- Email: [email protected]
Blood Pressure and Glucose Control in Patients With Diabetes
AJH
2007; 20:3S– 8S
ORIGINAL CONTRIBUTIONS
Blood Pressure and Glucose Control in Patients With Diabetes Giuseppe Mancia Type 2 diabetes mellitus and hypertension are comorbid clinical conditions that synergize to create a vascular environment that significantly increases the risk of macrovascular disease (eg, myocardial infarction, stroke, and cardiovascular mortality) and microvascular disease (eg, nephropathy and retinopathy). Given the prevalence of this comorbid association, the large majority of patients with newly diagnosed Type 2 diabetes are hypertensive. The co-management of diabetes, through glucose control (targeting a hemoglobin A1c ⬍7.0% in current clinical practice guidelines), and of hypertension, through bloodpressure (BP) control (systolic BP/diastolic BP ⬍130/80 mm Hg), has become central to the treatment of macrovascular and microvascular disease in diabetic patients. These BP goals, however, are rarely attained in these patients, and a treatment that combines ⱖ2 drugs is needed in most individuals. With the aim of attaining a synergistic benefit from the simultaneous lowering of hemoglobin A1c and BP, treatment strategies that combine multiple hyper-
tensive agents and glucose-controlling agents are being investigated. Treatments that include an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker may be of particular value, because these drug classes inhibit the renin-angiotensin system, which mediates the increase in renovascular resistance and intraglomerular pressure observed in diabetic kidneys. Inhibition of the renin-angiotensin system, which protects the kidney through a variety of mechanisms, may also provide renal and cardiovascular benefits that extend beyond those attributable to BP control. Thus, the effective co-management of diabetes and hypertension through combined glucose and BP control remains an unmet medical need for which strategies still need to be developed. Am J Hypertens 2007;20:3S– 8S © 2007 American Journal of Hypertension, Ltd.
ype 2 diabetes mellitus and hypertension are comorbid clinical conditions that synergize to create a vascular environment that significantly increases the risk of macrovascular disease (eg, myocardial infarction, stroke, and cardiovascular mortality), and microvascular disease (eg, nephropathy and retinopathy).1 The prevalence of this comorbid association was assessed in epidemiologic studies which estimated that a large number of patients with newly diagnosed Type 2 diabetes are hypertensive.2 In light of the fact that the prevalence and severity of diabetes and hypertension increase with age, the co-management of diabetes, through glucose control, and of hypertension, through bloodpressure (BP) control, has become central to the treatment of macrovascular and microvascular disease and the reduction in cardiovascular risk in diabetic patients.
A close association exists between blood glucose levels, macrovascular disease, and cardiovascular risk, including
coronary heart disease and stroke.3–7 Current clinical practice guidelines recommend tight blood glucose control, and a target hemoglobin A1c (HbA1c) of ⱕ7.0%.8 For example, in the Asia Pacific Cohort Studies Collaboration, a 1.0-mmol/L difference in fasting blood glucose was associated with a 21% difference in stroke risk and a 23% decrease in ischemic heart disease risk.3 Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS 35), an average HbA1c change of 1.0% over 10 years resulted in a risk modification of 21% for diabetes-related mortality and 14% for myocardial infarction (Fig. 1).5 With regard to intervention trials, tight blood glucose control proved beneficial in reducing microvascular complications such as retinopathy and nephropathy.9 For example, the UKPDS 339 showed that lowering HbA1c by an average of 0.9% in 10 years reduced retinopathy by 25%. Also, in the Heart Outcomes Prevention Evaluation Study, a 1% rise in glycated hemoglobin increased microalbuminuria by 8% and predicted overt nephropa-
Received February 27, 2007. Accepted April 28, 2007. From Clinica Medica and Department of Clinical Medicine and Prevention, University of Milan-Bicocca, and S. Gerardo Hospital, Monza, Milan, Italy.
Address correspondence and reprint requests to Professor Giuseppe Mancia, Department of Clinica Medica, S. Gerardo Hospital, Via Pergolesi 33, Monza 4MI7, 20052 Milan, Italy; e-mail: Giuseppe.mancia@ unimib.it
T
Tight Glucose Control Is Needed
© 2007 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Key Words: Diabetes mellitus, hypertension, angiotensin-converting enzyme inhibitors.
