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Outcome survey in unselected hypertensive patients with type 2 diabetes mellitus: effects of ace inhibition
AJH
2001; 14:672– 678
Outcome Survey in Unselected Hypertensive Patients With Type 2 Diabetes Mellitus: Effects of ACE Inhibition Roland Veelken, Christian Delles, Karl F. Hilgers, and Roland E. Schmieder Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63 ⫾ 10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24 ⫾ 17 mm Hg and diastolic blood pressure by 12 ⫾ 11 mm Hg. An increase in serum creatinine (⬎ 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P ⬍ .05). Serum creatinine
T
decreased more frequently in patients with renal involvement than in those without (26% ⫾ 4% v 12% ⫾ 3.8%; P ⬍ .05). Overall renal function in patients with diabetic nephropathy (n ⫽ 318) improved (2.1 ⫾ 1.6 mg/dL v 1.7 ⫾ 1.4 mg/dL; P ⬍ .05). The frequency of proteinuria was lower after 1 year than at baseline (62% ⫾ 9% v 82% ⫾ 8%; P ⬍ .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P ⬍ .01). Scores for edema formation and exertional dyspnea improved as well (P ⬍ .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function. Am J Hypertens 2001;14:672– 678 © 2001 American Journal of Hypertension, Ltd. Key Words: ACE inhibitors, type 2 diabetes mellitus, therapy, outcome survey.
ype 2 diabetes mellitus and arterial hypertension are commonly associated conditions, both of which carry an increased risk of cardiovascular and renal disease.1 The prevalence of arterial hypertension in type 2 diabetes mellitus is higher than that in the general population. At the age of 45 years, approximately 40% of patients with type 2 diabetes mellitus are hypertensive, with the proportion increasing to 60% by the age of 75 years.2 Arterial hypertension clearly increases the already high risk of cardiovascular disease associated with type 2 diabetes mellitus, and is also a risk factor for the development of microalbuminuria and retinopathy.2– 4 Diabetic nephropathy is the most common single cause of end-stage renal disease in the United States and Europe.5,6 The magnitude of the problem of diabetic nephropathy in type 2 diabetes mellitus is observable in the growing number of diabetic patients with end-stage renal disease.7 Progressive glomerulosclerosis associated with
arterial hypertension and proteinuria is strongly causative of renal failure and mortality in these patients.8 In the general population, antihypertensive treatment reduces the incidence of stroke and myocardial infarction, particularly in elderly people.9 In hypertensive patients with type 2 diabetes mellitus, proven evidence of the benefits of blood pressure lowering has been scarce until recently.10 Lowering blood pressure decreases albuminuria in type 2 diabetes mellitus and may decrease the risk of end-stage renal or of cardiac disease.3,11 Controlled trials tend to underestimate the “true” effects of blood pressure–lowering therapy. One reason is the frequent cross-over between control and treatment groups.12 More important, however, is the issue that the selection of patients according to the inclusion criteria of a controlled study design does not reflect the heterogeneous population of a general practice.13 The pivotal value of prospective, double-blind clinical studies is well estab-
Received July 20, 2000. Accepted December 5, 2000. From the Department of Internal Medicine, University of ErlangenNu¨rnberg, Nu¨rnberg, Germany.
Address correspondence and reprint requests to Roland E. Schmieder, MD, Department of Medicine IV, University of Erlangen-Nu¨rnberg, Breslauerstr 12, Krankenhaus Nu¨rnberg-Su¨d, 90471 Nu¨rnberg, Germany.
