Miles Fisher. Coronary disease DIABETES AND ATHEROGENESIS RESISTANCE AND THE METABOLIC SYNDROME

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1 336 Correspondene to: Dr Miles Fisher, Wards 4 & 5, Glasgow Royal Infirmary, Glasgow, G4 0SF, UK; miles.fisher@northglasgow. sot.nhs.uk Coronary disease DIABETES AND ATHEROGENESIS INSULIN T Miles Fisher Heart 2004; 90: doi: /hrt he exessive ardiovasular morbidity and mortality assoiated with diabetes (sometimes termed the burden of heart disease in diabetes ) has been reognised for a long time. Beause of this, I have suggested that diabetes should be defined as a state of premature ardiovasular death whih is assoiated with hroni hyperglyaemia and may also be assoiated with blindness and renal failure. This was first plaed in ontext by the Framingham study, where middle aged people with diabetes had an inreased oronary heart disease morbidity and mortality that ould not be explained by the traditional ardiovasular risk fators of smoking, age, raised holesterol, raised blood pressure, or obesity. 1 This suggested a possible unique role for diabetes as a risk fator for the development of ardiovasular disease. Women with diabetes had the same prevalene of ardiovasular problems as men with diabetes, greatly inreasing the risk ompared to non-diabeti women, leading to the phrase women with diabetes loose the protetion of their gender. An exess of ongestive ardia failure was also noted that ould not be explained by the presene of oronary heart disease, adding support to the existene of a possible diabeti ardiomyopathy. From a ritial perspetive, however, this study was guilty of many of the problems that have affeted researh in this area ever sine. A ombination of patients with type 1 and type 2 diabetes was studied, and no attempt was made to lassify the type of diabetes in an individual subjet. The diagnosti riteria for diabetes were not onsistent within the various publiations from the Framingham study, leading to differing numbers of patients with diabetes in different publiations. The number of subjets with diabetes was very small, whih may have exaggerated the risks of some of the end points, suh as ardia failure in women with diabetes. The small number of subjets also means that the Framingham equation based on these data is muh less exat for estimating ardiovasular risk in people with diabetes. Only middle aged and elderly subjets were studied, where the absolute risk is highest, and no attempt was made to study younger diabeti subjets, where the relative risk for people with diabetes is extraordinarily raised ompared to non-diabeti subjets, yet the absolute risk remains relatively low. A reent review by Timmis desribed onsiderations in the ardiologial treatment of people with diabetes. 2 This review examines the possible differing mehanisms of heart disease in people with type 1 and type 2 diabetes. The effets of measures to ontrol blood gluose on vasular outomes are desribed in these groups of patients. Finally, studies on the redution of ardiovasular risk in diabetes by the treatment of hypertension and dyslipidaemia, inluding several newer publiations in this area, are desribed in detail. RESISTANCE AND THE METABOLIC SYNDROME The onept of insulin resistane was first introdued in the 1960s when it was notied that patients following myoardial infartion had high insulin onentrations. Similar high insulin values were also seen in patients with hypertension, and this assoiation was onfirmed in many large, epidemiologial studies. It was suggested that the panreas inreased the prodution of insulin to try and overome the insulin resistane, and that this relative hyperinsulinaemia aused sodium retention and inreased sympatheti nervous tone, so inreasing the blood pressure. In his 1988 Banting leture, Reaven noted that resistane to insulin stimulated gluose uptake was present in the majority of patients with type 2 diabetes and impaired gluose tolerane, and in 25% of non-obese individuals with normal gluose tolerane. 3 He suggested that gluose intolerane ould be prevented if the beta ell was able to inrease insulin seretion and maintain hroni hyperinsulinaemia. If this ould not be ahieved then deompensation of gluose tolerane ourred. He suggested that the relation between insulin resistane, hyperinsulinaemia, and gluose intolerane was mediated by hanges in free fatty aid onentrations, as plasma free fatty aids ould be redued by small inrements in insulin onentration. If hyperinsulinaemia ould not be maintained, inreased free fatty aids would lead to inreased hepati gluose prodution, and beause of resistane to insulin stimulated gluose uptake, to hyperglyaemia.

