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Newer targets and therapies for hypertension and dyslipidemia in diabetic patients

Aronow, Wilbert S.

Cardiovascular Endocrinology & Metabolism: March 2015 - Volume 4 - Issue 1 - p 11–16
doi: 10.1097/XCE.0000000000000043
Review articles
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Statins are the only lipid-lowering drugs that have been shown to reduce the incidence of cardiovascular events and mortality in patients with diabetes mellitus. This review article will discuss the studies demonstrating the efficacy of statins in reducing cardiovascular events and mortality in adults with diabetes mellitus and the current guidelines supporting this use of statins. Current guidelines support lowering of the systolic blood pressure in diabetic patients with hypertension to less than 140 mmHg. This article will discuss the studies supporting this optimal systolic blood pressure goal. The selection of antihypertensive drug therapy in patients with diabetes mellitus depends on associated medical conditions. The American Diabetes Society 2013 guidelines recommend that the drug regimen should include an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker unless the patient is pregnant.

Department of Medicine, Cardiology Division, New York Medical College, Valhalla, New York, USA

Correspondence to Wilbert S. Aronow, MD, FACC, FAHA, Department of Medicine, Cardiology Division, New York Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595, USA Tel: +1 914 493 5311; fax: +1 914 235 6274; e-mail: wsaronow@aol.com

Received October 8, 2014

Accepted November 3, 2014

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Introduction

Diabetes mellitus, hypertension, and dyslipidemia are independent risk factors for the development of coronary artery disease (CAD) 1–5, ischemic stroke 2–4,6,7, peripheral arterial disease (PAD) 3,4,8,9, and of congestive heart failure 2,4,10,11. Diabetic patients with hypertension or dyslipidemia have a higher prevalence and incidence of CAD, ischemic stroke, PAD, and of congestive heart failure than diabetic patients without hypertension. Diabetic patients are more often obese and have higher serum triglycerides levels and lower serum high-density lipoprotein (HDL) cholesterol levels than do nondiabetics. The most common serum low-density lipoprotein (LDL) cholesterol level in diabetic patients is 130–159 mg/dl (3.36–4.11 mmol/l) 12. These risk factors contribute to the higher incidence of cardiovascular morbidity and mortality in diabetic patients than in nondiabetics. Hypertension and dyslipidemia must be treated in diabetic patients with or without cardiovascular disease. Most of the clinical trials were carried out in patients with type 2 diabetes mellitus. Type 1 diabetic patients with hypertension and dyslipidemia should be treated similarly to type 2 diabetic patients 13. This review article will discuss the newer targets and therapies of dyslipidemia and of hypertension in diabetic patients with and without cardiovascular disease.

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Dyslipidemia

Clinical trials

At 5.4-year median follow-up of 202 type 2 diabetic patients with CAD and hypercholesterolemia in the Scandinavian Simvastatin Survival Study (4S), compared with placebo, simvastatin reduced all-cause mortality (43%) (P=0.087), major CAD events (55%) (P=0.002), and any atherosclerotic event (37%) (P=0.018) 14. This was a substudy 14. At 5-year follow-up of 586 diabetic patients with CAD and a mean serum total cholesterol of 209 mg/dl (5.4 mmol/l) in the Cholesterol and Recurrent Events (CARE) trial, compared with placebo, pravastatin decreased fatal coronary event or nonfatal myocardial infarction by 25% (37–29%) (P=0.05) 15. At 6.1-year follow-up of 782 diabetic patients with CAD and serum total cholesterol levels between 155 and 271 mg/dl (4.1–7.0 mmol/l) in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, compared with placebo, pravastatin insignificantly reduced all-cause mortality by 19% (23–19%) 16.

