Insulin Resistance, Diabetes, Hypertension, and Renin—Angiotensin System Inhibition: Reducing Risk for Cardiovascular Disease

Abstract

Insulin resistance, diabetes mellitus, and hypertension are associated with significant cardiovascula: morbidity and mortality. Lifestyle modifications effectively decrease the risk of progression to diabetes in high‐risk patients, but intensive interventions can be costly and difficult for patients to maintain. The addition of pharmacotherapy is often necessary to treat hyperglycemia and hypertension and lower the risk of cardiovascular complications. Clinical trial data suggest the use of insulin‐sensitizing and antihyperglycemic agents to delay the progression to diabetes. Similarly, analysis of data from clinical trials of angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers indicate that the use of these agents results in fewer cases of new‐onset diabetes among patients with hypertension, when compared with other antihypertensive agents. Angiotensin II has direct and indirect effects on insulin and its signaling pathways, providing support for the biologic mechanism underlying the benefits of renin‐angiotensin system inhibition in preventing diabetes and cardiovascular events. Clinical trials now under way will further evaluate the role of renin‐angiotensin system inhibition in preventing diabetes and its microvascular and macrovascular complications.

Diabetes mellitus is a growing problem both worldwide and nationally. In the year 2000, approximately 3% of all individuals in the world had diabetes, totaling 171 million people globally. ¹ The number affected is expected to rise to 221 million by 2010 and to 366 million by 2030. ¹ , ² In the United States in 2002, there were approximately 14 million diagnosed cases of diabetes, and the prevalence continues to rise, with type 2 diabetes accounting for >90% of all cases of diabetes. ¹ Patients with diabetes are at an increased risk of cardiovascular (CV) disease; among patients aged 35 years and older with diabetes, the prevalence of CV disease was 37% in 2000. ¹ Death from heart disease or stroke is 2–4 times more common among adults with diabetes than those without diabetes, and two thirds to three fourths of all patients with diabetes die from heart or vascular disease. ¹ The presence of hypertension in diabetes dramatically increases risk.

The development of diabetes is believed to be preceded by peripheral insulin resistance. Insulin resistance is highly prevalent: approximately 49–69 million Americans may have insulin resistance, and 25% of these persons will develop type 2 diabetes. ¹ Accumulated evidence indicates that insulin resistance plays a significant role in the relationship between diabetes, hypertension, and CV disease. ³

Insulin resistance is frequently associated with mildly elevated glucose levels (impaired fasting glucose or impaired glucose tolerance [IGT]), a key component of the metabolic syndrome. The metabolic syndrome is a constellation of closely related abnormalities associated with significant risk for heart and vessel disease. ⁴ Various definitions of the metabolic syndrome have been promulgated by expert professional organizations such as the World Health Organization (WHO), ⁵ the National Cholesterol Education Program (NCEP), ⁶ the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), ⁷ and the International Diabetes Federation (IDF). ⁸ All definitions include some degree of insulin resistance, elevated fasting glucose or IGT, and blood pressure elevation. Other components incorporated into all definitions of the metabolic syndrome are excess abdominal adipose tissue (abdominal obesity) and dyslipidemia (elevated triglycerides and low levels of high‐density lipoprotein cholesterol). ⁴ , ⁹ , ¹⁰ Although it has been questioned whether the metabolic syndrome can be fully classified as a distinct medical condition and a predictor of disease, ¹¹ clinicians agree that it is important to identify all CV disease risk factors and to treat them aggressively and individually. Current targets of intervention include implementing lifestyle changes, improving glucose tolerance, increasing insulin sensitivity, reducing elevated lipid levels, and lowering blood pressure. This paper will focus on therapies that reduce the incidence of type 2 diabetes and its consequences.

APPROACHES TO PREVENTION AND TREATMENT OF DIABETES AND CV DISEASE

One study indicates that new‐onset diabetes in persons treated for hypertension carries long‐term CV risk similar to that of preexisting diabetes. ¹² Some observers do not believe that, at present, there is sufficient evidence that clinical outcome is similar in patients with new‐onset diabetes when compared with patients with pretreatment diabetes. ¹³ Prevention or delay of diabetes might be expected to provide cardioprotection, although this assumption has yet to be confirmed in clinical trials. In persons with preexisting diabetes, blood pressure is a major determinant of CV morbidity and mortality. Inhibitors of the renin‐angiotensin system (RAS) are effective antihypertensive agents that lower CV risk and are recommended as initial treatment for all diabetic patients by the American Diabetes Association. ¹⁴ Even so, the high morbidity and mortality rates associated with macrovascular and microvascular complications of diabetes require multifaceted approaches for optimal CV risk reduction.