2 Reaven also identified a lustering of risk fators for oronary heart disease, inluding hyperinsulinaemia, impaired gluose tolerane, inreased plasma triglyeride onentrations, dereased high density lipoprotein (HDL) holesterol onentrations, and hypertension that he named syndrome X. Several other omponents of syndrome X or the metaboli syndrome have been added, inluding viseral adiposity, miroalbuminuria, endothelial dysfuntion, abnormal fibrinolysis, and markers of inflammation. It remains unlear if this is just a oinidental lustering of ardiovasular disease risk fators that are shared with risk fators for diabetes (the ommon soil hypothesis) or whether there is a single aetiologial determinant as suggested by Reaven. The single determinant might be geneti, insulin resistane, viseral obesity, endothelial dysfuntion, or inflammation, or there might be multiple interating determinants. A reent study from Italy measured insulin resistane using a homeostasis model assessment (HOMA), and found that insulin resistane was a strong independent preditor of ardiovasular disease in type 2 diabetes. 4 This mathematial model utilises basal onentrations of gluose and insulin, and provides an index of relative insulin sensitivity. New oral hypoglyaemi treatments that target insulin resistane are desribed below, but insulin resistane is not at present a separate target for intervention in type 2 diabetes. HEART DISEASE AND TYPE 1 DIABETES Patients with type 1 diabetes tend to be younger than patients with type 2 diabetes (the average age of onset for type 1 diabetes is 14 years versus 60 years for type 2 diabetes). The pathophysiology of ardiovasular disease is probably different to that in type 2 diabetes, although reent studies suggest that many patients with type 1 diabetes beome insulin resistant following the initiation of insulin treatment. As in the general population and in patients with type 2 diabetes, this may be explained by dereased physial ativity and exessive food intake leading to viseral adiposity. This has been termed double diabetes, but it is not ertain if these are the only patients with type 1 diabetes that are at inreased ardiovasular risk. Several older studies suggested that the exessive risk was assoiated with varying degrees of renal impairment in patients with type 1 diabetes. Longstanding type 1 diabetes an also lead to autonomi neuropathy and a diabeti ardiomyopathy, 5 and o-segregation of these problems in patients with poor glyaemi ontrol is a possibility. Reent studies have foused on new ways of ardiologially identifying patients with type 1 diabetes who have early ardiovasular problems, as the detetion of proteinuria is not suffiiently sensitive to predit ardiovasular outomes in type 1 diabetes, and investigation for autonomi neuropathy or the diabeti ardiomyopathy is not routinely performed. Estimation of the degree of oronary artery alifiation using eletron beam tomography is beoming inreasingly aepted for risk stratifiation in the asymptomati diabeti patient. 6 GLYCAEMIC CONTROL AND REDUCTION OF CARDIOVASCULAR RISK Type 1 diabetes The landmark trial of tight glyaemi ontrol in people with type 1 diabetes was the diabetes ontrol and ompliations trial (DCCT). 7 Tight ontrol, based on a ontinuous subutaneous insulin infusion or basal bolus insulin regimen, was assoiated with a signifiant redution in the development or progression of mirovasular diabeti ompliations, inluding diabeti retinopathy and diabeti nephropathy, on a mean of 6.5 years of follow up. Careful analysis was performed of ardiovasular end points in the DCCT, inluding aute myoardial infartion and death from ardiovasular disease. 7 There were a very small number of ardiovasular events in the study, however, and no signifiant effet of tight glyaemi ontrol on vasular outomes was demonstrated. Four definite myoardial infartions were reorded, and all ourred in the onventional treatment group. A subsequent meta-analysis based on the DCCT study but also inluding several smaller studies onluded that intensive insulin treatment redued the number of total major marovasular events, inluding myoardial infartion, but that mortality was not affeted with intensive insulin treatment. Type 2 diabetes The landmark trial of tight glyaemi ontrol in people with type 2 diabetes was the UK prospetive diabetes study (UKPDS) in 4209 subjets with reently diagnosed diabetes. 