Prevention of Type 2 Diabetes Mellitus to Reduce Cardiovascular Morbidity and Mortality: A Review of the Evidence

Abstract

Cardiovascular disease accounts for the majority of deaths in patients with type 2 diabetes mellitus. Lifestyle interventions aimed at weight loss and increased physical activity and therapy with antidiabetic drugs have proven effective in reducing the risk of new‐onset diabetes in high‐risk individuals. Substantial evidence also suggests that drugs that inhibit the renin‐angiotensin system, namely angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers, also prolong the time to onset of clinical diabetes. An open question is whether delay of new‐onset diabetes with antidiabetic or antihypertensive agents reduces cardiovascular morbidity and mortality. A large ongoing study is investigating whether therapy with an oral antidiabetic drug or an angiotensin II receptor blocker reduces the incidence of new‐onset diabetes and cardiovascular events in high‐risk patients.

Although type 2 diabetes mellitus is associated with a number of microvascular complications, including renal and retinal disease and neuropathy, the leading cause of death in people with diabetes is macrovascular or cardiovascular disease (CVD). ¹ A number of randomized controlled clinical trials have demonstrated that reducing CVD risk factors in persons at high risk for type 2 diabetes reduces the risk of new‐onset diabetes. Whether such intervention also reduces the risk of CVD is still to be determined.

Concept of Prediabetes

According to current criteria for the diagnosis of diabetes, a fasting plasma glucose (FPG) level ≥126 mg/dL or 2‐hour post‐challenge glucose level ≥200 mg/dL constitutes diabetes, with FPG <100 mg/dL and post‐challenge glucose level <140 mg/dL considered “normal.” Impaired fasting glucose (IFG; FPG, 100–125 mg/dL) and impaired glucose tolerance (IGT; post‐challenge glucose, 140–199 mg/dL), hyperglycemic states that do not meet the criteria for diabetes, are termed prediabetes, ² and an estimated 57 million adults and children in the United States are prediabetic. ³ Neither IFG nor IGT are benign states, as they impart an increased risk of both progression to overt diabetes and CVD. ⁴ In a recently released consensus statement, the American College of Endocrinology (ACE) and American Association of Clinical Endocrinologists (AACE) recommended targeting hyperglycemia and comorbid risk factors, including hypertension and dyslipidemia, in patients with prediabetes. ⁵ Lifestyle intervention is recommended as first‐line treatment, with the addition of pharmacologic therapies, including hypoglycemic and antihypertensive agents that inhibit the renin‐angiotensin system (RAS), where appropriate.

Interventions to Prevent or Delay the Onset of Diabetes and CVD

Lifestyle interventions aimed at weight loss and increased physical activity ⁶ , ⁷ and therapy with antidiabetic drugs ⁸ , ⁹ , ¹⁰ have proven effective in reducing the risk of new‐onset diabetes in high‐risk individuals, while the role of lipid‐lowering agents is less clear ¹¹ , ¹² , ¹³ , ¹⁴ (Table I).

Table I.

 Randomized Controlled Clinical Trials Assessing the Effects of Lifestyle Modification and Pharmacologic Therapy With Antidiabetic and Lipid‐Lowering Drugs on Risk of NOD