The Heart Protection Study (HPS) randomized 20 536 men and women (5806 of whom were aged between 70 and 80 years) with prior myocardial infarction (8510 individuals), other CAD (4876 individuals), and no CAD (7150 individuals) and a serum total cholesterol level of 135 mg/dl (3.5 mmol/l) or higher to simvastatin 40 mg daily or to double-blind placebo 17. At 5-year follow-up of the 5963 diabetic patients in this study, compared with placebo, simvastatin significantly decreased first major vascular events from 25.1 to 20.2% (P<0.0001) 17. The significant reduction in major vascular events occurred regardless of initial levels of serum lipids, age, or sex 17.

In the Collaborative Atorvastatin Diabetes Study (CARDS), 2838 patients (62% older than 60 years) with diabetes mellitus, no cardiovascular disease, and a serum LDL cholesterol less than 160 mg/dl (4.2 mmol/l) were randomized to atorvastatin 10 mg daily or to double-blind placebo 18. At 3.9-year median follow-up, compared with placebo, atorvastatin significantly reduced time to first recurrence of acute coronary events, coronary revascularization, or stroke by 37% (P=0.001), acute coronary events by 36% (9–55%), stroke by 48% (11–69%), and all-cause mortality by 27% (P=0.059) 18.

In an observational prospective study of 529 patients, mean age 79 years, with prior myocardial infarction, diabetes mellitus, and a serum LDL cholesterol of 125 mg/dl (3.2 mmol/l) or higher, 53% of patients were treated with statins 19. At 29-month follow-up, compared with no treatment with statins, use of statins reduced coronary heart death or nonfatal myocardial infarction by 37% (P<0.0001) and stroke by 47% (P<0.0001) 19. In this study, 83% of diabetic patients treated with statins had hypertension. The lower the serum LDL cholesterol by treatment with statins, the greater was the reduction in coronary events 20 and in stroke 21.

A meta-analysis was performed in 14 randomized trials of statins in 18 686 diabetic patients, mean age 63 years (1466 with type 1 diabetes and 17 220 with type 2 diabetes) 22. The mean follow-up was 4.3 years. Compared with placebo, statins decreased all-cause mortality by 9% per mmol/l reduction in serum LDL cholesterol (P=0.02), decreased cardiovascular mortality by 13% per mmol/l reduction in serum LDL cholesterol (P=0.008), and decreased major cardiovascular events by 21% per mmol/l decrease in serum LDL cholesterol (P<0.0001) 22. After 5 years, 42 [95% confidence interval (CI) 30–55] fewer diabetic patients had major cardiovascular events per 1000 treated with statins 22.

Randomized placebo-controlled trials have not demonstrated a significant reduction in cardiovascular events and mortality in diabetic patients treated by other lipid-lowering drugs. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether combination therapy with a statin plus a fibrate compared with statin monotherapy would decrease cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events 23. In this study, 5518 type 2 diabetic patients treated with simvastatin were randomized to receive either fenofibrate or placebo. At 4.7-year follow-up, compared with simvastatin plus placebo, simvastatin plus fenofibrate did not decrease the primary outcome of first occurrence of nonfatal myocardial infarction, nonfatal stroke, nor death from cardiovascular causes or any secondary outcome 23. A subgroup analysis suggested a possible benefit for patients with both a high baseline triglyceride level and a low baseline level HDL cholesterol (P=0.057 for interaction) 23.

In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9795 diabetic patients were randomized to fenofibrate or placebo 24. At 5-year median follow-up, there was no significant difference in the primary endpoint of CAD death or nonfatal myocardial infarction in patients treated with fenofibrate or placebo 24. On the basis of a Food and Drug Administration review and committee deliberation, the benefit of adding a fibrate to statin therapy in reducing cardiovascular events in diabetic patients is unproven 25.