0895-7061/01/$20.00 PII S0895-7061(01)01300-0
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–July 2001–VOL. 14, NO. 7, PART 1
lished to analyze the effects of treatment strategies, but it remains unclear whether the conclusions drawn from these well controlled clinical studies subsequently hold true in the setting of general practitioners. For example, in double blind prospective studies, only a minority of patients screened for inclusion are finally entered into the study due to numerous inclusion and exclusion criteria (eg, in the STOP trial, 1627 patients were included, but 4668 had to be screened for the study and 3041 subjects were excluded).14,15 Thus, it cannot be assumed a priori that the results of prospective, double-blind clinical studies can be transferred to most of the patients seen by general practitioners. This problem becomes even worse if one takes into account that the growing number of evidence-based guidelines to be observed by general practitioners are often derived from the results of controlled trials without properly addressing the limitations of prospective randomized, double-blind clinical studies. Recently, Messerli et al pointed out that there is a distinct difference between the “healthy” elderly population with hypertension enrolled in various studies and even the normotensive elderly population with respect to the incidence of comorbid conditions in the latter.16 Hence, it is apparent that most of the clinical trials in the elderly are not dealing with patients who are representative of the general elderly population with hypertension. In the current outcome study, we tested the hypothesis whether the heterogeneous, nonselected population of hypertensive patients with type 2 diabetes mellitus, with and without nephropathy, who are seen by general practitioners will profit from treatment with an ACE inhibitor with respect to their cardiovascular, renal, and metabolic complications.
Patients and Methods We studied hypertensive patients with type 2 diabetes mellitus, without and with nephropathy. Patients had been recruited to this survey study by general practitioners throughout the Federal Republic of Germany who were asked to include patients ⬎18 years. A total of 2504 patients with arterial hypertension and type 2 diabetes mellitus were recruited, as they met the study’s entry criteria (diastolic blood pressure ⬎ 95 mm Hg and ⬍ 115 mm Hg, and fasting plasma glucose concentration ⬎ 6 mmol/L). No further inclusion criteria were applied. Because we were interested in studying an unselected group of patients as part of the usual population treated by German general practitioners, the outcome survey was prospective but unblinded, without any randomization, and no further explicit exclusion criteria were applicable. As soon as the doctor’s decision was made that a particular patient could benefit from a treatment with the ACE inhibitor cilazapril, the patient was eligible for the study. The inclusion period lasted 12 months. Individual pa-
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tients were followed-up for another 12 months. A longer period was not feasible, as the open design of the study caused a steep and substantial loss to follow-up after this period. Of the 2504 patients included, 2176 patients had type 2 diabetes mellitus and lack of renal involvement. Of these patients, 531 were lost to follow-up before the end of the survey. Of the remaining 328 hypertensive patients with type 2 diabetes mellitus and nephropathy, 71 patient records could not be completed. Patients with serum creatinine ⬎ 1.3 mg/dL or proteinuria were included in this subgroup of patients with nephropathy. Accompanying diseases and treatments for the remaining patients were routinely noted. The median duration of arterial hypertension and accompanying diseases were noted when patients were enrolled. Only patients with complete records were included in the final analysis. Treatment Protocol Cilazapril was usually started at a dose of 1 mg daily and could be titrated up to 2.5 mg daily in hypertensive patients with type 2 diabetes mellitus. Other antihypertensive agents were not discontinued; instead, cilazapril was added to achieve blood pressure control to ⬍ 140/90 mm Hg. In cases in which patients already received an ACE inhibitor, the drug was switched to cilazapril. Clinic Visits Patients visited study clinics every 3 months, to a total of 12 months. At each visit, patients, blood pressure, heart rate, body weight, and blood glucose concentration were measured with routine methods. Changes in accompanying diseases and medication were assessed. Symptoms including any drug side effects and clinical events were noted. Blood Pressure Measurements Blood pressure was measured by a trained clinician while the patient was sitting and had rested for 5 min, according to World Health Organization recommendations. The average of the two consecutive readings 5 min apart was used in the study. Clinical Examination At entry to the prospective type 2 diabetes mellitus survey and subsequently every 3 months, all patients had a routine clinical examination, including follow-up of edema formation. Furthermore, cardiovascular fitness and well-being was assessed with a set of standard questions concerning shortness of breath while climbing stairs, vigorous walking, or walking at a normal pace. No further diagnostic procedures were performed unless warranted by special events at the physician’s discretion.