Study	Patient Population	Interventions a	Prespecified End Point?	Results
Lifestyle intervention
Finnish Diabetes  Prevention Study 6	522 obese patients (mean BMI, 31 kg/m2) with IGT (2‐hour post‐challenge glucose, 140–200 mg/dL)	Individual counseling to reduce weight and increase physical activity or placebo for 3.2 years	Yes	NOD developed in 11% of patients in the intervention group and 23% in the placebo group (RR, 0.40; 95% CI, 0.30–0.70; P<.001)
DPP 7	3234 nondiabetic obese patients (mean BMI, 34 kg/m2) with IFG (FPG, 95–125 mg/dL) and IGT (2‐hour post‐challenge glucose, 140–199 mg/dL)	Lifestyle intervention (goal of ≥7% weight loss and ≥150 min physical activity/wk); metformin (850 mg 2 times/d); or placebo for 2.8 years	Yes	58% reduction in risk of NOD with lifestyle intervention vs placebo (RR, 0.42; 95% CI, 0.34–0.52; P<.001); 31% reduction in risk of NOD with metformin vs placebo (RR, 0.69; 95% CI, 0.57–0.83; P<.001)
Antidiabetic drugs
STOP‐NIDDM 8	1368 patients with IGT (140–199 mg/dL) and IFG (FPG, 100–140 mg/dL) with no history of CVD events within the previous 6 months	Acarbose (100 mg 3 times/d) or placebo for 3.3 years	Yes	25% reduction in risk of NOD with acarbose vs placebo (RR, 0.75; 95% CI, 0.63–0.90; P=.0015)
TRIPOD 9	266 Hispanic women with previous gestational diabetes	Troglitazone (100 mg/d) or placebo for 2.5 years (median)	Yes	65% reduction in risk of NOD with troglitazone vs placebo (RR, 0.45; 95% CI, 0.25–0.83; P<.01)
DREAM 10	5269 patients with IFG (FPG, 110–124 mg/dL) and/or IGT (2‐hour post‐challenge glucose, 140–199 mg/dL) but without CVD or renal disease	Rosiglitazone (8 mg/d) or placebo for 3.0 years (median)	Yes	62% reduction in risk of NOD with rosiglitazone vs placebo (RR, 0.38; 95% CI, 0.33–0.44; P<.0001); Reversion to normoglycemia in 50.5% of rosiglitazone group vs 30.3% of placebo group (RR, 1.71; 95% CI, 1.57–1.87; P<.001)
Lipid‐lowering drugs
WOSCOPS 11	5974 nondiabetic men aged 45–64 years with dyslipidemia, normal renal function, and no history of MI, UA, or coronary revascularization	Pravastatin (40 mg/d) or placebo for 4.9 years	No	30% reduction in risk of NOD with pravastatin vs placebo (RR, 0.70; 95% CI, 0.50–0.99; P=.042)
Heart Protection Study 12	14,573 patients with occlusive arterial disease without MI, stroke, or hospitalization for angina within 6 months, or substantially impaired renal function	Simvastatin (40 mg/d) or placebo for 5.0 years	Yes	15% increase in risk of NOD with simvastatin vs placebo (RR, 1.15; 95% CI, 0.99–1.34; P=NS)
LIPID 13	6997 patients with dyslipidemia and MI or hospitalization for UA within 3 to 36 months	Pravastatin (40 mg/d) or placebo for 6 years	No	11% reduction in risk of NOD with pravastatin vs placebo (RR, 0.89; 95% CI, 0.70–1.13; P=NS)
ASCOT‐LLA 14	19,342 hypertensive patients with ≥3 other CVD risk factors	Atorvastatin (10 mg/d) or placebo for 3.3 years (median)	Yes	15% increase in risk of NOD with atorvastatin vs placebo (RR, 1.15; 95% CI, 0.91–1.44; P=NS)

Abbreviations: ASCOT‐LLA, Anglo‐Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; DPP, Diabetes Prevention Program; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LIPID, Long‐Term Intervention With Pravastatin in Ischemic Disease; MI, myocardial infarction; NS, not significant; NOD, new‐onset diabetes; RR, relative risk; STOP‐NIDDM, Study to Prevent Non–Insulin‐Dependent Diabetes Mellitus; TRIPOD, Troglitazone in Prevention of Diabetes; UA, unstable angina; WOSCOPS, West of Scotland Coronary Prevention Study. ^aMean years of follow‐up unless indicated.

Lifestyle Interventions

Two different studies have convincingly demonstrated that lifestyle interventions that promote weight loss and increased physical activity can delay the onset of new diabetes in high‐risk persons. In the first, the Finnish Diabetes Prevention Study, in obese adults with IGT, individualized counseling aimed at reducing weight and increasing physical activity for 3.2 years was associated with a 58% reduction in risk of new‐onset diabetes. ⁶ Similar results were observed in the Diabetes Prevention Program (DPP), in which obese high‐risk patients were randomized to lifestyle intervention, pharmacologic therapy (metformin), or placebo. ⁷ Compared with placebo, both interventions reduced the incidence of new‐onset diabetes.