Niacin has been used in clinical practice to reduce cardiovascular events in diabetic patients. The AIM-HIGH (Niacin Plus Statins to Prevent Vascular Events) trial randomized 3414 patients (34% with diabetes mellitus) with stable CAD and a low serum HDL cholesterol (median level of 35 mg/dl) (0.91 mmol/l) treated with simvastatin or simvastatin plus ezetimibe to 1500–2000 mg of extended-release niacin or placebo 26. Niacin increased serum HDL cholesterol by 25%, decreased serum LDL cholesterol by 12%, and decreased serum triglycerides by 29%. The trial was stopped by the National Heart, Lung, and Blood Institute Data and Safety Monitoring Board at 3 years because the primary endpoint of myocardial infarction, ischemic stroke, death because of CAD, hospitalization for an acute coronary syndrome, or symptom-driven revascularization was 16.4% in patients treated with niacin versus 16.2% in patients treated with placebo, and because niacin increased ischemic stroke by 61% (P=0.11) 26.

In the Heart Protection Study-2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study, 25 673 high-risk patients (32% with diabetes mellitus) were randomized to treatment with simvastatin or simvastatin/ezetimibe plus extended-release niacin plus the antiflushing agent laropiprant or to treatment with simvastatin or simvastatin/ezetimibe 27. At 3.9-year follow-up, compared with treatment with simvastatin or simvastatin/ezetimibe, addition of niacin did not reduce the primary outcome of major vascular events but increased 31 serious adverse events per 1000 niacin-treated patients. Excess diabetic complications were increased by 3.7% (P<0.0001). Excess new diabetes was increased by 1.3% (P<0.0001). Excess infection was increased by 1.4% (P<0.0001). Excess gastrointestinal complications were increased by 1% (P<0.0001). Excess bleeding (gastrointestinal and intracranial) was increased by 0.7% (P<0.0001) 27.

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Lifestyle measures

Lifestyle measures are important in the treatment of dyslipidemia in diabetic patients 28. The person should achieve and maintain a desirable weight. The diet should be low in cholesterol (<200 mg daily). Less than 30% of total caloric intake should be fatty acids. Saturated fatty acids should comprise less than 7% of total calories, polyunsaturated acids up to 10% of total calories, and monounsaturated fatty acids 10–15% of total calories. The diet should also be high in fiber and high in fruits and vegetables. There is no strong evidence to support any dietary supplements. A more liberalized diet is warranted in elderly persons prone to malnutrition. Moderate intensity exercise is recommended for 30–60 min daily. Smoking should be stopped, hypertension treated, and diabetes controlled. Secondary causes of dyslipidemia should be treated.

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Guideline recommendations for treatment of dyslipidemia in diabetic patients

The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines on treatment of hypercholesterolemia support the use of statins in treatment of diabetic patients 29. Diabetic patients with clinical atherosclerotic cardiovascular disease should be treated with high-dose statins. High-dose statins reduce serum LDL cholesterol by at least 50% and include atorvastatin 40–80 mg daily and rosuvastatin 20–40 mg daily. Diabetic patients with a serum LDL cholesterol of at least 190 mg/dl (4.9 mmol/l) should also be treated with high-dose statins. The ACC/AHA guidelines recommend for primary prevention in diabetic patients with a serum LDL cholesterol between 70 and 189 mg/dl (1.8–4.9 mmol/l) moderate-dose statins. If the 10-year risk of developing atherosclerotic cardiovascular disease (CAD, stroke, transient ischemic attack, or atherosclerotic PAD) by the Pooled Cohort Equations is at least 7.5%, high-dose statins should be given 29. There are no data supporting the routine use of nonstatin drugs combined with statin therapy to further reduce atherosclerotic cardiovascular events 26. Fenofibrate may be considered with use of a low-intensity or moderate-intensity statin for triglyceride lowering when the serum triglycerides are at least 500 mg/dl (13.0 mmol/l) 29. If ω-3 fatty acids are used to treat serum triglycerides of 500 mg/dl or more (13.0 mmol/l), the patient must be evaluated for gastrointestinal disturbances, skin changes, and bleeding 29.