0895-7061/07/$32.00 doi:10.1016/j.amjhyper.2007.04.016
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AJH–July 2007–VOL. 20, NO. 7
more effectively reduced (a difference of 6.0/4.6 mm Hg) had 36% fewer strokes, compared with 11% fewer strokes in patients with diabetes receiving less intensive treatment.15 The UKPDS 38 Study recorded a 44% reduction in strokes and a 32% reduction in deaths related to diabetes in the group assigned to tight BP control compared with the group assigned to less tight control.11 In the Appropriate Blood Pressure Control in Diabetes Study, in Type 2 diabetic patients,16,17 drug treatments that lowered BP to ⬍130 mm Hg systolic and ⬍80 mm Hg diastolic were associated with a reduction in the incidence of stroke, with the benefit also being seen when treatment was initiated in individuals in whom the initial BP was ⬍140/90 mm Hg. Confirmatory data were also obtained by post hoc analysis of prospective trials. For example, in the Irbesartan Type 2 Diabetic Nephropathy Trial,18 –20 Type 2 diabetic patients with nephropathy showed a progressively lower reduction in the incidence of congestive heart failure when
FIG. 1. Hazard ratios, with 95% confidence intervals as floating absolute risks, as estimates of association between categories of updated mean hemoglobin A1c concentration and (B) myocardial infarction and (A) diabetes-related mortality. Reference category (hazard ratio, 1.0) is hemoglobin A1c ⬍6% with log-linear scales. The P value reflects the contribution of glycemia to the multivariate model. Data are adjusted for age at diagnosis of diabetes, sex, ethnic group, smoking status, presence of albuminuria, systolic blood pressure, high-density and low-density lipoprotein cholesterol, and triglycerides. Reproduced with permission from Stratton et al: Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 35): prospective observational study. Br Med J [Clin Res] 2000;321:405– 412.5 In Stratton et al,5 exposure to glycemia was measured first at baseline as hemoglobin A1c concentration, and then over time as an updated mean of annual measurements of hemoglobin A1c concentration, calculated for each individual from baseline to each year of followup. For example, at 1 year, the updated mean is the average of baseline and 1-year values, and at 3 years is the average of baseline, 1-year, 2-year, and 3-year values.
thy.10,11 Because overt nephropathy is associated with a marked increase in the incidence of cardiovascular disease,5,7,9 –11 this may imply long-term cardiovascular protection. However, it should be pointed out that in UKPDS, the effect of blood glucose control on macrovascular complications was small and inconclusive.12 Furthermore, achieving high BP goals is difficult, and the maintenance of this goal often requires a progressive use of antidiabetic drugs and other treatment procedures.
Tight BP Control Is Needed Prospective, observational studies showed that in patients with diabetes, lowering BP is associated with a decrease in serious cardiovascular disease (Fig. 2).12–14 A recent meta-analysis of available trials also showed that more aggressive BP reductions were accompanied by a greater degree of benefit: patients with diabetes in whom BP was
FIG. 2. Hazard ratios (95% confidence intervals as floating absolute risks) as estimate of the association between category of updated mean systolic blood pressure and any endpoint related to diabetes (A), death related to diabetes (B), and all-cause mortality (C) with log-linear scales. Reference category (hazard ratio, 1.0) is systolic blood pressure ⬍120 mm Hg. The P value reflects the contribution of systolic blood pressure to the multivariate model. Data are adjusted for age at diagnosis, ethnic group, smoking status, presence of microalbuminuria, hemoglobin A1c, high-density and low-density lipoprotein cholesterol, and triglyceride. Reproduced with permission from Adler et al: Association of systolic blood pressure with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 36): prospective observational study. Br Med J [Clin Res] 2000;321:412– 419.14
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systolic BP was reduced to approximately 120 mm Hg, regardless of the treatment employed.20 Within this range, neither an upper nor a lower limit systolic blood pressure (SBP) threshold was observed: the lower the SBP, the lower the risk of complications.19 Tight BP control also delayed and lessened microvascular disease.10,11,14,18 –20 In the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan Trial, multivariate analysis showed that the risk of endstage renal disease or death was increased by 6.7% with every 10 mm Hg increase in baseline SBP.21 Similarly, in the Irbesartan Type 2 Diabetic Nephropathy Trial, the risk of end-stage renal disease or serum creatinine doubling was increased twofold in subjects with an SBP ⬎149 mm Hg, compared with those with an SBP ⬍134 mm Hg.18 –20 In both observational studies and intervention trials, no deviation from the linear relationship between microvascular or macrovascular events and SBP was observed, suggesting that at the achieved BP values, organ perfusion is not involved in the increase in risk (the J-curve phenomenon). Although BP objectives for diabetics are currently a SBP/diastolic BP ⬍130/80 mm Hg, these targets are rarely attained (Fig. 3).11,13,22 For patients in whom tight BP goals are achieved, not only are combination therapies often needed,12,13,21 but SBP values tend to remain somewhat higher in diabetic than in nondiabetic patients.22 These data suggest that achieving blood BP targets and
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normalizing as many patients as possible are still unmet medical needs in diabetic patients.