8 Compared to the DCCT there was a smaller separation between the intensive and ontrol groups. In the DCCT the average HbA1 in the intensive group was 7.2% ompared to 9.1% in the onventional group. In the UKPDS the figures were 7.0% and 7.9% for the intensive and onventional groups, respetively. Tight ontrol, based on either treatment with sulfonylureas or insulin, was assoiated with a signifiant redution in the development of mirovasular ompliations, inluding diabeti retinopathy and nephropathy, on a mean of 10 years of follow up. 8 Myoardial infartion was the most ommon single end point and ourred in around 12% of all patients. The mortality from myoardial infartion was around 50%. The risk of a myoardial infartion was 14.7 events per 1000 patient years in the intensive group, and 17.4 events per 1000 patient years in the onventional group, a non-signifiant differene (p = 0.052). For overweight patients a further possible randomisation was to intensive treatment with metformin, whih exerts its prinipal hypoglyaemi effet by suppressing basal hepati gluose prodution. Somewhat to the surprise of the investigators this group of diabeti patients did best, with a signifiant redution in myoardial infartions, ardiovasular deaths, and total mortality ompared to the onventional treatment group. 9 Based on the results of the UKPDS the treatment of first hoie for overweight patients with type 2 diabetes not ontrolled by dieting is metformin, with sulfonylureas reserved as first hoie for the minority of patients that are not overweight or annot tolerate metformin. Reently, a newer lass of oral hypoglyaemi agents, the thiazolidenediones or glitazones, has beome available for the treatment of type 2 diabetes. They at by binding to the peroxisome proliferator-ativated reeptor (PPAR) in the nuleus of the ell. They sensitise the body to its own insulin, reduing insulin resistane and enabling peripheral tissues to inrease the uptake of gluose from the plasma. These drugs lower blood sugar, and also redue blood pressure, miroalbuminuria, and inrease HDL holesterol onentrations. Body weight inreases, and omplex hanges in other lipids are desribed. Preliminary studies have demonstrated redutions in onentrations of C reative protein, and white blood ell ount, 10 suggesting the possibility of extended benefit beyond blood gluose lowering effets; this is being tested in 337

3 338 Trial aronyms AFCAPS/TexCAPS: Air Fore/Texas Coronary Atheroslerosis Prevention Study ALLHAT: Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attak Trial CARE: Cholesterol And Reurrent Events trial DAIS: Diabetes Atheroslerosis Intervention Study DCCT: Diabetes Control and Compliations Trial HDS: Hypertension in Diabetes Study HOPE: Heart Outomes Prevention Evaluation study HOT: Hypertension Optimal Treatment trial HPS: Heart Protetion Study IDNT: Irbesartan Diabeti Nephropathy Trial IRMA2: Irbesartan in Patients with Type 2 Diabetes and Miroalbuminuria Study LIFE: Losartan Intervention For Endpoint Redution in Hypertension LIPID: Long-Term Intervention with Pravastatin in Ishaemi Disease study RENAAL: Redution of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan 4S: Sandinavian Simvastatin Survival Study SHEP: Systoli Hypertension in the Elderly Program Syst-Eur: Systoli Hypertension in Europe trail UKPDS: United Kingdom Prospetive Diabetes Study VA-HIT: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial WOSCOPS: West of Sotland Coronary Prevention Study several large randomised studies with ardiovasular outomes in people with diabetes. Two other drugs have reently beome available for the treatment of type 2 diabetes. Like sulfonylureas, repaglinide and nateglinide work by stimulating panreati potassium hannels, releasing insulin. They are short ating, have to be taken more than one daily to ontrol blood gluose onentrations, and offer no distint advantages over sulfonylurea treatment. Reent epidemiologial analysis shows that the level of postprandial hyperglyaemia may be a better preditor of ardiovasular outomes than a fasting blood gluose onentration. The rapid onset of ation of these agents means that improvements in postprandial hyperglyaemia are demonstrated when these drugs are ompared to older agents, but there is as yet no published evidene that the use of these agents leads to improvements in ardiovasular outomes. RISK FACTOR REDUCTION Blood pressure ontrol Evidene of benefit in reduing blood pressure in people with diabetes has ome from subgroup analysis of several large studies (table 1), and from a small number of studies onduted in speifi groups of patients with diabetes. The hypertension in diabetes study (HDS) was nested within the UKPDS and therefore inluded subjets with hypertension and reently diagnosed diabetes. 11 Tight ontrol of blood pressure, based on treatment with aptopril or atenolol, redued mirovasular (diabeti retinopathy) and marovasular (stroke) ompliations ompared to less tight ontrol. Interestingly, the blood pressure attained in the tight ontrol group was similar to that whih gave maximum benefit for diabeti subjets in the hypertension optimal treatment (HOT) study, using a felodipine based treatment regimen. The more reent LIFE (losartan intervention for endpoint redution in hypertension) study examined people with hypertension and ECG evidene of left ventriular hypertrophy, and ompared a regimen based on losartan with a regimen based on atenolol. 