Both the Finnish Diabetes Prevention Study and the DPP demonstrated a reduction in cardiovascular risk factors. In the Finnish study, patients in the intervention group had significantly greater reductions in weight (P<.001), systolic (P=.007) and diastolic (P=.02) blood pressure, serum triglycerides (P=.001), and FPG levels (P<.001) at 1 year compared with the placebo group. ⁶ In the DPP, the incidence of metabolic syndrome was reduced by 41% in the lifestyle group (P<.001) and by 17% in the metformin group (P<.03) compared with placebo. ¹⁵

Antidiabetic Agents

A number of studies assessing the use of different classes of antidiabetic drugs to prevent diabetes have shown delay or prevention of diabetes. ⁸ , ⁹ , ¹⁰ The Study to Prevent Non–Insulin‐Dependent Diabetes Mellitus (STOP‐NIDDM) assessed the effect of the α‐glucosidase inhibitor acarbose or placebo in patients with IGT. At 3.3‐year follow‐up, acarbose reduced the incidence of new‐onset diabetes by 25%. ⁸ In a secondary analysis of STOP‐NIDDM, the incidence of CVD events was reduced with active treatment from 4.7% to 2.1% (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28–0.95; P=.03), mainly due to a reduction in myocardial infarction (MI) (HR, 0.09; 95% CI, 0.01–0.72; P=.02). ¹⁶ There was also a reduction in the incidence of new‐onset hypertension (blood pressure >140/90 mm Hg [HR, 0.66; 95% CI, 0.49–0.89; P=.006]).

Similarly, in the glycemic arm of the 3‐year Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) trial, rosiglitazone significantly reduced the incidence of the primary composite outcome of new‐onset diabetes or death. ¹⁰ When the components of the primary outcome were analyzed separately, rosiglitazone was associated with a significant reduction in the incidence of new‐onset diabetes, but not in all‐cause mortality or in CVD event rates.

Lipid‐Lowering Agents

Lipoprotein abnormalities are common in patients at high risk for diabetes. ¹⁷ As a result, the new ACE/AACE guidelines recommend that lipid goals in prediabetic patients be the same as those in patients with diabetes: low‐density lipoprotein cholesterol <100 mg/dL, non–high‐density lipoprotein cholesterol <130 mg/dL, and apolipoprotein B <90 mg/dL. ⁵ Post hoc analyses of placebo‐controlled clinical trials of lipid‐lowering agents, primarily statins, have reported conflicting results. In the West of Scotland Coronary Prevention Study (WOSCOPS), pravastatin reduced the incidence of new‐onset diabetes by 30%. ¹¹ By contrast, in the Heart Protection Study, ¹² the Long‐Term Intervention With Pravastatin in Ischemic Disease (LIPID), ¹³ and the Anglo‐Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT‐LLA), ¹⁴ statin therapy did not prevent the development of diabetes.

Antihypertensive Agents

Approximately 70% of patients with type 2 diabetes also have blood pressure values >140/90 mm Hg. ¹⁸ Type 2 diabetes is 2.5 to 5 times more likely to develop in patients with elevated blood pressure than in their normotensive counterparts. ¹⁹ , ²⁰ A number of studies, including the Systolic Hypertension in Europe ²¹ and the Hypertension Optimal Treatment ²² trials, have clearly demonstrated that reductions in blood pressure significantly reduce the risk of major CVD events in diabetic patients. Current hypertension treatment guidelines suggest that blood pressure should be controlled to ≤130/80 mm Hg in both diabetic and prediabetic patients. ⁵ , ²³ , ²⁴ Data from the United Kingdom Prospective Diabetes Study (UKPDS) indicate that lowering systolic blood pressure to as low as 110 mm Hg may also provide benefit. ²⁵ In general, antihypertensive agents that inhibit the RAS—angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are recommended as first‐line agents. ⁵

The discussion of diabetes in the context of antihypertensive therapy has historically focused on the increased risk of new‐onset diabetes associated with the use of diuretics and β‐blockers; by contrast, alpha‐1 adrenoreceptor antagonists have been shown to improve insulin sensitivity. Newer clinical trials in patients with and without hypertension have demonstrated that calcium channel blockers have neutral metabolic effects, while ACE inhibitors and ARBs improve insulin sensitivity and reduce the risk of new‐onset diabetes. ²⁶