Combining Tight Glucose and BP Control To lessen the synergistic impact of diabetes and hypertension on macrovascular and microvascular disease, therapeutic strategies designed to combine glucose and BP control are under investigation. In the diabetic cohort of the Steno-2 Study, clinical outcomes of macrovascular and microvascular disease, including nephropathy, were improved in patients undergoing a multifactorial treatment that involved glucose-lowering (with gliclazide), BP-lowering, and statin therapy, compared with patients randomized to conventional treatments.23 However, Steno-2 and other studies such as the UKPDS were neither designed nor powered to determine whether the benefits of tight BP and glucose control are additive or extend beyond an additive effect. Results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)24 and Action to Control Cardiovascular Risk in Diabetes (www.accordtrial.org) Studies, which were designed to investigate the effects of multifactorial treatments on macrovascular and microvascular endpoints, are eagerly awaited, to develop a better understanding of the cumulative benefits of tight glucose control and BP lowering.
FIG. 3. Effects of antihypertensive drug treatment on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in diabetic hypertensive patients from several trials. Values at trial entry and during treatment are shown for each trial. Dashed horizontal lines refer to blood pressure (BP) treatment goals as recommended by international guidelines. Reproduced with permission from Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes: Mancia G, Grassi G: Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens 2002;20:1461-1465.22
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Therapeutic Choices for Hypertension Treatment in Patients With Diabetes Several classes of antihypertensive treatments lower BP and rates of cardiovascular events in patients with diabetes, and can therefore be used alone or in combination to achieve these goals. However, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may be of particular value, because blocking the renin-angiotensin system may have specific renal-protective effects. Pathophysiological studies documented that in diabetes, intraglomerular pressure is increased because of a loss of autoregulation in the afferent arteriole, which leads to transmission of high pressure from the large arterial compartment to the glomerulus. The resulting excess protein filtration causes tubular damage, inflammation, and scarring that favor the appearance and progression of renal damage. This can be opposed by drugs blocking the renin-angiotensin system, because their antihypertensive effect is complemented by reduced constriction of the efferent arteriole, the tone of which is exquisitely dependent on angiotensin II. In addition, blocking the renin angiotensin system reduces the glomerular permeability that potentiates protein loss.25–27 The conclusions of pathophysiological studies are supported by important clinical data.24 –27 Both ACE inhibitors and ARBs reduce microalbuminuria and proteinuria much more effectively than do calcium antagonists and other antihypertensive drugs.28,29 The ACE inhibitors were shown to reduce progression of renal damage and end-stage renal disease in Type 1 diabetic patients with nephropathy,29,30 and to prevent the appearance of diabetic nephropathy in Type 2 diabetic patients.30,31 Similarly, angiotensin II antagonists were shown to protect against renal deterioration, end-stage renal disease, and death in Type 2 diabetic nephropathy more effectively than did conventional drugs.32 Because the BP reduction was small in several studies (Microvascular, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation),11,18,19,29,30 and because the achieved BP values were similar in the group receiving the renin-angiotensin system blocker and in other treatment groups, it is likely that the nephroprotective effect is not exclusively due to BP reduction, but also to the specific organ-protective properties of these two classes of drugs, although other mechanisms such as a differential effect on central BP may also be involved.33 For the above reasons, guidelines on the management of hypertension recommend initiating treatment with a renin-angiotensin system blocker in diabetic nephropathy, and consider the inclusion of this agent mandatory when more than one drug is needed to achieve BP control.34,35 This is the case in most patients, because the low target BP values that minimize progressive renal deterioration (⬍125/75 mm Hg in the presence of marked microalbuminuria or proteinuria) can only exceptionally be achieved
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with monotherapy, and in most instances, require a combination of ⱖ2 drugs.34,35 Guidelines also recommend the use of an ACE inhibitor or an angiotensin receptor antagonist whenever there is increased urinary protein excretion (microalbuminuria or proteinuria), irrespective of the existing BP values.34,35 It should be emphasized that although both agents oppose the renin-angiotensin system, the mechanism of action of ACE inhibitors and of angiotensin receptor antagonists is different. The ACE inhibitors inhibit the enzyme that allows the production of angiotensin II, whereas ARBs act further downstream by binding to the AT1 receptor and preventing its activation by angiotensin II. This difference in mechanism of action (which accounts for the difference in the incidence of cough) suggests that these two therapeutic classes may not be interchangeable, thus providing a rationale for the trials that compared their beneficial effects. These comparisons, however, did not show substantial differences in long-term nephroprotection.36 Furthermore, in patients with congestive heart failure or postmyocardial infarction, no substantial differences were observed in individuals randomized to one or the other class of agent. There is, however, the possibility that an advantage may be obtained by combining the two. To date, this has been found for the antiproteinuric effect, which was reported to be greater when an ACE inhibitor and an angiotensin receptor antagonist were administered together, compared with either component given alone.37 The ACE inhibitor/angiotensin II receptor antagonist combination was also found to be more protective in patients with heart failure.38 It is not known, however, whether the same benefit can be obtained by simply increasing the dose of the administered ACE inhibitor or angiotensin receptor antagonist.