Lifestyle Interventions

Lifestyle interventions for patients at risk for type 2 diabetes were evaluated in studies conducted by the Diabetes Prevention Program (DPP) Research Group. ¹⁵ DPP recommendations included weight loss of 7% of body weight through dietary modifications and increased physical activity, amounting to 150 minutes of moderate exercise per week. ¹⁶ In persons with elevated fasting and post‐load glucose concentrations, metformin or DPP lifestyle interventions each lowered the incidence of diabetes, but lifestyle interventions led to a 39% (95% confidence interval [CI], 24%–51%) greater reduction in new‐onset diabetes than did metformin (Figure 1). ¹⁵ Lifestyle interventions also improved the CV risk factor profile of study participants compared with metformin, including greater reductions in hypertension, triglyceride levels, and proatherogenic low‐density lipoprotein cholesterol particles. There were, however, no differences in CV event rates between treatment groups after 3 years of follow‐up. ¹⁷

Figure 1.

Cumulative incidence of type 2 diabetes mellitus according to study group in the Diabetes Prevention Program. Reprinted with permission from N Engl J Med. 2002;346:393–403. ¹⁵

Although lifestyle interventions are effective, patients often have difficulty adhering to them, and the cost effectiveness of some programs remains in question. Patients in the DPP studies had individual case managers and access to supervised exercise sessions and other motivational classes; ¹⁵ however, such intensive patient management is impractical for most clinical practices. In addition, there is debate over the financial feasibility of implementing DPP intensive lifestyle modifications for all patients at risk for diabetes. ¹⁸ Two recent analyses assessed the costs associated with lifestyle modifications in the prevention of type 2 diabetes using different models to simulate the progression of diabetes. ¹⁹ , ²⁰ Both analyses found that lifestyle interventions would delay new‐onset diabetes, decrease the incidence of complications, and extend life. ¹⁸ However, the average costs per quality‐adjusted life‐year gained were widely divergent ($8000 vs $62,000). ¹⁸ Nonetheless, all patients should at least receive encouragement to make appropriate lifestyle changes.

Treatment of Insulin Resistance

Many patients require pharmacotherapy to improve insulin sensitivity. Metformin (which reduces glucose production and increases insulin sensitivity) has been shown to reduce the risk of progression to diabetes, but it is not sufficiently effective as a monotherapy. ¹⁵ Thiazolidinediones (the glitazones) are insulin‐sensitizing medications that have been shown to lower the risk of new‐onset diabetes. ²¹ The Actos Now For Prevention of Diabetes (ACT‐NOW) trial ²² will examine the role of pioglitazone in the prevention of progression to type 2 diabetes and improvement of CV risk factors in approximately 600 patients with IGT and at least one other component of the metabolic syndrome. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial ²³ is evaluating the comparative effects of the angiotensin‐converting enzyme (ACE) inhibitor ramipril and rosiglitazone on diabetes incidence, mortality, and atherosclerosis of the carotid artery in more than 5200 patients with IGT or impaired fasting glucose.

The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) ²⁴ assessed the role of pioglitazone in decreasing CV events in patients with preexisting type 2 diabetes and at high macrovascular risk. PROactive showed a nonsignificant reduction in the primary composite end point (all‐cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, cardiac or leg revascularization, and amputation above the ankle). The secondary end point of all‐cause mortality, myocardial infarction, or stroke was, however, significantly decreased (hazard ratio, 0.84; 95% CI, 0.72–0.98; P=.027). ²⁴ These results will need to be confirmed by additional studies, and the role of insulin sensitizers in the prevention of CV events needs further clarification. ²⁵