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Hypertension

In the absence of randomized control data, the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended that patients with diabetes mellitus and hypertension should have their blood pressure lowered to less than 130/80 mmHg 30. In the absence of randomized control data, the American Diabetes Association recommended that patients with diabetes mellitus and hypertension should have their blood pressure reduced to less than 130/80 mmHg 31. In the absence of randomized control data, the AHA 2007 guidelines recommended that patients with hypertension at high risk for coronary events including those with diabetes mellitus should have their blood pressure reduced to less than 130/80 mmHg 32.

However, the 2009 European Society of Hypertension guidelines recommended that reducing the blood pressure to less than 130/80 mmHg in patients at high risk for cardiovascular events was unsupported by prospective trial data, and that the systolic blood pressure (SBP) should be lowered to less than 140 mmHg in these patients 33. The ACC/AHA 2011 expert consensus document on hypertension in the elderly recommended that the blood pressure should be reduced to less than 140/90 mmHg in adults younger than 80 years at high risk for cardiovascular events 34. On the basis of data from the Hypertension in the Very Elderly trial 35, these guidelines recommended that the SBP should be reduced to 140–145 mmHg, if tolerated, in adults aged 80 years and older. I concur with these guidelines 34.

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Studies of optimal blood pressure goal in diabetic patients

An observational subgroup analysis was performed in 6400 of the 22 576 patients in the International Verapamil SR-Trandolapril Study (INVEST) 36. These patients had diabetes mellitus and CAD. Patients were categorized as having tight control of their blood pressure if they could maintain their SBP below 130 mmHg and their diastolic blood pressure below 85 mmHg, usual control if they could maintain their SBP between 130 and 139 mmHg, and uncontrolled if their SBP was 140 mmHg or higher.

During 16 893 patient-years of follow-up, a cardiovascular event rate of 12.6% occurred in patients with usual control of blood pressure versus 19.8% in patients with uncontrolled hypertension (adjusted hazard ratio=1.46; 95% CI 1.25–1.71; P<0.001) 36. The incidence of cardiovascular events was 12.6% in patients with usual control of blood pressure versus 12.7% in patients with tight control of blood pressure (P not significant). The all-cause mortality rate was 11.0% with tight control of blood pressure versus 10.2% with usual control of blood pressure (P=0.06). When extended follow-up to 5 years following the close of INVEST was included, the all-cause mortality rate was 22.8% with tight control of blood pressure versus 21.8% with usual control of blood pressure (adjusted hazard ratio=1.15; 95% CI 1.01–1.32; P=0.04) 36.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial randomized 4733 patients with type 2 diabetes mellitus to intensive blood pressure control with a target SBP of less than 120 mmHg or to standard blood pressure control with a target SBP of less than 140 mmHg 37. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Mean follow-up was 4.7 years. After 1 year, the mean SBP was 119.3 mmHg in the intensive blood pressure control group versus 133.5 mmHg in the standard blood pressure control group. The annual rate of the primary outcome was 1.87% in the intensive blood pressure control group versus 2.09% in the standard blood pressure control group (P not significant) 37. The annual rate of death from any cause was 1.28% in the intensive blood pressure control group versus 1.19% in the standard blood pressure control group (P not significant). The annual rate of death from cardiovascular causes was 0.52% in the intensive blood pressure control group versus 0.49% in the standard blood pressure control group (P not significant). The annual stroke rate, a prespecified secondary outcome, was 0.32% in the intensive blood pressure control group versus 0.53% in the standard blood pressure control group (P=0.01) (number needed to treat to reduce one stroke in 1 year=476 patients). Serious adverse events attributed to antihypertensive treatment occurred in 3.3% of the intensive blood pressure control group versus 1.3% of the standard blood pressure control group (P<0.001) 37.

The number of major CAD events was also much higher than the number of strokes in both the intensive blood pressure control group (253 major CAD events vs. 36 strokes) and in the standard blood pressure control group (270 major CAD events vs. 62 strokes) 37. Therefore, intensive blood pressure control in diabetic patients is not justified by the evidence 37.

