro- and macrovascular complications among patients with diabetes and the metabolic syndrome and on strategies for optimizing BP treatment to reduce these complications.



Deficiencies in Hypertension Management and the Role of Combination Therapy

On average, how many drugs are needed to reach blood pressure goals?

  1. 0-1
  2. 2-3
  3. 3-4
  4. 5 or more

Numerous physician and patient factors contribute to deficiencies in the management of HTN. Barriers to treatment include acceptance of inadequate control by physicians and poor adherence to treatment regimens by patients.3,29-30 Many clinicians accept higher BP thresholds for the diagnosis and treatment of HTN than is recommended by the seventh report of the Joint National Committee (JNC-7) and American Diabetes Association (ADA) guidelines. As a result, nearly one-third of patients with diabetes receive no treatment for their HTN.3-5 Among those who do receive treatment, a recent survey found that almost half received only monotherapy and less than half received treatment with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB).3

Rather than intensify treatment (i.e. prescribe additional medications that take advantage of the different drug classes and mechanisms of BP lowering), physicians may be switching from one suboptimal monotherapy regimen to another. Patients’ fears of perceived side effects and poor adherence to multiple agents and frequent dosing further augment the problem. Clinicians who do not receive adequate education about evidence-based treatment guidelines and the role of combination therapy in achieving BP goals may not, in turn, be communicating the potential grave consequences of suboptimal treatment or the positive risk-to-benefit ratio of HTN therapies to their patients.31

Review of several large-scale clinical trials evaluating the safety and efficacy of antihypertensive therapies, as shown in Figure 2, clearly illustrates the need for combination therapy to achieve target BP goals in the majority of patients, often with an average of 3 to 4 agents.12,24,32-35 Moreover, drugs that block the renin-angiotensin-aldosterone system (RAAS), including ACEIs and ARBs, are an important component of combination therapy, particularly for those with diabetes and the metabolic syndrome. (The cardiovascular- and renoprotective effects of ACEIs and ARBs will be further described in a subsequent section of this monograph.)13,24-26,36-37 The benefits of combination therapy have been endorsed by worldwide organizations (see Table 1) and validated by recent studies.36-41

Fox et al performed a randomized controlled study comparing conventional monotherapy with JNC-7 recommended combination therapy for the treatment of HTN in patients with diabetes. At 4 weeks, a significantly greater percentage of patients who received initial therapy utilizing an ARB and diuretic combination (losartan/hydrochlorothiazide [HCTZ]) reached BP goals (30.5% achieved goal diastolic BP, 29.8% achieved goal systolic BP) than those who received an ACEI (ramipril) alone (14.4% achieved goal diastolic and systolic BP).38

The IrbesartaN/HCTZ bLood pressUre reductionS in dIVErse patient populations (INCLUSIVE) trial evaluated the efficacy and safety of irbesartan/HCTZ 150/12.5 mg and 300/25 mg fixed combinations in a diverse population of adults with systolic BP uncontrolled on monotherapy. One thousand and five patients were initially enrolled in the study, including 30% with type 2 diabetes and 46% with the metabolic syndrome. By week 18, 77% of INCLUSIVE patients achieved target systolic BP (<140 mm Hg or <130 mm Hg in diabetes subgroup); 83% achieved target diastolic BP (<90 mm Hg or <80 mm Hg in diabetes subgroup); and 69% achieved combined BP goals. Over 70% of patients achieved BP control in all of the patient subgroups except for patients with diabetes, in whom 56% reached systolic BP and 63% reached diastolic BP goals. The results of the INCLUSIVE trial convincingly demonstrate the benefits of combination therapy.39-41



Review of Evidence-Based Treatment Guidelines

Which of the following treatment regimens should be recommended for a patient with diabetes who has a blood pressure of 154/92 mm Hg?