Proposed Mechanisms for RAS Inhibitors and New‐Onset Diabetes.  The underlying mechanisms by which RAS inhibition reduces the development of diabetes are not clear. ACE inhibitors and ARBs have beneficial effects on insulin sensitivity that are likely attributable to a combination of factors. One possibility is that the vasodilatory effects of RAS inhibitors result in increased blood flow, thereby increasing insulin delivery to peripheral skeletal muscles. ²⁷ , ²⁸ Likewise, ACE inhibitors and ARBs may improve glucose metabolism via increased GLUT4‐mediated transportation in skeletal muscle and fat cells. ²⁹ RAS blockade is associated with potassium retention, which may lead to enhanced pancreatic secretion of insulin ²⁸ and may protect pancreatic islets from glucotoxicity and oxidative stress by inhibiting NAD(P)H oxidase. ³⁰ In addition, some ARBs activate peroxisome proliferator‐activated receptor‐γ, which is the same target as insulin‐sensitizing drugs such as glitazone. ²⁸ Moreover, ARBs increase levels of adiponectin, an adipocyte‐derived protein thought to enhance insulin sensitivity. ³⁰

Clinical Trial Evidence.  A recent meta‐analysis of the results of 13 randomized clinical trials with a total of 93,451 patients with or without hypertension demonstrated that RAS blockade with an ACE inhibitor or ARB was associated with a 26% reduction in risk of new‐onset diabetes (odds ratio [OR], 0.74; 95% CI, 0.66–0.81; P<.001). ³¹ A separate network meta‐analysis of the results of 22 trials involving 143,153 patients with or without hypertension found that among the various classes of antihypertensive agents, ARBs and ACE inhibitors are associated with the lowest proportion of diabetes development during clinical trial follow‐up (OR, 0.57; 95% CI, 0.46–0.72; P<.0001 for ARBs and OR, 0.67; 95% CI, 0.56–0.80; P<.0001 for ACE inhibitors), compared with initial diuretic therapy. ³² While useful, these meta‐analyses are based on post hoc analyses of trials for which development of diabetes was not a primary end point. However, among recently completed clinical trials of RAS inhibitors and diabetes, a number included new‐onset diabetes as a prespecified primary composite or secondary outcome measure (Table II). ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³

Table II.

 Randomized Double‐Blind Clinical Trials Assessing the Effects of Inhibition of the Renin‐Angiotensin System on Risk of NOD