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Laboratory Investigations In line with the main purpose of our study, only routine laboratory tests were used. Serum creatinine, blood glucose, and plasma HbA1c were assessed at every visit. Proteinuria and glucosuria were recorded in a semiquantitative manner with dipsticks, a method recommended to establish the diagnosis of early nephropathy in type 2 diabetes mellitus. Clinical End Points Although no exclusion criteria were used, end points were given as follows: 1) increases in serum creatinine ⬎ 50% during follow up; 2) side effects of the ACE inhibitors, such as severe cough or angioneurotic edema; or 3) death. Statistical Analysis Analysis consisted of descriptive evaluation calculating mean, standard deviation (SD), geometric mean (1 SD interval), or median (interquartile range), as well as minimum and maximum values for the respective parameters. Ordinal data were assessed by their distribution. Two main criteria for response were used for analysis of blood pressure responses: 1) diastolic blood pressure ⬍ 90 mm Hg, or 2) difference from inclusion pressure of 10 mm Hg. Serious adverse events were classified according to individual reports or organ classes. Incidences were described by 95% confidence intervals using multinomial and binomial distribution. Data were analyzed with Wilcoxon or 2 tests for comparisons if appropriate.
Results Demography and Follow-Up A total of 2504 hypertensive patients with arterial hypertension and type 2 diabetes mellitus were included in our study. Of this group, 328 patients had a serum creatinine ⬎ 1.3 mg/dL or proteinuria and were included in the subgroup of hypertensive patients with type 2 diabetes mellitus and nephropathy. Further demographic details are given in Table 1. In the group of patients without renal disease, 531 patients were lost to follow-up. In the group with nephropathy, 71 patients were lost to follow-up (eg, they no longer visited the physicians who enrolled them into the outcome survey, for whatever reasons). Of the patients that could be followed-up for the whole survey period of 12 months, drug-related cough occurred in 8.2% of patients. In an additional 0.4% of this population, angioneurotic edema was diagnosed. These latter patients and 4% of the patients with cough had to be switched back to other antihypertensive drugs. The main medical problems to be taken care of related to pre-existing cardiovascular disease, mainly coronary heart disease and congestive heart failure. In patients with type 2 diabetes mellitus with nephropathy, the ACE inhibitor caused a ⬎ 50% increase in baseline serum creatinine in only 2 patients, and increases
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Table 1. Demographic data on patients with type 2 diabetes mellitus and hypertension* Normal Kidney Function Mean ⫾ SD Number Age (y) Male/female(%) Median Known duration of hypertension (y) Known duration of diabetes (y) Known duration of nephropathy (y)
Nephropathy
2176 62.7 ⫾ 10 44/56
531 65.7 ⫾ 10 43/47
6
5.3
7.2
4.8 2.8
* No significant differences could be detected between the groups.
in ⬎ 0.2 mg/dL were seen in 19%. In patients with type 2 diabetes mellitus without nephropathy, treatment with the ACE inhibitor did not cause a 50% increase in baseline serum creatinine in any of the patients. In contrast, 9% exhibited a nonsignificant decline in renal function within the first 6 months. In all, 0.7% of the patients with type 2 diabetes mellitus (n ⫽ 18) in the outcome survey died, mainly as a consequence of heart disease. None of the deaths were judged by the review board to be related to the ACE inhibitor. Control of Blood Pressure Mean systolic/diastolic blood pressure was 169 ⫾ 12/97 ⫾ 9 mm Hg in patients without nephropathy at the beginning of the study and 144 ⫾ 16/83 ⫾ 11 mm Hg at the last visit. The respective values for patients with renal involvement were 170 ⫾ 12/96 ⫾ 11 mm Hg v 143 ⫾ 13/82 ⫾ 5 mm Hg at the end of the outcome survey. Fig. 1A and 1B as well as Fig. 2A and 2B display a stratified time course for systolic and diastolic blood pressure in patients both with and without diabetic nephropathy. Although most patients had diastolic blood pressure values ⬍ 140/90 mm Hg, 11% of the patients had still diastolic blood pressure ⬎ 95 mm Hg. The primary study goal (control of diastolic blood pressure ⱕ 90 mm Hg) was achieved in 56.4% without and 53.3% with diabetic nephropathy at the end of the study. Of the remaining patients, 44% had a drop in diastolic blood pressure of ⱖ 10 mm Hg, thus fulfilling the second main response criterion. Renal Function and Proteinuria The mean serum creatinine on inclusion was 2.1 ⫾ 1.6 mg/dL for patients with nephropathy and 1.0 ⫾ 0.2 mg/dL for patients without renal involvement. Serum creatinine improved in 26% of patients with nephropathy and in 12% of patients without concomitant renal disease. The mean serum creatinine at the last study visit was 1.7 ⫾ 1.4
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FIG. 1. Stratified time course of the development of diastolic blood pressure (DBP) in patients with type 2 diabetes and normal kidney function (A) and diabetic nephropathy (B). At the end of the outcome survey the vast majority of the patients exhibited a diastolic blood pressure below 85 mm Hg.