Treatment of IGT

Patients with IGT may be treated with antihyperglycemic medications, such as the α‐glucosidase inhibitor acarbose or thiazolidinediones. The Study to Prevent Non‐Insulin‐Dependent Diabetes Mellitus (STOP‐NIDDM) ²⁶ demonstrated that acarbose treatment of glucose intolerance significantly reduced the risk of CV events compared with placebo (hazard ratio, 0.47; 95% CI, 0.24–0.90; P=.02) and new cases of hypertension (hazard ratio, 0.62; 95% CI, 0.45–0.86; P=.004). The benefits of treating IGT will be further evaluated in the ongoing Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which will measure the effects of the angiotensin II type 1 receptor blocker (ARB) valsartan or the antidiabetic agent nateglinide, which stimulates insulin release, vs placebo in reducing the two primary end points of new‐onset diabetes or CV morbidity and mortality. ²⁷ Approximately 9500 patients with IGT who are at high risk for CV disease have been randomized to receive lifestyle interventions that include weight loss, reduction of dietary fat, and increased exercise in addition to assigned study drug. Results from NAVIGATOR are not expected to be reported before 2010.

Treatment of Hypertension

All of the major classes of antihypertensive agents effectively lower blood pressure while also reducing the risk of CV events. The United Kingdom Prospective Diabetes Study (UKPDS) 39, ²⁸ which used an ACE inhibitor or a β‐blocker as the primary antihypertensive therapy, reported similar blood pressure reductions with the two classes of agents as well as similar effects of treatment on preventing the macrovascular and microvascular complications of diabetes. According to the latest analysis from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) ²⁹ based on data from 27 randomized trials, total CV events were reduced to a comparable extent in the short‐to‐medium term in patients with and without diabetes by regimens based on ACE inhibitors, calcium channel blockers, ARBs, and diuretics/β‐blockers. The authors noted, however, that their analysis did not address the effects of different blood pressure‐lowering regimens on renal outcomes, the risk of new‐onset diabetes, or progression of existing diabetes, conceding that there may be differences for these outcomes, particularly in the longer term. ²⁹

The BPLTTC analysis notwithstanding, beneficial and detrimental effects of certain antihypertensive agents in patients at risk for developing diabetes as well as in patients with existing diabetes cannot be excluded. For example, some antihypertensive agents have been associated with metabolic side effects that increase the risk of diabetes. Diuretics, particularly thiazides, and β‐blockers with the exception of carvedilol, may increase insulin resistance. ³⁰ In the Glycemic Effects in Diabetes Mellitus: Carvedilol‐Metoprolol Comparison in Hypertensives (GEMINI) trial, ³¹ carvedilol improved insulin resistance in the presence of RAS blockade compared with metoprolol. By contrast, long‐acting calcium channel blockers appear to ameliorate insulin sensitivity in hypertensive patients with and without obesity. ³² , ³³ Given the possible risks associated with new‐onset diabetes, ¹² some antihypertensive agents, such as those that antagonize the RAS, may be more appropriate for the treatment of hypertension in patients at risk for developing diabetes.

RAS BLOCKADE IN DIABETES PREVENTION AND TREATMENT

In addition to efficacy in treating hypertension, blockade of the RAS has been shown to decrease the risk of developing diabetes when compared with other antihypertensive agents and to improve CV outcomes in patients with diabetes. ³⁴ Meta‐analyses of randomized clinical trials of ACE inhibitors and ARBs found that these drugs lowered the relative risk of new‐onset type 2 diabetes by 22% ³⁵ and 25% (Figure 2) ³⁶ in patients with hypertension, coronary artery disease, heart failure, or at high risk for diabetes. This effect was consistently seen in comparisons of a variety of agents, including β‐blockers, diuretics, and a metabolically neutral calcium channel blocker. ³⁰ , ³⁵ , ³⁶ In addition, data from experimental studies suggest that the benefits of RAS blockade may be attributable to multiple interactions between insulin and angiotensin II.

Figure 2.