  1. ARB alone
  2. Diuretic alone
  3. ARB and diuretic
  4. Amlodipine

The JNC-7, ADA, and numerous other evidence-based guidelines recommend a BP target of less than 130/80 mm HG in patients with diabetes (see Table 1). Note that the blood pressure goal has been lowered since JNC-6 for high-risk patients, including those with diabetes, from less than 130/85 mg Hg to less than 130/80 mm HG. Other key changes of the JNC-7 guidelines are noted in Table 2. The benefits of lowering BP to less than 130/80 mm Hg have been demonstrated by several randomized clinical trials including the UKPDS 36: association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes; UKPDS 38: tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes; and Hypertension Optimal Treatment (HOT) studies.12,34,42 Moreover, the deleterious effects of BP greater than 115/75 mmHg have been shown in epidemiologic studies.43-44

For patients with diabetes who have BP levels greater than 20/10 mm Hg above goal, treatment guidelines recommend starting combination therapy with an ACEI or ARB and thiazide diuretic (see Table 1) in conjunction with lifestyle modification. For individuals with reduced a glomerular filtration rate (GFR) of less than 60 ml/min a loop diuretic should be given in place of a thiaziade diuretic. A calcium channel blocker CCB or betablocker, preferably carvedilol, should then be added, and the dose titrated upwards as needed, if BP goals are not reached on an ACEI or ARB and diuretic combination. If BP goals are still not met, a subgroup of CCB should be added for those initially given a CCB and a CCB added for those initially given a beta-blocker. A low dose aldosterone antagonist may also be considered for African American patients. Treatment can be further intensified with the addition of a vasodilator and/or the patient should be referred to a clinical hypertension specialist if BP goals are still not reached. This evidence-based treatment algorithm is illustrated in Figure 3.

If systolic BP is less than 20 mm Hg above goal, an ACEI or ARB should be prescribed and titrated upwards. If BP goals are not met, additional drugs should be prescribed in the following order: a long-acting thiazide diuretic followed by a CCB or beta blocker, followed by a subgroup of CCB for those initially given a CCB and a CCB for those initially given a beta-blocker. Again, a low-dose aldosterone antagonist may be considered for African American patients and treatment can be further intensified with the addition of a vasodilator and/or the patient should be referred to a clinical hypertension specialist if BP goals are still not reached.



Cardiovascular- and Renoprotective Effects of ACEIs and ARBs

ACEIs and ARBs provide cardiovascular and renal protection both dependently and independently of their blood pressure-lowering effects.

  1. True
  2. False

As previously discussed, drugs that interrupt the RAAS are an important component of combination therapy, particularly for those with diabetes and the metabolic syndrome. Cardiovascular and renal protection by these agents occurs through a variety of mechanisms, including:

  • Hemodynamic effects
    • Decrease systemic BP
    • Decrease glomerular capillary pressure due to efferent glmerular arteriolar dilation
    • Decrease proteinuria
  • Non-hemodynamic effects
    • Inhibition of macrophage/monocyte infiltration
    • Decrease inflammation
    • Decrease oxidative stress

The positive effects of these agents on renal and cardiovascular outcomes in patients with diabetes have been demonstrated by numerous randomized controlled studies as summarized in Table 3.

The ACEIs were the first class of antihypertensive medications shown to have renal protective effects independent of their blood pressure lowering effects in patients with diabetes.14,56 In a study of 409 patients with type 1 diabetes, Lewis et al found a 48% reduction in the risk of a doubling of the serum creatinine concentration and a 50% reduction in the combined endpoints of death, dialysis, and transplantation in captopril-treated patients as compared to placebo-treated patients. Results of the MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) substudy of the HOPE trial were confirmative. In this study, 3,500 people with diabetes who had a previous cardiovascular event or at least one other cardiovascular risk factor and no clinical proteinuria were randomly assigned to ramipril or placebo. Ramipril was shown to reduce the risk of overt nephropathy by 24% risk. In addition, ramipril reduced the risk of combined primary outcome by 25%, MI by 22%, risk of stroke by 33%, cardiovascular death by 37%, total mortality by 24%, and revascularization by 17%.