Study	Patient Population	Intervention a	Prespecified End Point?	Results
ACE inhibitors
HOPE 33	9297 patients with history of CAD, stroke, PVD, or diabetes and ≥1 other CVD risk factor	Ramipril (up to 10 mg/d) or placebo for 5.0 years	Yes	34% reduction in risk of NOD with ramipril vs placebo (RR, 0.66; 95% CI, 0.51–0.85; P<.001)
ALLHAT 34	33,357 hypertensive patients with ≥1 other CVD risk factor and no history of hospitalization or treatment for symptomatic HF or LVEF <35%	Chlorthalidone (12.5–25 mg/d), amlodipine (2.5–10 mg/d), or lisinopril (10–40 mg/d) for 4.9 years	No	Incidence of NOD at 4 years was 11.6% in the chlorthalidone group, 9.8% in the amlodipine group (P=0.4 vs chlorthalidone), and 8.1% in the lisinopril group (P<.001 vs chlorthalidone)
PEACE 35	8290 with stable CAD and normal or slightly reduced left ventricular function	Trandolapril (2–4 mg/d) or placebo for 4.8 years (median)	No	17% reduction in risk of NOD with trandolapril vs placebo (RR, 0.83; 95% CI, 0.72–0.96; P=.001)
ASCOT‐BPLA 36	19,257 hypertensive patients with ≥3 other CVD risk factors and no history of MI, currently treated angina, cerebrovascular event within 3 months, or uncontrolled arrhythmias	Amlodipine (5–10 mg/d) (± perindopril [4–8 mg/d]) or atenolol (50–100 mg/d) (± bendroflumethiazide [1.25–2.5 mg/d]) for 5.5 years (median)	Yes	30% reduction in risk of NOD with amlodipine (± perindopril) vs atenolol (± diuretic) (RR, 0.70; 95% CI, 0.63–0.78; P<.0001)
DREAM 37	5269 patients with IFG and/or IGT but without CVD or renal disease	Ramipril (up to 15 mg/d) or placebo for 3.0 years (median)	Yes	NOD developed in 17.1% of patients in the ramipril group and 18.5% in the placebo group (RR, 0.91; 95% CI, 0.80–1.03; P=NS); reversion to normoglycemia in 42.5% of ramipril group vs 32.2% of placebo group (RR, 1.16; 95% CI, 1.07–1.27; P=.001)
ARBs
LIFE 38	9193 hypertensive patients with LVH without MI or stroke within 6 months, HF or LVEF ≤40%	Losartan (50–100 mg/d) (± HCTZ [12.5–25 mg/d]) or atenolol (50–100 mg/d) (± HCTZ [12.5–25 mg/d]) for 4.8 years	Yes	25% reduction in risk of NOD with losartan vs atenolol (RR, 0.75; 95% CI, 0.63–0.86; P=.001)
SCOPE 39	4964 hypertensive patients aged 70–89 years without MI or stroke within 6 months or decompensated HF	Candesartan (8–16 mg/d) or placebo/other drugs for 3.7 years	No	19% reduction in risk of NOD with candesartan vs placebo (RR, 0.81; 95% CI, 0.61–1.02; P=.09)
CHARM 40	7599 patients with HF (LVEF ≤40%)	Candesartan (4–32 mg/d) or placebo for 3.1 years	Yes	22% reduction in risk of NOD with candesartan vs placebo (RR, 0.78; 95% CI, 0.64–0.96; P=.02)
VALUE 41	15,245 hypertensive patients with high risk of CVD events without history of MI or severe renal disease	Valsartan (80–160 mg/d) (± HCTZ [12.5–25 mg/d]) or amlodipine (5–10 mg/d) (± HCTZ [12.5–25 mg/d]) for 4.2 years	Yes	23% reduction in risk of NOD with valsartan vs amlodipine (RR, 0.77; 95% CI, 0.69–0.86; P<.0001)
TRANSCEND 41	5926 patients intolerant to ACE inhibitors with CAD, PVD, CBVD, or diabetes with end organ damage	Telmisartan (80 mg/d) or placebo for 4.7 years (median)	Yes	15% reduction in risk of NOD with telmisartan vs placebo (RR, 0.85; 95% CI, 0.71–1.02; P=.081)
ACE inhibitor/ARB combination
ONTARGET 43	25,620 patients with CAD, PVD, CBVD, or diabetes with end organ damage	Ramipril (10 mg/d), telmisartan (80 mg/d), or ramipril (10 mg/d) + telmisartan (80 mg/d) for 4.7 years (median)	Yes	12% increase in risk of NOD with telmisartan vs ramipril (RR, 1.12; 95% CI, 0.97–1.29; P=NS); 9% reduction in risk of NOD with ramipril + telmisartan vs ramipril (RR, 0.91; 95% CI, 0.78–1.06; P=NS)

Abbreviations: ACE, angiotensin‐converting enzyme; ALLHAT, Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial; ARB, angiotensin II receptor blocker; ASCOT‐BPLA, Anglo‐Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; CAD, coronary artery disease; CBVD, cerebrovascular disease; CHARM, Candesartan in Heart failure–Assessment of Reduction in Morbidity and Mortality; CI, confidence interval; CVD, cardiovascular disease; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; HCTZ, hydrochlorothiazide; HF, heart failure; HOPE, Heart Outcomes Prevention Evaluation; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LIFE, Losartan Intervention for End Point Reduction in Hypertension; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; MI, myocardial infarction; NOD, new‐onset diabetes; NS, not significant; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; PEACE, Prevention of Events With Angiotensin‐Converting Enzyme Inhibition; PVD, peripheral vascular disease; RR, relative risk; SCOPE, Study on Cognition and Prognosis in the Elderly; TRANSCEND, Telmisartan Randomized Assessment Study in ACE‐Intolerant Subjects With Cardiovascular Disease; VALUE, Valsartan Long‐term Use Evaluation. ^aMean years of follow‐up unless indicated.