Risk ratios (95% confidence intervals) for development of new‐onset type 2 diabetes mellitus (DM) in clinical trials of angiotensin‐converting enzyme inhibitor (ACE‐I) and angiotensin II type 1 receptor blocker (ARB) therapy. CAPPP indicates Captopril Prevention Project; STOP‐2, Second Swedish Trial in Old Patients With Hypertension; HOPE, Heart Outcomes Prevention Evaluation; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ALLHAT, Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Study; SCOPE, Study on Cognition and Prognosis in the Elderly; ALPINE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation; CHARM, Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity; SOLVD, Studies of Left Ventricular Dysfunction; VALUE, Valsartan Antihypertensive Long‐Term Use Evaluation; and PEACE, Prevention of Events With Angiotensin Converting Enzyme Inhibition. Reprinted with permission from Abuissa et al. ³⁶

In patients with preexisting diabetes, elevated blood pressure increases the risk of CV events, diabetic nephropathy, and renal disease. ³⁴ Evidence from numerous clinical trials that included patients with diabetes demonstrates that stringent blood pressure control in these patients lowers the risk of stroke and other CV events. ³⁴ Similarly, a meta‐analysis of antihypertensive treatments in patients with preexisting diabetes found that ACE inhibitors, ARBs, or diuretics might be preferred as initial treatment for hypertension based on trials with microvascular and macrovascular outcomes. ³⁷

ACE Inhibitor Trials

In the Captopril Prevention Project (CAPPP), ³⁸ the risk of new‐onset diabetes was lower with captopril than with diuretics or β‐blockers (relative risk, 0.86; 95% CI, 0.74–0.99). The Heart Outcomes Prevention Evaluation (HOPE) ³⁹ reported that, among patients with vascular disease but without diabetes at baseline, treatment with ramipril significantly reduced the risk of new‐onset diabetes compared with placebo during a mean follow‐up of 4.5 years (3.6% vs 5.4%; P<.001). The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ⁴⁰ found no significant differences between lisinopril, amlodipine, and chlorthalidone in the primary CV outcome among patients with hypertension at high risk for coronary heart disease. However, ALLHAT did report a lower risk of new‐onset diabetes among patients taking lisinopril compared with amlodipine and chlorthalidone (8.1%, 9.8%, and 11.6%, respectively) after 4 years. Despite these differences, however, outcome for some subsets of patients was better with the diuretic than with the calcium channel blocker or ACE inhibitor. Benefit was noted in both diabetics and nondiabetics. More recently, the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial ⁴¹ investigated the addition of an ACE inhibitor to current standard therapy in subjects with stable coronary artery disease. Although the PEACE study did not show a reduction in the combined primary end point of death from CV causes, myocardial infarction, or coronary revascularization, it did demonstrate an absolute risk reduction of 1.7% (hazard ratio, 0.83; 95% CI, 0.72–0.96; P=.01) in new‐onset diabetes in this patient population. ⁴¹ The long‐term implications of treatment differences in decreasing the risk of new‐onset diabetes need to be considered.

ACE inhibitors have also proven beneficial in patients with preexisting diabetes. The CAPPP showed that captopril decreased the relative risk of a combined CV end point (fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, other CV deaths) by 41% (95% CI, 9%–62%; P=.018) compared with conventional therapy in subjects with diabetes, primarily due to reductions in CV mortality. ⁴² In the 37.5% of HOPE participants who had diabetes at study entry, ramipril significantly reduced the absolute risk of combined myocardial infarction, CV death, or stroke by 4.5% compared with placebo (relative risk reduction, 25%; 95% CI, 12%–36%; P=.0004). ⁴³ There is some question regarding these benefits—were they secondary to better blood pressure reduction or specific therapy? Similarly, the European Trial on Reduction of Cardiac Events With Perindopril in Patients With Stable Coronary Artery Disease (EUROPA) ⁴⁴ showed that perindopril reduced the primary end point of CV death, myocardial infarction, or cardiac arrest by 20% vs. placebo (95% CI, 9%–29%; P=.0003) in the overall population, and results were similar in diabetic and nondiabetic subgroups.

ARB Trials

Clinical trial evidence also supports the efficacy of ARBs in preventing progression to diabetes and improving CV outcomes in patients with diabetes. In the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, ⁴⁵ a losartan‐based regimen significantly reduced the risk of new‐onset diabetes compared with an atenolol‐based program among patients with hypertension and left ventricular hypertrophy (relative risk, 0.75; 95% CI, 0.63–0.88; P<.001). More than 20% of these patients also received a diuretic. The Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE) trial ⁴⁶ reported that in high‐risk patients with hypertension, the incidence of diabetes was significantly reduced with valsartan compared with the metabolically neutral calcium channel blocker amlodipine (hazard ratio, 0.77; 95% CI, 0.69–0.86; P<.0001) at 4 years. Despite this fact, no differences in combined CV end points were observed in the overall study population. A similar reduction in new‐onset diabetes (hazard ratio, 0.78; 95% CI, 0.64–0.96; P=.020) was reported in the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) program, ⁴⁷ which compared candesartan with placebo in heart failure patients already receiving background pharmacotherapy (β‐blockers, diuretics, ACE inhibitors), after a mean treatment period of 3.5 years.