12 For the study as a whole, a signifiant redution was seen in the primary omposite with losartan ompared to atenolol. In partiular, there were signifiant redutions in the number of strokes, with insignifiant effets on ardiovasular death and myoardial infartions. By ontrast, for the diabeti subgroup there was no signifiant redution in strokes or myoardial infartions, but signifiant redutions were demonstrated in ardiovasular deaths and total mortality when the group treated with losartan were ompared with those treated with atenolol. 12 The reasons for these differenes are not lear. Angiotensin reeptor antagonists have also been studied in hypertensive patients with type 2 diabetes and varying degrees of diabeti nephropathy. The IRMA2 (irbesartan in patients with type 2 diabetes and miroalbuminuria) study examined diabeti patients with miroalbuminuria, whih ours in one third of patients with type 2 diabetes. 13 Irbesartan was better than plaebo in slowing the progression from miroalbuminuria to overt proteinuria. For subjets with overt proteinuria, irbesartan and losartan were better than plaebo and amlodipine respetively in the IDNT (irbesartan diabeti nephropathy trial) and RENAAL (redution in endpoints in NIDDM with the angiotensin II antagonist losartan) studies in reduing the omposite end point of doubling of serum reatinine, end stage renal disease, and death When the omponents of the omposite were examined, there were benefits in the renal outomes of end stage renal disease or doubling of serum reatinine, but no effet on death. Unfortunately, these studies were terminated at around 2.5 years beause of the renal benefit, and there was no signifiant benefit in reduing a mixture of seondary ardiovasular outomes. It remains unertain whether these drugs will give ardiovasular benefit over and above any benefit of blood pressure lowering on renal funtion, as has been suggested for ramipril in the HOPE (heart outomes prevention evaluation) study (see below). In the reently published ALLHAT study (antihypertensive and lipid-lowering treatment to prevent heart attak trial), hlorthalidone based hypotensive treatment was if anything better than treatment based on enalapril or amlodipine. 16 All three were useful, safe, and well tolerated, dismissing previous fears that amlodipine might be of less benefit in people with diabetes. Patients with diabetes will often need two or more hypotensive agents to reah treatment targets, and regimens an inlude a ombination of diuretis, ACE inhibitors, angiotensin II reeptor antagonists, b blokers, and alium hannel blokers. For patients with either miroalbuminuria or overt proteinuria an ACE inhibitor or an angiotensin II reeptor antagonist should be inluded in the ombination. HOPE study The interpretation of the results of the HOPE study remains ontroversial. Using a simple study design, over 9297 people at high ardiovasular risk, inluding 3577 diabeti patients, reeived ramipril or plaebo. Ramipril lowered the risk of the primary omposite end point of myoardial infartion, stroke or ardiovasular death, inluding signifiant redutions in

4 Table 1 Major trials of blood pressure lowering treatment in diabetes Key trials ontaining large numbers of subjets with diabetes ALLHAT: hlorthalidone, amlodipine, lisinopril, subjets, with diabetes HOT: felodipine, subjets, 1501 with diabetes LIFE: losartan, atenolol, 9193 subjets, 1195 with diabetes and left ventriular hypertrophy SHEP: 4736 subjets, 583 with diabetes and systoli hypertension Syst-Eur: 4695 subjets, 492 with diabetes and systoli hypertension Major trials ontaining only subjets with diabetes IRMA2: irbesartan, 590 subjets with diabetes and miroalbuminuria IDNT: irbesartan, 1715 subjets with diabetes and nephropathy RENAAL: losartan, amlodipine, 1513 subjets with diabetes and nephropathy UKPDS/HDS: atenolol, aptopril, 1148 subjets with hypertension and newly diagnosed diabetes See box for explanation of trial aronyms. eah of the omponents of the omposite and in total mortality. Data on blood pressure responses were not olleted in detail, so it is unertain whether this redution in risk was as a result of blood pressure lowering in a high risk group of patients, or whether this was due to extended effets of ACE inhibition. The results for the diabeti subjets were published separately. 17 In addition to ardiovasular benefit, there was a signifiant redution in the development of overt diabeti nephropathy. Unfortunately, there was infrequent sampling of the degree of proteinuria throughout the study, with a single sample at baseline, one year, and five years. There was no signifiant effet of ramipril on the development of new miroalbuminuria, but there was a redution in the progression of miroalbuminuria as measured by the mean albumin/reatinine ratio. Several post-ho subgroup publiations from the HOPE study provide useful information in people with diabetes. The degree of albuminuria was measured in 97% of patients in the HOPE study. Miroalbuminuria was deteted in 32% of diabeti subjets at baseline and 15% of non-diabeti subjets, and was assoiated with the duration of diabetes, inreasing HbA1, hypertension, smoking, and left ventriular hypertrophy. 