Conclusions The benefit of tight BP and glucose control in diabetes is well-understood. However, these therapeutic goals are not easily or frequently reached in patients with diabetes. Furthermore, no conclusive evidence exists on whether treatment strategies that combine multiple antihypertensive agents and glucose control further reduce the marked increase in macrovascular and microvascular complications typical of diabetic hypertensive patients. The results of ADVANCE, a trial combining these two approaches, are eagerly awaited.24
References 1.
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Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR: Additive effects of glycaemia and blood pressure exposure on risk of complications in Type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia 2006;49:1761–1769. Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting Type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens 1993;11:309 –317.
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Lawes CM, Parag V, Bennett DA, Suh I, Lam TH, Whitlock G, Barzi F, Woodward M: Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care 2004;27:2836 – 2842. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH: Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141:421– 431. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 35): prospective observational study. Br Med J [Clin Res] 2000;321:405– 412. Stettler C, Allemann S, Juni P, Cull CA, Holman RR, Egger M, Krahenbuhl S, Diem P: Glycemic control and macrovascular disease in Types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J 2006;152:27–38. Gerstein HC, Pogue J, Mann JF, Lonn E, Dagenais GR, McQueen M, Yusuf S: The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE Study: a prospective epidemiological analysis. Diabetologia 2005;48:1749 –1755. Standards of medical care in diabetes. Diabetes Care 2005;28(Suppl 1):S4 –S36. UK Prospective Diabetes Study (UKPDS) Group: Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet 1998;352:837– 853. Gerstein HC, Mann JF, Pogue J, Dinneen SF, Halle JP, Hoogwerf B, Joyce C, Rashkow A, Young J, Zinman B, Yusuf S: Prevalence and determinants of microalbuminuria in high-risk diabetic and nondiabetic patients in the Heart Outcomes Prevention Evaluation Study. The HOPE Study Investigators. Diabetes Care 2000;23(Suppl 2): B35–B39. Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE Study and MICROHOPE Substudy. Lancet 2000;355:253–259. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes: UKPDS 38. Br Med J [Clin Res] 1998;317:703–713. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: 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. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR: Association of systolic blood pressure with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 36): prospective observational study. Br Med J [Clin Res] 2000;321:412– 419. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S, Blood Pressure Lowering Treatment Trialists’ Collaboration: Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005;165:1410 –1419. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared to enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998;338:645– 652. Schrier RW, Estacio RO, Jeffers B: Appropriate Blood Pressure Control in NIDDM (ABCD) Trial. Diabetologia 1996;39:1646 – 1654. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesar-
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tan in patients with nephropathy due to Type 2 diabetes. N Engl J Med 2001;345:851– 860. Pohl MA, Blumenthal S, Cordonnier DJ, De Alvaro F, Deferrari G, Eisner G, Esmatjes E, Gilbert RE, Hunsicker LG, de Faria JB, Mangili R, Moore J Jr, Reisin E, Ritz E, Schernthaner G, Spitalewitz S, Tindall H, Rodby RA, Lewis EJ: Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the Irbesartan Diabetic Nephropathy Trial: clinical implications and limitations. J Am Soc Nephrol 2005;16:3027– 3037. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, Drury PL, Esmatjes E, Hricik D, Pohl M, Raz I, Vanhille P, Wiegmann TB, Wolfe BM, Locatelli F, Goldhaber SZ, Lewis EJ, Collaborative Study Group: Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. J Am Soc Nephrol 2005;16:2170 –2179. Bakris GL, Weir MR, Shanifar S, Zhang Z, Douglas J, van Dijk DJ, Brenner BM: Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL Study. Arch Intern Med 2003;163:1555–1565. Mancia G, Grassi G: Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens 2002;20:1461–1464. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O: Multifactorial intervention and cardiovascular disease in patients with Type 2 diabetes. N Engl J Med 2003;348:383–393. The ADVANCE Collaborative Group: Rationale and design of the ADVANCE Study: a randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with Type 2 diabetes mellitus. Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation. J Hypertens 2001;19(Suppl):S21–S28. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286: 421– 426. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke 1996;27:2033–2039. Macleod JM, Lutale J, Marshall SM: Albumin excretion and vascular deaths in NIDDM. Diabetologia 1995;38:610 – 616. Marre M, Leblanc H, Suarez L, Guyenne TT, Menard J, Passa P: Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med J [Clin Res] 1987;294:1448 –1452. Euclid Study Group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997;349:1787–1792. Lewis EJ, Hunsicker LG, Bain RP, Rohde R: The effect of ACE inhibitors on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;392:1456 –1462. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R: Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with Type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982–988. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: The effect of irbesartan on the development of diabetic nephropathy in patients with Type 2 diabetes. N Engl J Med 2001; 345:870 – 878. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O’Rourke M, for the CAFÉ Investigators Differential Impact of Blood Pressure-Lowering Drugs on Central Aortic Pressure and Clinical Outcomes: Principal results of the Conduit Artery Function Evaluation (CAFÉ) Study. Circulation 2006;113:1213–1225.
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34. European Society of Hypertension-European Society of Cardiology Guidelines Committee: 2003 European Society of HypertensionEuropean Society of Cardiology guidelines for the management of arterial hypertension. J. Hypertens 2003;21:1011–1053. 35. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: 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. 36. Strippoli GF, Craig M, Craig JC: Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 2005;CD004136.
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37. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesartan and Lisinopril Microalbuminuria (CALM) Study. Br Med J [Clin Res] 2000;321:1440 –1444. 38. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurrary JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, CHARM Investigators and Committees: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme. Lancet 2003;362:759 –766.
2007; 20:3S– 8S
ORIGINAL CONTRIBUTIONS
Blood Pressure and Glucose Control in Patients With Diabetes Giuseppe Mancia Type 2 diabetes mellitus and hypertension are comorbid clinical conditions that synergize to create a vascular environment that significantly increases the risk of macrovascular disease (eg, myocardial infarction, stroke, and cardiovascular mortality) and microvascular disease (eg, nephropathy and retinopathy). Given the prevalence of this comorbid association, the large majority of patients with newly diagnosed Type 2 diabetes are hypertensive. The co-management of diabetes, through glucose control (targeting a hemoglobin A1c ⬍7.0% in current clinical practice guidelines), and of hypertension, through bloodpressure (BP) control (systolic BP/diastolic BP ⬍130/80 mm Hg), has become central to the treatment of macrovascular and microvascular disease in diabetic patients. These BP goals, however, are rarely attained in these patients, and a treatment that combines ⱖ2 drugs is needed in most individuals. With the aim of attaining a synergistic benefit from the simultaneous lowering of hemoglobin A1c and BP, treatment strategies that combine multiple hyper-
tensive agents and glucose-controlling agents are being investigated. Treatments that include an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker may be of particular value, because these drug classes inhibit the renin-angiotensin system, which mediates the increase in renovascular resistance and intraglomerular pressure observed in diabetic kidneys. Inhibition of the renin-angiotensin system, which protects the kidney through a variety of mechanisms, may also provide renal and cardiovascular benefits that extend beyond those attributable to BP control. Thus, the effective co-management of diabetes and hypertension through combined glucose and BP control remains an unmet medical need for which strategies still need to be developed. Am J Hypertens 2007;20:3S– 8S © 2007 American Journal of Hypertension, Ltd.
ype 2 diabetes mellitus and hypertension are comorbid clinical conditions that synergize to create a vascular environment that significantly increases the risk of macrovascular disease (eg, myocardial infarction, stroke, and cardiovascular mortality), and microvascular disease (eg, nephropathy and retinopathy).1 The prevalence of this comorbid association was assessed in epidemiologic studies which estimated that a large number of patients with newly diagnosed Type 2 diabetes are hypertensive.2 In light of the fact that the prevalence and severity of diabetes and hypertension increase with age, the co-management of diabetes, through glucose control, and of hypertension, through bloodpressure (BP) control, has become central to the treatment of macrovascular and microvascular disease and the reduction in cardiovascular risk in diabetic patients.