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) enrolled 9603 diabetic patients and 15 981 nondiabetics with hypertension at high risk for cardiovascular events 38,39. A progressive increase in the proportion of visits in which the blood pressure was decreased to less than 140/90 mmHg or to less than 130/80 mmHg was associated with a progressive decrease in stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in individuals with albuminuria 38. However, the adjusted risk of cardiovascular events was decreased by increasing the frequency of blood pressure control to less than 140/90 mmHg but not to less than 130/80 mmHg 38.

The primary outcome in ONTARGET was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Mean follow-up was 4.6 years. Compared with nondiabetics, diabetic patients had a 48% significant increase (95% CI 1.38–1.57) in the primary endpoint, a 56% significant increase (95% CI 1.42–1.71) in cardiovascular death, a 30% significant increase (95% CI 1.17–1.46) in myocardial infarction, a 39% significant increase (95% CI 1.23–1.56) in stroke, and a 206% significant increase (95% CI 1.82–2.32) in hospitalization for congestive heart failure 39.

In both diabetic patients and nondiabetics, antihypertensive drug treatment reduced the primary outcome if the baseline SBP was between 143 and 155 mmHg 39. Except for stroke, there was no benefit in reducing fatal or nonfatal cardiovascular outcomes by lowering the SBP below 130 mmHg in diabetic patients and in nondiabetics. The lowest incidence of death from cardiovascular causes in diabetic patients occurred with a SBP of 135.6 mmHg (range 130.6–140.5 mmHg). The lowest incidence of death from cardiovascular causes in nondiabetics occurred with a SBP of 133.1 mmHg (range 128.8–137.4 mmHg) 39.

The mean SBP was 144 mmHg in the intensively treated diabetic patients in the United Kingdom Prospective Diabetes Study 40, 143.7, 141.4, and 139.7 mmHg in the three diastolic blood pressure target subgroups in the post-hoc subgroup analysis of the Hypertension Optimal Treatment trial 41, and 135 mmHg in the intensively treated diabetic patients in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE study) 42. Therefore, these three studies cannot be used to compare the incidence of cardiovascular events in diabetic patients with hypertension treated to lower the blood pressure to less than 140/90 mmHg versus less than 130/80 mmHg.

On the basis of these clinical trial data, the ACC/AHA 2011 expert consensus document on hypertension in the elderly 34, the European Society of Hypertension/European Society of Cardiology 2013 guidelines 43, the American Diabetes Society 2013 guidelines 28, and the 2014 guidelines report from the Eighth Joint National Committee (JNC 8) 44 recommend that the blood pressure in diabetic patients should be reduced to less than 140/90 mmHg. I concur with this recommendation. The American Diabetes Association 2013 guidelines also state that an SBP of less than 130 mmHg may be considered in younger patients with long life expectancy if achieved with few drugs and without side effects 28.

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Antihypertensive drug treatment in diabetic patients

The selection of antihypertensive drug therapy in patients with diabetes mellitus depends on associated medical conditions 34. Diabetic patients with hypertension may be treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, or diuretics 34,43,45. The American Diabetes Society 2013 guidelines recommend that the drug regimen should include an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker unless the patient is pregnant 28. JNC 8 guidelines recommend that initial treatment of hypertension in nonblack diabetic patients should include a thiazide-type diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker 44. These guidelines recommend that initial treatment of hypertension in black diabetic patients should include a thiazide-type diuretic or calcium channel blocker 44.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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References