FIG. 2. Stratified time course of the development of systolic blood pressure (SBP) in patients with type 2 diabetes and normal kidney function (A) and diabetic nephropathy (B). At the end of the outcome survey the vast majority of the patients exhibited a systolic blood pressure between 140 –160 mm Hg.
mg/dL for patients with nephropathy (P ⬍ .05 before versus after medication) and 1.0 ⫾ 0.1 mg/dL for patients without renal involvement. Fig. 3 displays the time course of renal function stratified according to serum creatinine in patients with diabetic nephropathy. Clearly, the antihypertensive treatment with cilazapril led to a decrease of proteinuria in patients with diabetic nephropathy (P ⬍ .05) (see Table 2). Hence, despite some cases with progression toward renal failure, overall, patients with renal involvement did benefit from treatment with the ACE inhibitor.
values had significantly improved to 131 ⫾ 40 mg/dL and 134 ⫾ 40 mg/dL, respectively (P ⬍ .05). Values for HbA1c were 8.2% ⫾ 2.6% in patients with nephropathy and 7.8% ⫾ 1.7% in the group without renal involvement. At the end of the study, these values had slightly improved to 8.0% ⫾ 2.7% and 7.2% ⫾ 2.6%, respectively (P ⬍ .05). Hence, in general, the metabolic control improved in patients with type 2 diabetes mellitus.
Metabolic Follow-Up and Type 2 Diabetes Mellitus Body mass index was 28.3 ⫾ 4 kg/m2 at the beginning and 27.2 ⫾ 4 kg/m2 at the end of the study, taking into account all of the patients. It therefore did not change significantly. No differences between patients with and without nephropathy could be detected. Blood glucose levels were 165 ⫾ 57 mg/dL in patients with nephropathy and 158 ⫾ 51 mg/dL in the group without renal involvement. At the end of the study, these
FIG. 3. Stratified time course of the development of serum SCrea (serum creatinine) in patients with type 2 diabetes and nephropathy. At the end of the outcome survey an increased number of the patients exhibited a serum creatinine below 1,2 mg/dL.
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Table 2. Proteinuria in patients with hypertension and type 2 diabetes mellitus with diabetic nephropathy Proteinuria
Initial Visit (%)
Last Visit (%)
0 ⫹ ⫹⫹ ⫹⫹⫹
17.9 80.8 0.7 0.6
36.5* 63.0* 0.5 0
* P ⬍ .05. FIG. 4. Stratified time course of the development of excertion dyspnea in patients with type 2 diabetes. Already after 6 months all patients showed improved physical fitness as assessed with the help of the 2 test.
Edema Formation and Fitness Clinical evidence of edema in all patients declined at the end of the study (P ⬍ .05) (Table 3). The decreasing incidence of edema formation suggests an improved overall cardiovascular status. Similarly, cardiovascular fitness also improved (Fig. 4). Hence, cardiovascular fitness was favorably influenced in these patients, suggesting an improvement in quality of life.