A close association exists between blood glucose levels, macrovascular disease, and cardiovascular risk, including
coronary heart disease and stroke.3–7 Current clinical practice guidelines recommend tight blood glucose control, and a target hemoglobin A1c (HbA1c) of ⱕ7.0%.8 For example, in the Asia Pacific Cohort Studies Collaboration, a 1.0-mmol/L difference in fasting blood glucose was associated with a 21% difference in stroke risk and a 23% decrease in ischemic heart disease risk.3 Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS 35), an average HbA1c change of 1.0% over 10 years resulted in a risk modification of 21% for diabetes-related mortality and 14% for myocardial infarction (Fig. 1).5 With regard to intervention trials, tight blood glucose control proved beneficial in reducing microvascular complications such as retinopathy and nephropathy.9 For example, the UKPDS 339 showed that lowering HbA1c by an average of 0.9% in 10 years reduced retinopathy by 25%. Also, in the Heart Outcomes Prevention Evaluation Study, a 1% rise in glycated hemoglobin increased microalbuminuria by 8% and predicted overt nephropa-
Received February 27, 2007. Accepted April 28, 2007. From Clinica Medica and Department of Clinical Medicine and Prevention, University of Milan-Bicocca, and S. Gerardo Hospital, Monza, Milan, Italy.
Address correspondence and reprint requests to Professor Giuseppe Mancia, Department of Clinica Medica, S. Gerardo Hospital, Via Pergolesi 33, Monza 4MI7, 20052 Milan, Italy; e-mail: Giuseppe.mancia@ unimib.it
T
Tight Glucose Control Is Needed
© 2007 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Key Words: Diabetes mellitus, hypertension, angiotensin-converting enzyme inhibitors.
0895-7061/07/$32.00 doi:10.1016/j.amjhyper.2007.04.016
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BP AND GLUCOSE CONTROL IN DIABETES
AJH–July 2007–VOL. 20, NO. 7
more effectively reduced (a difference of 6.0/4.6 mm Hg) had 36% fewer strokes, compared with 11% fewer strokes in patients with diabetes receiving less intensive treatment.15 The UKPDS 38 Study recorded a 44% reduction in strokes and a 32% reduction in deaths related to diabetes in the group assigned to tight BP control compared with the group assigned to less tight control.11 In the Appropriate Blood Pressure Control in Diabetes Study, in Type 2 diabetic patients,16,17 drug treatments that lowered BP to ⬍130 mm Hg systolic and ⬍80 mm Hg diastolic were associated with a reduction in the incidence of stroke, with the benefit also being seen when treatment was initiated in individuals in whom the initial BP was ⬍140/90 mm Hg. Confirmatory data were also obtained by post hoc analysis of prospective trials. For example, in the Irbesartan Type 2 Diabetic Nephropathy Trial,18 –20 Type 2 diabetic patients with nephropathy showed a progressively lower reduction in the incidence of congestive heart failure when
FIG. 1. Hazard ratios, with 95% confidence intervals as floating absolute risks, as estimates of association between categories of updated mean hemoglobin A1c concentration and (B) myocardial infarction and (A) diabetes-related mortality. Reference category (hazard ratio, 1.0) is hemoglobin A1c ⬍6% with log-linear scales. The P value reflects the contribution of glycemia to the multivariate model. Data are adjusted for age at diagnosis of diabetes, sex, ethnic group, smoking status, presence of albuminuria, systolic blood pressure, high-density and low-density lipoprotein cholesterol, and triglycerides. Reproduced with permission from Stratton et al: Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 35): prospective observational study. Br Med J [Clin Res] 2000;321:405– 412.5 In Stratton et al,5 exposure to glycemia was measured first at baseline as hemoglobin A1c concentration, and then over time as an updated mean of annual measurements of hemoglobin A1c concentration, calculated for each individual from baseline to each year of followup. For example, at 1 year, the updated mean is the average of baseline and 1-year values, and at 3 years is the average of baseline, 1-year, 2-year, and 3-year values.
thy.10,11 Because overt nephropathy is associated with a marked increase in the incidence of cardiovascular disease,5,7,9 –11 this may imply long-term cardiovascular protection. However, it should be pointed out that in UKPDS, the effect of blood glucose control on macrovascular complications was small and inconclusive.12 Furthermore, achieving high BP goals is difficult, and the maintenance of this goal often requires a progressive use of antidiabetic drugs and other treatment procedures.