The benefits of ACEIs in improving cardiovascular outcomes in high-cardiovascular-risk patients have been demonstrated in patients with and without HTN.14,62 In people with diabetes these benefits have been demonstrated, along with the MICRO-HOPE trial, by the ABCD (Appropriate Blood Pressure Control in Diabetes trial), FACET (Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial), HOT (Hypertension Optimal Treatment), STOP Hypertension-2 (Swedish Trial in Old Patients with Hypertension-2), and UKPDS 39 (UK Prospective Diabetes Study) studies.

Some studies suggest that ACE inhibitors may be superior to dihydropyridine calcium channel blockers (DCCBs) in reducing cardiovascular events.32,57 Conversely, the INVEST (International Verapamil Study), which evaluated >22,000 people with coronary artery disease and HTN, demonstrated that the non-DCCB, verapamil, had a similar reduction in cardiovascular mortality to a beta blocker. This relationship held true in the diabetic subgroup.63

Three pivotal studies have demonstrated the cardiovascular and renal protective effects of ARBs. Brenner et al for the RENAAL Study Investigators evaluated the effects of losartan versus placebo in 1,513 patients with type 2 diabetes and nephropathy. Losartan was found to reduce the risk of doubling of the serum creatinine concentration by 25% and the risk of ESRD by 28%. Although the composite morbidity and mortality from cardiovascular causes was similar in both groups, the rate of first hospitalization for heart failure was significantly lower with losartan.

The IDNT (Irbesartan Diabetic Nephropathy Trial) was designed to determine whether an ARB or CCB (amlodipine) would provide protection against the progression of nephropathy due to type 2 diabetes beyond that attributable to lowering of the blood pressure (n=1,715). In this study irbesartan was found to reduce the risk of the primary composite endpoint of doubling of the serum creatinine concentration, development of ESRD, or death from any cause by 20% lower than placebo and 23% lower than amlodipine. Furthermore, irbesartan reduced the risk of doubling of serum creatinine concentration by 33% lower than placebo and 37% lower than amlodipine; and reduced risk of ESRD by 23% lower than both other groups. Serum creatinine concentration increased 24% more slowly with irbesartan than with placebo and 21% more slowly than with amlodipine. No significant differences in composite cardiovascular endpoint or in rates of death from any cause were observed.24

Finally, Parving et al for the Microalbuminuria Study Group evaluated the effects of irbesartan versus placebo in 590 hypertensive patients with type 2 diabetes and microalbuminuria. After 2 years of follow-up, 5.2% of patients treated with irbesartan 300 mg reached the primary endpoint of time to onset of diabetes as compared to 9.7% of patients treated with irbesartan 150 mg and 14.9% of patients treated with placebo. The study concluded that irbesartan is renoprotective independently of its blood-pressure-lowering effects.

In people with diabetic nephropathy, ARBs may be superior to DCCBs for reducing cardiovascular events.64-65 The MOSES (Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention) trial, which enrolled 1,405 hypertensive stroke patients, found that eprosartan significantly lowered the combined primary endpoint of total mortality, and all cardiovascular and cerebrovascular events.64-65 The superiority of an ARB (losartan) over a beta blocker (atenolol) in improving cardiovascular outcomes in a subset of diabetic patients with HTN and left ventricular hypertrophy has also been demonstrated in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study).15



Summary

Early and aggressive treatment of HTN is crucial in preventing cardiovascular and renal complications among individuals with diabetes and the metabolic syndrome. Reaching and maintaining BP goals is achievable, but requires combination therapy in the majority of patients. Blockade of the RAAS with an ACEI or ARB provides several mechanisms of cardiovascular and renal protection and is an important component of combination therapy. Fixed-dose ACEI or ARB and diuretic combinations are readily available and are very useful in simplifying the management of HTN. However, whether ACEI are superior to ARBs or visa versa in preventing cardiovascular and renal complications has not yet been determined. Additional randomized, controlled, prospective studies comparing ACEI and ARBs are currently underway to investigate this issue.



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