Discussion Our outcome survey, carried out with the help of German general practitioners, analyzed the efficacy of ACE inhibition in patients with type 2 diabetes mellitus and arterial hypertension, either with or without diabetic nephropathy. According to our study design, no further inclusion or exclusion criteria were applied. Our results indicate that the beneficial effects of ACE inhibition seen in doubleblind, prospective, controlled studies extend to unselected patients with type 2 diabetes mellitus. The lack of exclusion criteria and randomization imply that the results of our outcome survey could only be interpreted subsequent to and in light of controlled clinical trials, the putative shortcomings of which, for decision making in general practice, are that they underestimate the heterogeneity of an outpatient population.12,13 Furthermore, in contrast to controlled trials, no concomitant diseases influenced the eligibility of a patient to participate in this study. In all, 328 patients in this group had a serum creatinine ⬎ 1.2 mg/dL or proteinuria and were therefore
Table 3. Edema formation in patients with hypertension and type 2 diabetes mellitus with and without diabetic nephropathy Edema
Initial Visit
Last Visit
Normal kidney function (%) Nephropathy (%)
43.9 52.9
12.4* 16.0*
* P ⬍ .05.
included in the subgroup of hypertensive patients with type 2 diabetes mellitus and nephropathy. Because the blood pressure lowering potential of ACE inhibitors is established beyond doubt,17,18 it is important to ask whether these drugs have advantages for patients with diabetes mellitus, arterial hypertension, and, eventually, diabetic nephropathy. In a large controlled multicenter trial by the UK Prospective Diabetes Group in Great Britain, blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications.2,3 Captopril and atenolol reduced blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg, respectively, with a similar proportion of patients requiring three or more antihypertensive treatments. This study provided no evidence that either drug had any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used. The Hypertension Optimal Treatment (HOT) study showed that lowering the diastolic blood pressure to 82.6 mm Hg was especially beneficial for patients with arterial hypertension and diabetes mellitus.19 In the HOT trial, felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen, to achieve the required blood pressure level. Both studies stress the fact that substantial blood pressure reduction may be especially important for diabetic patients with arterial hypertension. In the Ramipril Efficacy in Nephropathy study trial, ACE inhibition proved to be effective and superior to other drugs in treating nondiabetic nephropathy with proteinuria and hypertension.20 With respect to type 1 diabetes mellitus, Lewis et al reported the beneficial effects of captopril on diabetic nephropathy and blood pressure control.21 The Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency trial suggested that ACE inhibition might be useful in the treatment of a variety of diseases with hypertension and nephropathy, including type 2 diabetes mellitus.22 However, the number of patients with type 2 diabetes mellitus included in this trial was relatively small. In conclusion, current evidence from controlled
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trials suggests that ACE inhibitors might be important antihypertensive agents in the treatment of type 2 diabetes mellitus with renal involvement, although data are still incomplete and inconclusive in this group of diabetic patients.11 The results of our outcome survey confirm and extend the data of the above-mentioned controlled trials. After 1 year of treatment with the ACE inhibitor cilazapril, regardless of previous history and blood pressure medication, the majority of patients included exhibited blood pressure values in the range of 140 to 160 mm Hg systolic and ⬍ 85 mm Hg diastolic. At the beginning of the surveillance period, the majority of patients exhibited blood pressure values of 160 to 180 mm Hg systolic and 95 to 105 mm Hg diastolic. Hence, diastolic blood pressure was lowered sufficiently, whereas systolic blood pressure was still too high, if we apply the lessons learned from controlled clinical trials to our outcome survey.2,3,19 –21 The effects of the ACE inhibitor treatment were beneficial for renal function in our patients. In the group with diabetic nephropathy, serum creatinine levels improved significantly and proteinuria decreased, both markers indicating a less severe degree of diabetic nephropathy. The fact that blood pressure was lowered to a more favorable range with respect to end-organ damage suggests that the patients had good compliance without the close monitoring seen in controlled trials, or that they were well instructed about the beneficial effects of treatment of high blood pressure on their health and quality of life. Apparently, in our survey population, the benefit from the treatment was seen as compensatory for any side effects of the medication, as the blood pressure lowering effect of the therapy in the majority of patients suggests a continuous adherence to the prescribed medication.23 The use of ACE inhibitors has been associated with increased insulin sensitivity in diabetic patients.24 These results could explain why long-term cilazapril therapy improved glucose metabolism in hypertensive patients with impaired glucose tolerance.25 However, tight blood pressure control in patients with arterial hypertension and type 2 diabetes mellitus itself achieved a clinically important reduction in the complications related to diabetes mellitus.3 We observed an improvement of the metabolic situation in our outcome survey. This might be due to several factors besides the influence on ACE inhibitors on insulin sensitivity: an improved cardiovascular fitness also as a consequence of ACE inhibition,26 and a subsequent increase in quality of life are likely to influence the patient’s lifestyle in various respects.23 The improvement of HbA1c in the study population might be due to the fact that doctors got better at managing diabetes, because they became more attentive while enrolling patients into the outcome survey. In summary, in the reported outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively low-
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ered blood pressure, which was associated with improved glucose metabolism and beneficial effects on cardiac function and diabetic nephropathy. The open study design proved to be useful to assess the effects of the drugs prescribed in the mostly unselected patient population in general practice. The treatment proved to be safe, without severe systemic or renal side effects.