Tight BP Control Is Needed Prospective, observational studies showed that in patients with diabetes, lowering BP is associated with a decrease in serious cardiovascular disease (Fig. 2).12–14 A recent meta-analysis of available trials also showed that more aggressive BP reductions were accompanied by a greater degree of benefit: patients with diabetes in whom BP was
FIG. 2. Hazard ratios (95% confidence intervals as floating absolute risks) as estimate of the association between category of updated mean systolic blood pressure and any endpoint related to diabetes (A), death related to diabetes (B), and all-cause mortality (C) with log-linear scales. Reference category (hazard ratio, 1.0) is systolic blood pressure ⬍120 mm Hg. The P value reflects the contribution of systolic blood pressure to the multivariate model. Data are adjusted for age at diagnosis, ethnic group, smoking status, presence of microalbuminuria, hemoglobin A1c, high-density and low-density lipoprotein cholesterol, and triglyceride. Reproduced with permission from Adler et al: Association of systolic blood pressure with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 36): prospective observational study. Br Med J [Clin Res] 2000;321:412– 419.14
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systolic BP was reduced to approximately 120 mm Hg, regardless of the treatment employed.20 Within this range, neither an upper nor a lower limit systolic blood pressure (SBP) threshold was observed: the lower the SBP, the lower the risk of complications.19 Tight BP control also delayed and lessened microvascular disease.10,11,14,18 –20 In the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan Trial, multivariate analysis showed that the risk of endstage renal disease or death was increased by 6.7% with every 10 mm Hg increase in baseline SBP.21 Similarly, in the Irbesartan Type 2 Diabetic Nephropathy Trial, the risk of end-stage renal disease or serum creatinine doubling was increased twofold in subjects with an SBP ⬎149 mm Hg, compared with those with an SBP ⬍134 mm Hg.18 –20 In both observational studies and intervention trials, no deviation from the linear relationship between microvascular or macrovascular events and SBP was observed, suggesting that at the achieved BP values, organ perfusion is not involved in the increase in risk (the J-curve phenomenon). Although BP objectives for diabetics are currently a SBP/diastolic BP ⬍130/80 mm Hg, these targets are rarely attained (Fig. 3).11,13,22 For patients in whom tight BP goals are achieved, not only are combination therapies often needed,12,13,21 but SBP values tend to remain somewhat higher in diabetic than in nondiabetic patients.22 These data suggest that achieving blood BP targets and
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normalizing as many patients as possible are still unmet medical needs in diabetic patients.
Combining Tight Glucose and BP Control To lessen the synergistic impact of diabetes and hypertension on macrovascular and microvascular disease, therapeutic strategies designed to combine glucose and BP control are under investigation. In the diabetic cohort of the Steno-2 Study, clinical outcomes of macrovascular and microvascular disease, including nephropathy, were improved in patients undergoing a multifactorial treatment that involved glucose-lowering (with gliclazide), BP-lowering, and statin therapy, compared with patients randomized to conventional treatments.23 However, Steno-2 and other studies such as the UKPDS were neither designed nor powered to determine whether the benefits of tight BP and glucose control are additive or extend beyond an additive effect. Results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)24 and Action to Control Cardiovascular Risk in Diabetes (www.accordtrial.org) Studies, which were designed to investigate the effects of multifactorial treatments on macrovascular and microvascular endpoints, are eagerly awaited, to develop a better understanding of the cumulative benefits of tight glucose control and BP lowering.