18 Miroalbuminuria inreased the adjusted relative risk of major ardiovasular risk on subsequent follow up. One tenth of the subjets in the study had renal insuffiieny at baseline, as determined by a mild inrease in serum reatinine onentration (patients with more severe Table 2 Major trials of lipid lowering treatment in diabetes Major trials ontaining large numbers of subjets with diabetes for seondary prevention 4S: simvastatin, 4444 subjets, 202 with diabetes CARE: pravastatin, 4159 subjets, 586 with diabetes LIPID: pravastatin, 9014 subjets, 782 with diabetes HPS: simvastatin, subjets, subjets with prior myoardial infartion or other oronary heart disease, 1981 with diabetes VA-Hit: gemfibrozil, 2531 subjets, 627 with diabetes Major trial ontaining large numbers of subjets with diabetes for primary prevention HPS: simvastatin, 7150 subjets with no prior oronary heart disease, 3982 subjets with diabetes See box for explanation of trial aronyms. Diabetes and atherogenesis: key points For patients with type 1 diabetes the exessive ardiovasular burden may only affet a small number of people, espeially those with renal ompliations, and ways of identifying these people need to be refined For people with type 2 diabetes, the exessive ardiovasular burden is not ompletely explained by onventional ardiovasular risk fators, and novel risk fators may have an important role Treatment of glyaemia using older agents may be of limited benefit. The use of newer oral hypoglyaemi agents, that give some improvements in both traditional and novel risk fators, is urrently being explored Aggressive treatment of dyslipidaemia and hypertension is of proven effiay degrees of renal impairment were exluded). 19 The umulative inidene of the primary outome was higher in patients with renal insuffiieny than in those without, emphasising the high ardiovasular event rate in patients with renal impairment. A partiular benefit in the redution in ardiovasular events with ramipril was demonstrated in diabeti subjets with a raised serum reatinine ompared to other groups. Lipidloweringtreatment People with type 2 diabetes have been well represented in the landmark trials of lipid lowering treatment for the seondary prevention of ardiovasular disease (table 2). Separate subgroup analysis for people with diabetes has been published for several of these trials. Figure 1 illustrates the benefit of lipid lowering treatment on the ombined end point of ardiovasular death and non-fatal myoardial infartion in people with diabetes ompared to non-diabeti subjets in the older statin trials. Generally, people with diabetes have obtained similar or greater relative risk redution from the use of statins (or gemfibrozil), but beause of the muh greater event rate they have obtained a greater absolute benefit. In the heart protetion study (HPS), the event rate (ardiovasular death, myoardial infartion, stroke, revasularisations) in the plaebo group for diabeti subjets with prior oronary disease was an astonishing 37.8%, whih was the highest for any subgroup in the study. This was redued to 33.4% by simvastatin 40 mg. 20 By ontrast, people with diabetes were not well represented in the older landmark primary prevention studies, and so subgroup analysis is not feasible. In the HPS there were nearly 4000 patients with diabetes and no prior oronary heart disease, and the results for these patients are ontained within the prinipal publiation in the Lanet. However, this group inluded some people with prior erebrovasular or peripheral vasular disease. In subsequent orrespondene, the authors indiated that 2912 patients with diabetes did not have any diagnosed olusive vasular disease at entry, and the major vasular event rate was redued from 13.5% to 9.3% by simvastatin in these diabeti subjets. The typial lipid abnormalities that are seen in type 2 diabetes and the insulin resistane syndrome are an inrease in triglyerides, a fall in HDL holesterol, and no real inrease in total or low density lipoprotein (LDL) holesterol. This pattern of dyslipidaemia might be expeted to respond better to treatment with fibrates than statins. There were a 339