Acknowledgment This study was supported by a grant-in-aid from Merck KGA, Darmstadt, Germany.
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Muggeo M: Accelerated complications in type 2 diabetes mellitus: the need for greater awareness and earlier detection. Diabet Med 1998;15(suppl 4):S60 –S62 UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 39. Br Med J 1998;317:713– 720. 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 1998;317:703–713. Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batle D: Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. The Collaborative Study Group. Nephrol Dial Transplant 1998;13:2547–2552. National Institute of Diabetes, Digestive and Kidney Diseases. United States renal data system (USRDS);Chapter II: Incidence and prevalence of endstage renal disease (1998). http://www.med. umich.edu/usrds/chapters/ch02/ch02.html. Jacobs C, Selwood NH: Renal replacement therapy for end-stage renal failure in France: current status and evolutive trends over the last decade. Am J Kidney Dis 1995;25:188 –195. Chukwuma CS: Type II diabetic nephropathy in perspective. J Diabetes Complications 1995;9:55– 67. Hsueh WA, Anderson PW: Systemic hypertension and the reninangiotensin system in diabetic vascular complications. Am J Cardiol 1993;72:14H–21H. Gorelick PB, Sacco RL, Smith DB, Alberts M, Mustone-Alexander L, Ra der D, Ross JL, Raps E, Ozer MN, Brass LM, Malone ME, Goldberg S, Booss J, Hanley DF, Toole JF, Greengold NJ, Rhew DC: Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA 1999;281:1112–1120. Ismail N, Becker B, Strzelczyk P, Ritz E: Renal disease and hypertension in non-insulin-dependent diabetes mellitus. Kidney Int 1999;55:1–28. Ritz E: Nephropathy in type 2 diabetes. J Intern Med 1999;245: 111–126. World Health Organization–International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens 1999;17:151–183. Linjer E, Hansson L: Underestimation of the true benefits of antihypertensive treatment: an assessment of some important sources of error (editorial). J Hypertens 1997;15:221–225. Dahlof B, Hansson L, Lindholm L, Schersten B, Wester PO: STOPHypertension—preliminary communication from the pilot study of the Swedish Trial in Old Patients with Hypertension. J Hypertens 1987;5(suppl):S607–S610 Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO: Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Lancet 1991;338:1281–1285.
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16. Messerli FH, Grodzicki T, Feng Z: Antihypertensive therapy in the elderly: evidence-based guidelines and reality. Arch Intern Med 1999;159:1621–1622. 17. Parmley WW: Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am J Med 1998;105:27S–31S. 18. Borghi C, Ambrosioni E: Evidence-based medicine and ACE inhibition. J Cardiovasc Pharmacol 1998;32(suppl 2):S24 –S35. 19. Hansson L, Zanchetti A, Carruthers SG, 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. 20. GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857– 1863. 21. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropa-
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2001; 14:672– 678
Outcome Survey in Unselected Hypertensive Patients With Type 2 Diabetes Mellitus: Effects of ACE Inhibition Roland Veelken, Christian Delles, Karl F. Hilgers, and Roland E. Schmieder Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63 ⫾ 10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24 ⫾ 17 mm Hg and diastolic blood pressure by 12 ⫾ 11 mm Hg. An increase in serum creatinine (⬎ 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P ⬍ .05). Serum creatinine
T
decreased more frequently in patients with renal involvement than in those without (26% ⫾ 4% v 12% ⫾ 3.8%; P ⬍ .05). Overall renal function in patients with diabetic nephropathy (n ⫽ 318) improved (2.1 ⫾ 1.6 mg/dL v 1.7 ⫾ 1.4 mg/dL; P ⬍ .05). The frequency of proteinuria was lower after 1 year than at baseline (62% ⫾ 9% v 82% ⫾ 8%; P ⬍ .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P ⬍ .01). Scores for edema formation and exertional dyspnea improved as well (P ⬍ .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function. Am J Hypertens 2001;14:672– 678 © 2001 American Journal of Hypertension, Ltd. Key Words: ACE inhibitors, type 2 diabetes mellitus, therapy, outcome survey.