ACE Inhibitors.  One of the first clinical studies to show a reduction in new‐onset diabetes with an ACE inhibitor was the Heart Outcomes Prevention Evaluation (HOPE) study, in which ramipril reduced the risk of new‐onset diabetes by 34% compared with placebo. ³³ In the original Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) report, lisinopril was associated with a significant reduction in new‐onset diabetes. ³⁴ Among individuals who were nondiabetic at baseline, the incidence of diabetes at 4 years was 11.6% in the chlorthalidone group, 9.8% in the amlodipine group, and 8.1% in the lisinopril group. ³⁴ A post hoc analysis in ALLHAT patients with the metabolic syndrome but not diabetes at baseline found that the incidence of new‐onset diabetes was 17.1% in the chlorthalidone group, 16.0% in the amlodipine group, and 12.6% in the lisinopril group (P<.05 for lisinopril vs chlorthalidone). By contrast, the incidence of new‐onset diabetes was less in the group without the metabolic syndrome: 7.7%, 4.2%, and 4.7% for chlorthalidone, amlodipine, and lisinopril, respectively (P<.05 for both comparisons). Moreover, the risk of combined CVD events was similar in those with and without the metabolic syndrome and in those in whom diabetes developed and those in whom it did not. ⁴⁴ A separate subgroup analysis of ALLHAT compared outcomes by race in nondiabetic patients with and without the metabolic syndrome and found that, despite their more favorable metabolic effects (including lower fasting glucose levels), the ACE inhibitor and calcium channel blocker failed to show benefit in long‐term cardiovascular risk reduction in hypertensive patients with the metabolic syndrome compared with the diuretic. ⁴⁵ The lack of cardiovascular benefit with these agents was especially striking in black patients with the metabolic syndrome.

In a new subgroup analysis of the Anglo‐Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT‐BPLA), the authors conclude that randomization of nondiabetic hypertensive patients to amlodipine with or without perindopril reduced the risk of new‐onset diabetes by 34% compared with atenolol with or without bendroflumethiazide. ⁴⁶ The authors postulated that the differential effects of the two antihypertensive regimens may be the result of the metabolically protective effects of perindopril combined with the neutral effects of amlodipine compared with the adverse metabolic effects of both atenolol and thiazide diuretics.

In the hypertension arm of the DREAM trial, patients at high risk for diabetes were randomized to ramipril or placebo for 3 years. There was no significant difference in incidence of the primary composite outcome measure of new‐onset diabetes or death in patients treated with ramipril vs placebo. ³⁷ Likewise, ramipril did not significantly reduce the incidence of new‐onset diabetes or CVD events. Ramipril‐based therapy was, however, associated with a significant increase in regression to normoglycemia compared with placebo, confirming the blood glucose–lowering effect of the ACE inhibitor. Proposed explanations for the failure of the ACE inhibitor to delay the onset of diabetes in DREAM include the short duration of the study (median 3 years vs median ∼4.5 years in previous ARB and ACE inhibitor trials) and the relatively low‐risk profile of the study participants (mean age, 55 years; mean blood pressure, 136/83 mm Hg) such that the degree of RAS activation in DREAM participants was lower than in other studies. In addition, baseline glucose levels were far from the diagnostic threshold for diabetes, making diabetes less likely to develop. ³⁷

The ongoing ACE Inhibitor‐Based vs Diuretic‐Based Antihypertensive Primary Treatment in Patients with Prediabetes (ADaPT) trial may help to clarify the impact of ACE inhibitors on new‐onset diabetes. ⁴⁷ ADaPT is a 4‐year open‐label trial to determine the effect on incidence of new‐onset diabetes of antihypertensive treatment based on ramipril vs treatment based on diuretics or β‐blockers. The results of the trial, which includes 2015 patients with hypertension, IFG, and hemoglobin A_1c values of 6% to 6.5%, are expected in 2010. ⁴⁷