Among patients with preexisting diabetes in LIFE, losartan significantly decreased the risk of CV morbidity and mortality compared with atenolol during a mean follow‐up of 4.7 years (relative risk, 0.76; 95% CI, 0.58–0.98; P=.031). ⁴⁸ In the overall CHARM program, the secondary end point of CV death or hospitalization for heart failure was reduced by candesartan similarly in patients with preexisting diabetes and in patients without diabetes. ⁴⁹

Possible Underlying Mechanisms

Insulin resistance is prevalent in many patients with hypertension, independent of obesity and glucose tolerance. ⁵⁰ , ⁵¹ Elevated insulin levels induce increased release of angiotensin II, the main effector peptide of the RAS. ⁵² Activation of the RAS may have a number of diabetogenic effects. For example, angiotensin II is a potent vasoconstrictor, and RAS blockade may increase perfusion to β cells (maintaining insulin secretion) and skeletal muscle (increasing glucose and insulin utilization). ⁵³ The RAS is also expressed in adipose tissue, and angiotensin II inhibits differentiation of adipocytes, which may increase insulin resistance. ⁵³ Angiotensin II also plays a role in two insulin signaling pathways: the phosphatidyl inositol 3‐kinase pathway and the mitogen‐activated protein kinase pathway. ⁵⁴ The phosphatidyl inositol 3‐kinase pathway leads to insulin‐mediated vasodilation, glucose uptake in skeletal muscle, and reduced inflammation, whereas the mitogen‐activated protein kinase pathway leads to insulin‐mediated promotion of smooth muscle cell growth and proliferation. ⁵⁵ , ⁵⁶ Angiotensin II inhibits the phosphatidyl inositol 3‐kinase pathway and enhances the mitogen‐activated protein kinase pathway. ⁵⁷ These effects may lead to proatherogenic conditions.

SUMMARY: IMPLICATIONS FOR CLINICAL OUTCOMES

Significant CV morbidity and mortality are associated with insulin resistance, diabetes, and hypertension. Evidence suggests that target organ damage begins early in the process, leading to diabetes, with microalbuminuria, carotid artery abnormalities, and increased left ventricular mass occurring at a higher rate among nondiabetic patients with the metabolic syndrome than in those without the metabolic syndrome. ⁵⁸ While a DPP‐type program of intensive lifestyle modifications is effective in decreasing the progression to diabetes, it may be too costly to implement on a societal level. ²⁰ Even so, appropriate lifestyle modifications should be initiated in all patients at high risk, and pharmacotherapy targeted at delaying progression to diabetes, lowering blood pressure, and preventing macrovascular complications will be necessary for many patients. Clinical trial data support the use of antihyperglycemic agents for improving insulin sensitivity, and RAS inhibition has been shown to prevent or delay new‐onset diabetes and reduce CV complications in patients with diabetes. In most patients, combination therapy, such as a combination of an RAS inhibitor and a diuretic, is necessary to reduce blood pressure and decrease CV events. Although the use of diuretics results in more cases of new‐onset diabetes than the use of an ACE inhibitor or an ARB, there is no evidence at present that this negatively impacts CV disease outcomes.

Acknowledgement and disclosures:

The author wishes to thank Raquel DeRosa for assistance in preparing this manuscript. Research support to Tulane University with grants from GlaxoSmithKline Inc, Novartis, Takeda Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Pfizer Inc, DPP‐type, Eli Lilly and Co, Daiichi Sankyo Co, National Institutes of Health, and the American Diabetes Association. Dr. Fonseca has also received honoraria for consulting and lectures from GlaxoSmithKline Inc, Novartis, Takeda Pharmaceuticals, Pfizer Inc, DPP‐type, and Eli Lilly and Co.