ype 2 diabetes mellitus and arterial hypertension are commonly associated conditions, both of which carry an increased risk of cardiovascular and renal disease.1 The prevalence of arterial hypertension in type 2 diabetes mellitus is higher than that in the general population. At the age of 45 years, approximately 40% of patients with type 2 diabetes mellitus are hypertensive, with the proportion increasing to 60% by the age of 75 years.2 Arterial hypertension clearly increases the already high risk of cardiovascular disease associated with type 2 diabetes mellitus, and is also a risk factor for the development of microalbuminuria and retinopathy.2– 4 Diabetic nephropathy is the most common single cause of end-stage renal disease in the United States and Europe.5,6 The magnitude of the problem of diabetic nephropathy in type 2 diabetes mellitus is observable in the growing number of diabetic patients with end-stage renal disease.7 Progressive glomerulosclerosis associated with
arterial hypertension and proteinuria is strongly causative of renal failure and mortality in these patients.8 In the general population, antihypertensive treatment reduces the incidence of stroke and myocardial infarction, particularly in elderly people.9 In hypertensive patients with type 2 diabetes mellitus, proven evidence of the benefits of blood pressure lowering has been scarce until recently.10 Lowering blood pressure decreases albuminuria in type 2 diabetes mellitus and may decrease the risk of end-stage renal or of cardiac disease.3,11 Controlled trials tend to underestimate the “true” effects of blood pressure–lowering therapy. One reason is the frequent cross-over between control and treatment groups.12 More important, however, is the issue that the selection of patients according to the inclusion criteria of a controlled study design does not reflect the heterogeneous population of a general practice.13 The pivotal value of prospective, double-blind clinical studies is well estab-
Received July 20, 2000. Accepted December 5, 2000. From the Department of Internal Medicine, University of ErlangenNu¨rnberg, Nu¨rnberg, Germany.
Address correspondence and reprint requests to Roland E. Schmieder, MD, Department of Medicine IV, University of Erlangen-Nu¨rnberg, Breslauerstr 12, Krankenhaus Nu¨rnberg-Su¨d, 90471 Nu¨rnberg, Germany.
0895-7061/01/$20.00 PII S0895-7061(01)01300-0
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–July 2001–VOL. 14, NO. 7, PART 1
lished to analyze the effects of treatment strategies, but it remains unclear whether the conclusions drawn from these well controlled clinical studies subsequently hold true in the setting of general practitioners. For example, in double blind prospective studies, only a minority of patients screened for inclusion are finally entered into the study due to numerous inclusion and exclusion criteria (eg, in the STOP trial, 1627 patients were included, but 4668 had to be screened for the study and 3041 subjects were excluded).14,15 Thus, it cannot be assumed a priori that the results of prospective, double-blind clinical studies can be transferred to most of the patients seen by general practitioners. This problem becomes even worse if one takes into account that the growing number of evidence-based guidelines to be observed by general practitioners are often derived from the results of controlled trials without properly addressing the limitations of prospective randomized, double-blind clinical studies. Recently, Messerli et al pointed out that there is a distinct difference between the “healthy” elderly population with hypertension enrolled in various studies and even the normotensive elderly population with respect to the incidence of comorbid conditions in the latter.16 Hence, it is apparent that most of the clinical trials in the elderly are not dealing with patients who are representative of the general elderly population with hypertension. In the current outcome study, we tested the hypothesis whether the heterogeneous, nonselected population of hypertensive patients with type 2 diabetes mellitus, with and without nephropathy, who are seen by general practitioners will profit from treatment with an ACE inhibitor with respect to their cardiovascular, renal, and metabolic complications.