1. Aronow WS, Ahn C. Risk factors for new coronary events in a large cohort of very elderly patients with and without coronary artery disease. Am J Cardiol 1996; 77:864–866.
2. Aronow WS, Ahn C, Kronzon I, Koenigsberg M. Congestive heart failure, coronary events and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. Am J Cardiol 1991; 67:295–299.
3. Stokes J III, Kannel WB, Wolf PA, Cupples LA, D’Agostino RB. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation 1987; 75 Pt 2 V65–V73.
4. Corriere MD, Kalyani RR, Durso SC Aronow WS, Fleg JL, Rich MW. Diabetes mellitus and cardiovascular disease in the elderly. Tresch and Aronow’s cardiovascular disease in the elderly 5th ed.. Boca Raton, London, New York: CRC Press; 2013:143–170.
5. Wong ND, Tehrani DM, Franklin SS Aronow WS, Fleg JL, Rich MW. Epidemiology of coronary heart disease in the elderly. Tresch and Aronow’s cardiovascular disease in the elderly 5th ed.. Boca Raton, London, New York: CRC Press; 2013:171–190.
6. Aronow WS, Ahn C, Gutstein H. Risk factors for new atherothrombotic brain infarction in 664 older men and 1,488 older women. Am J Cardiol 1996; 77:1381–1383.
7. Barrett-Connor E, Khaw KT. Diabetes mellitus: an independent risk factor for stroke? Am J Epidemiol 1988; 128:116–123.
8. Ness J, Aronow WS, Ahn C. Risk factors for symptomatic peripheral arterial disease in older persons in an academic hospital-based geriatrics practice. J Am Geriatr Soc 2000; 48:312–314.
9. Ness J, Aronow WS, Newkirk E, McDanel D. Prevalence of asymptomatic peripheral arterial disease, modifiable risk factors, and appropriate use of drugs in the treatment of peripheral arterial disease in older persons seen in a university general medicine clinic. J Gerontol: Med Sci 2005; 60A:255–257.
10. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34:29–34.
11. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 1999; 115:867–868.
12. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143–3421.
13. De Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, et al.. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care 2014; 37:2843–2863.
14. Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20:614–620.
15. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al.. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335:1001–1009.
16. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349–1357.
17. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22.
18. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364:685–696.
19. Aronow WS, Ahn C, Gutstein H. Reduction of new coronary events and new atherothrombotic brain infarction in older persons with diabetes mellitus, prior myocardial infarction, and serum low-density lipoprotein cholesterol >/=125 mg/dl treated with statins. J Gerontol A Biol Sci Med Sci 2002; 57:M747–M750.
20. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol > or = 125 mg/dl treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 89:67–69.
21. Aronow WS, Ahn C, Gutstein H. Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol > or = 125 mg/dl treated with statins versus no lipid-lowering drug. J Gerontol A Biol Sci Med Sci 2002; 57:M333–M335.
22. Cholesterol Treatment Trialists’ (CTT) Collaborators Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al.. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371:117–125.
23. ACCORD Study Group Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P, et al.. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–1574.
24. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1849–1861.
25. Goldfine AB, Kaul S, Hiatt WR. Fibrates in the treatment of dyslipidemias – time for a reassessment. N Engl J Med 2011; 365:481–484.
26. AIM-HIGH Investigators Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al.. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–2267.
27. HPS2-THRIVE Collaborative Group Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, et al.. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203–212.
28. American Diabetes Association. Standards of medical care in diabetes – 2013. Diabetes Care 2013; Suppl 1:S11–S66.
29. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:2889–2934.
30. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572.
31. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2003; Suppl 1:S33–S50.
32. Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, et al. American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007; 115:2761–2788.
33. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al.. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press 2009; 18:308–347.
34. Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al.. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol 2011; 57:2037–2114.
35. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358:1887–1898.
36. Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 2010; 304:61–68.
37. ACCORD Study Group Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al.. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362:1575–1585.
38. Mancia G, Schumacher H, Redon J, Verdecchia P, Schmieder R, Jennings G, et al.. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET). Circulation 2011; 124:1727–1736.
39. Redon J, Mancia G, Sleight P, Schumacher H, Gao P, Pogue J, et al. ONTARGET Investigators. Safety and efficacy of low blood pressures among patients with diabetes: subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). J Am Coll Cardiol 2012; 59:74–83.
40. [No authors listed]. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317:703–713.
41. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al.. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755–1762.
42. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al.ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370:829–840.
43. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al.. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159–2219.
44. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al.. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507–520.
45. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338:b1665.
Keywords:

antihypertensive drugs; diabetes mellitus; dyslipidemia; hypertension; statins

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