FIG. 3. Effects of antihypertensive drug treatment on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in diabetic hypertensive patients from several trials. Values at trial entry and during treatment are shown for each trial. Dashed horizontal lines refer to blood pressure (BP) treatment goals as recommended by international guidelines. Reproduced with permission from Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes: Mancia G, Grassi G: Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens 2002;20:1461-1465.22
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Therapeutic Choices for Hypertension Treatment in Patients With Diabetes Several classes of antihypertensive treatments lower BP and rates of cardiovascular events in patients with diabetes, and can therefore be used alone or in combination to achieve these goals. However, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may be of particular value, because blocking the renin-angiotensin system may have specific renal-protective effects. Pathophysiological studies documented that in diabetes, intraglomerular pressure is increased because of a loss of autoregulation in the afferent arteriole, which leads to transmission of high pressure from the large arterial compartment to the glomerulus. The resulting excess protein filtration causes tubular damage, inflammation, and scarring that favor the appearance and progression of renal damage. This can be opposed by drugs blocking the renin-angiotensin system, because their antihypertensive effect is complemented by reduced constriction of the efferent arteriole, the tone of which is exquisitely dependent on angiotensin II. In addition, blocking the renin angiotensin system reduces the glomerular permeability that potentiates protein loss.25–27 The conclusions of pathophysiological studies are supported by important clinical data.24 –27 Both ACE inhibitors and ARBs reduce microalbuminuria and proteinuria much more effectively than do calcium antagonists and other antihypertensive drugs.28,29 The ACE inhibitors were shown to reduce progression of renal damage and end-stage renal disease in Type 1 diabetic patients with nephropathy,29,30 and to prevent the appearance of diabetic nephropathy in Type 2 diabetic patients.30,31 Similarly, angiotensin II antagonists were shown to protect against renal deterioration, end-stage renal disease, and death in Type 2 diabetic nephropathy more effectively than did conventional drugs.32 Because the BP reduction was small in several studies (Microvascular, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation),11,18,19,29,30 and because the achieved BP values were similar in the group receiving the renin-angiotensin system blocker and in other treatment groups, it is likely that the nephroprotective effect is not exclusively due to BP reduction, but also to the specific organ-protective properties of these two classes of drugs, although other mechanisms such as a differential effect on central BP may also be involved.33 For the above reasons, guidelines on the management of hypertension recommend initiating treatment with a renin-angiotensin system blocker in diabetic nephropathy, and consider the inclusion of this agent mandatory when more than one drug is needed to achieve BP control.34,35 This is the case in most patients, because the low target BP values that minimize progressive renal deterioration (⬍125/75 mm Hg in the presence of marked microalbuminuria or proteinuria) can only exceptionally be achieved
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with monotherapy, and in most instances, require a combination of ⱖ2 drugs.34,35 Guidelines also recommend the use of an ACE inhibitor or an angiotensin receptor antagonist whenever there is increased urinary protein excretion (microalbuminuria or proteinuria), irrespective of the existing BP values.34,35 It should be emphasized that although both agents oppose the renin-angiotensin system, the mechanism of action of ACE inhibitors and of angiotensin receptor antagonists is different. The ACE inhibitors inhibit the enzyme that allows the production of angiotensin II, whereas ARBs act further downstream by binding to the AT1 receptor and preventing its activation by angiotensin II. This difference in mechanism of action (which accounts for the difference in the incidence of cough) suggests that these two therapeutic classes may not be interchangeable, thus providing a rationale for the trials that compared their beneficial effects. These comparisons, however, did not show substantial differences in long-term nephroprotection.36 Furthermore, in patients with congestive heart failure or postmyocardial infarction, no substantial differences were observed in individuals randomized to one or the other class of agent. There is, however, the possibility that an advantage may be obtained by combining the two. To date, this has been found for the antiproteinuric effect, which was reported to be greater when an ACE inhibitor and an angiotensin receptor antagonist were administered together, compared with either component given alone.37 The ACE inhibitor/angiotensin II receptor antagonist combination was also found to be more protective in patients with heart failure.38 It is not known, however, whether the same benefit can be obtained by simply increasing the dose of the administered ACE inhibitor or angiotensin receptor antagonist.
Conclusions The benefit of tight BP and glucose control in diabetes is well-understood. However, these therapeutic goals are not easily or frequently reached in patients with diabetes. Furthermore, no conclusive evidence exists on whether treatment strategies that combine multiple antihypertensive agents and glucose control further reduce the marked increase in macrovascular and microvascular complications typical of diabetic hypertensive patients. The results of ADVANCE, a trial combining these two approaches, are eagerly awaited.24
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37. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesartan and Lisinopril Microalbuminuria (CALM) Study. Br Med J [Clin Res] 2000;321:1440 –1444. 38. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurrary JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, CHARM Investigators and Committees: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme. Lancet 2003;362:759 –766.