5 340 reasonable number of diabeti subjets in the VA-HIT study (Veterans Affairs high-density lipoprotein holesterol intervention trial) of gemfibrozil, and separate subgroup analysis of diabeti subjets has reently been published. DAIS (diabetes atheroslerosis intervention study) was a study of the effets of fenofibrateinpeoplewithdiabetesonsurrogateangiographi markers. Fenofibrate was of some benefit in these subjets, but no differene was seen in harder ardiovasular outomes. Studies are underway omparing the effets of fenofibrate ompared to plaebo on hard ardiovasular outomes in patients with diabetes; in the longer term it is hoped to omplete omparative studies of fibrates and statins on hard ardiovasular outomes in people with diabetes. REFERENCES 1 Kannel WB, MGee DL. Diabetes and ardiovasular disease. The Framingham study. JAMA 1979;241: Key publiation of the Framingham diabetes data based on 118 men and 121 women with diabetes among 5209 subjets. 2 Timmis AD. Diabeti heart disease: linial onsiderations. Heart 2001;85: Reaven GM. Role of insulin resistane in human disease. Diabetes 1988;37: Review ombining observed lustering of risk fators and hypothesis about free fatty aids as a major aetiologial determinant. 4 Bonora E, Formentini G, Calaterra F, et al. HOMA-estimated insulin resistane is an independent preditor of ardiovasular disease in type 2 diabeti subjets. Diabetes Care 2002;25: Fisher BM, Frier BM. Evidene for a speifi heart disease of diabetes in humans. Diabet Med 1990;7: Budoff MJ. Diabeti patients and oronary alium: risk stratifiation, ompliane, and plaque progression. Diabetes Care 2003;26: The Diabetes Control and Compliations Trial (DCCT) Researh Group. Effet of intensive diabetes management on marovasular events and risk fators in the diabetes ontrol and ompliations trial. Am J Cardiol 1995;75: UK Prospetive Diabetes Study (UKPDS) Group. Intensive blood-gluose ontrol with sulphonylureas or insulin ompared with onventional treatment and risk of ompliations in patients with type 2 diabetes (UKPDS 33). Lanet 1998;352: Main results of UKPDS omparing intensive and onventional treatment based on insulin or sulfonylureas. Figure 1 Evidene for the benefits of lipid lowering. Primary and seondary holesterol lowering statin trials illustrating the perentage of patients with a oronary heart disease (CHD) event (ardiovasular death or non-fatal myoardial infartion) against the mean low density lipoprotein (LDL) holesterol during the study in intervention and plaebo groups. Adapted from LaRosa JC. Unresolved issues: unanswered questions. Eur Heart J 1999;1(suppl J): J UK Prospetive Diabetes Study (UKPDS) Group. Effet of intensive bloodgluose ontrol with metformin on ompliations in overweight patients with type 2 diabetes (UKPDS 34). Lanet 1998;352: UKPDS subgroup of overweight patients (. 120% ideal body weight) treated with metformin. 10 Haffner SM, Greenberg AS, Weston WM, et al. Effet of rosiglitazone treatment on nontraditional markers of ardiovasular disease in patients with type 2 diabetes. Cirulation 2002;106: UK Prospetive Diabetes Study Group. Tight blood pressure ontrol and risk of marovasular and mirovasular ompliations in type 2 diabetes: UKPDS 38. BMJ 1998;317: UKPDS substudy in 1148 patients omparing less tight and tight blood pressure ontrol based on atenolol or aptopril. 12 Lindholm LH, Ibsen H, Dahlof B, et al. for the LIFE Study Group. Cardiovasular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint redution in hypertension study (LIFE): a randomised trial against atenolol. Lanet 2002;359: Parving H-H, Lehnert H, Brohner-Mortensen J, et al. for the Irbesartan in Patients with Type 2 Diabetes and Miroalbuminuria Study Group. The effet of irbesartan on the development of diabeti nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: Lewis EJ, Hunsiker LG, Clarke WR, et al. for the Collaborative Study Group. Renoprotetive effet of the angiotensin-reeptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: Brenner BM, Cooper ME, de Zeeuw D, et al. for the RENAAL Study Investigators. Effets of losartan on renal and ardiovasular outomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: The ALLHAT Offiers and Coordinators for the ALLHAT Collaborative Researh Group. Major outomes in high-risk hypertensive patients randomized to angiotensin-onverting enzyme inhibitor or alium hannel bloker vs diureti. The antihypertensive and lipid-lowering treatment to prevent heart attak trial (ALLHAT). JAMA 2002;288: Heart Outomes Prevention Evaluation (HOPE) Study Investigators. Effets of ramipril on ardiovasular and mirovasular outomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lanet 2000;355: Gerstein HC, Man JFE, Yi Q, et al. for the HOPE Study Investigators. Albuminuria and risk of ardiovasular events, death, and heart failure in diabeti and nondiabeti individuals. JAMA 2001;286: Mann JFE, Gerstein HC, Pogue J, et al. for the HOPE Investigators. Renal insuffiieny as a preditor of ardiovasular outomes and the impat of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134: Heart Protetion Study Collaborative Group. MRC/BHF heart protetion study of holesterol lowering with simvastatin in high-risk individuals: a randomised plaebo-ontrolled trial. Lanet 2002;360:7 22.