ARBs.  Early evidence that ARBs reduce the risk of new‐onset diabetes was provided by the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, in which losartan was associated with a 25% reduction in new‐onset diabetes compared with atenolol in hypertensive patients with left ventricular hypertrophy. ³⁸ ARB‐based therapy was associated with a similar reduction in new‐onset diabetes (23%) in the Valsartan Long‐Term Use Evaluation (VALUE), in which high‐risk hypertensive patients were randomized to valsartan‐ or amlodipine‐based therapy. ⁴¹ After a mean follow‐up of 4.2 years, the incidence of new‐onset diabetes was 23% lower in the valsartan group. A post hoc analysis of VALUE revealed that patients with new‐onset diabetes during the 4.2‐year follow‐up period experienced significantly higher cardiac morbidity than those in whom diabetes did not develop; baseline diabetes was associated with doubling of risk of cardiac morbidity (HR, 2.20; 95% CI, 1.95–2.49; P<.0001), and new‐onset diabetes during the study was associated with significantly higher cardiac morbidity compared with diabetes not developing (HR, 1.42; 95% CI, 1.16–1.77; P=.0008). ⁴⁸ The post hoc analysis also revealed that the incidences of all‐cause mortality (HR, 0.61; 95% CI, 0.49–0.77; P=.0001) and cardiac mortality (HR, 0.44; 95% CI, 0.28–0.70; P=.0004) were actually lower in patients in whom diabetes developed compared with those who remained normoglycemic during the trial, possibly due to increased use of aspirin, β‐blockers, diuretics, and statins in these patients. ⁴⁸ , ⁴⁹

ACE Inhibitor/ARB Combination.  New‐onset diabetes was a predefined secondary outcome in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), in which patients with vascular disease or high‐risk diabetes received telmisartan, ramipril, or a combination of the 2 drugs. ⁴³ Despite greater blood pressure lowering with combination therapy compared with either drug alone, rates of the primary composite outcome (CVD death, MI, stroke, or hospitalization for heart failure) and of new‐onset diabetes were similar in the 3 treatment groups. Higher rates of adverse events with combination therapy, in addition to the lack of additional clinical benefit, suggest that full‐dose combination therapy with an ACE inhibitor and an ARB may not be advisable.

Ongoing Study

Many of the unanswered questions related to new‐onset diabetes and CVD risk are expected to be resolved in an ongoing clinical trial: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR). ⁵⁰ NAVIGATOR is a large‐scale, multinational, randomized, double‐blind, placebo‐controlled, 2×2 factorial study to determine whether treatment with the meglitinide drug nateglinide or valsartan will reduce progression to diabetes and new cardiovascular events in patients with IGT. A total of 9306 participants aged 50 years or older with IGT and known CVD or 55 years or older with IGT and ≥1 cardiovascular risk factor were randomized in a 1:1:1:1 ratio to treatment with nateglinide or matching placebo and to valsartan or matching placebo. The primary outcome measures are onset of diabetes and both a “hard” composite of major CVD events (death, MI, stroke, or hospitalization for heart failure) and an “expanded” composite including the components of the “hard” composite plus coronary revascularizations and hospitalizations for unstable angina pectoris. The results of NAVIGATOR, which are anticipated this year, may provide clarification regarding whether reducing postprandial hyperglycemia and preventing diabetes can reduce cardiovascular complications (nateglinide treatment arm) and whether the link between metabolic dysfunction and CVD is mediated by angiotensin II and might be lessened by treatment with an agent that inhibits the RAS (valsartan treatment arm). ⁵⁰

Conclusions

Reducing the incidence of diabetes may lead to a reduction in CVD‐related morbidity and mortality. Both lifestyle changes and antidiabetic pharmacologic interventions delay the onset of diabetes. Similarly, antihypertensive therapy with RAS blockade delays the onset of new diabetes. However, the potential association between new‐onset diabetes and CVD outcomes has been identified only in post hoc analysis and not as a predetermined endpoint. The findings from NAVIGATOR are eagerly awaited to identify this association. Meanwhile, it is advisable to treat high‐risk patients—those with prediabetes—with appropriate lifestyle measures to reduce weight and increase physical activity. The use of antidiabetic agents, RAS inhibitors, and statins to reduce cardiovascular risk factors, including hyperglycemia, hypertension, and dyslipidemia, should also be considered.