Patients and Methods We studied hypertensive patients with type 2 diabetes mellitus, without and with nephropathy. Patients had been recruited to this survey study by general practitioners throughout the Federal Republic of Germany who were asked to include patients ⬎18 years. A total of 2504 patients with arterial hypertension and type 2 diabetes mellitus were recruited, as they met the study’s entry criteria (diastolic blood pressure ⬎ 95 mm Hg and ⬍ 115 mm Hg, and fasting plasma glucose concentration ⬎ 6 mmol/L). No further inclusion criteria were applied. Because we were interested in studying an unselected group of patients as part of the usual population treated by German general practitioners, the outcome survey was prospective but unblinded, without any randomization, and no further explicit exclusion criteria were applicable. As soon as the doctor’s decision was made that a particular patient could benefit from a treatment with the ACE inhibitor cilazapril, the patient was eligible for the study. The inclusion period lasted 12 months. Individual pa-
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tients were followed-up for another 12 months. A longer period was not feasible, as the open design of the study caused a steep and substantial loss to follow-up after this period. Of the 2504 patients included, 2176 patients had type 2 diabetes mellitus and lack of renal involvement. Of these patients, 531 were lost to follow-up before the end of the survey. Of the remaining 328 hypertensive patients with type 2 diabetes mellitus and nephropathy, 71 patient records could not be completed. Patients with serum creatinine ⬎ 1.3 mg/dL or proteinuria were included in this subgroup of patients with nephropathy. Accompanying diseases and treatments for the remaining patients were routinely noted. The median duration of arterial hypertension and accompanying diseases were noted when patients were enrolled. Only patients with complete records were included in the final analysis. Treatment Protocol Cilazapril was usually started at a dose of 1 mg daily and could be titrated up to 2.5 mg daily in hypertensive patients with type 2 diabetes mellitus. Other antihypertensive agents were not discontinued; instead, cilazapril was added to achieve blood pressure control to ⬍ 140/90 mm Hg. In cases in which patients already received an ACE inhibitor, the drug was switched to cilazapril. Clinic Visits Patients visited study clinics every 3 months, to a total of 12 months. At each visit, patients, blood pressure, heart rate, body weight, and blood glucose concentration were measured with routine methods. Changes in accompanying diseases and medication were assessed. Symptoms including any drug side effects and clinical events were noted. Blood Pressure Measurements Blood pressure was measured by a trained clinician while the patient was sitting and had rested for 5 min, according to World Health Organization recommendations. The average of the two consecutive readings 5 min apart was used in the study. Clinical Examination At entry to the prospective type 2 diabetes mellitus survey and subsequently every 3 months, all patients had a routine clinical examination, including follow-up of edema formation. Furthermore, cardiovascular fitness and well-being was assessed with a set of standard questions concerning shortness of breath while climbing stairs, vigorous walking, or walking at a normal pace. No further diagnostic procedures were performed unless warranted by special events at the physician’s discretion.
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Laboratory Investigations In line with the main purpose of our study, only routine laboratory tests were used. Serum creatinine, blood glucose, and plasma HbA1c were assessed at every visit. Proteinuria and glucosuria were recorded in a semiquantitative manner with dipsticks, a method recommended to establish the diagnosis of early nephropathy in type 2 diabetes mellitus. Clinical End Points Although no exclusion criteria were used, end points were given as follows: 1) increases in serum creatinine ⬎ 50% during follow up; 2) side effects of the ACE inhibitors, such as severe cough or angioneurotic edema; or 3) death. Statistical Analysis Analysis consisted of descriptive evaluation calculating mean, standard deviation (SD), geometric mean (1 SD interval), or median (interquartile range), as well as minimum and maximum values for the respective parameters. Ordinal data were assessed by their distribution. Two main criteria for response were used for analysis of blood pressure responses: 1) diastolic blood pressure ⬍ 90 mm Hg, or 2) difference from inclusion pressure of 10 mm Hg. Serious adverse events were classified according to individual reports or organ classes. Incidences were described by 95% confidence intervals using multinomial and binomial distribution. Data were analyzed with Wilcoxon or 2 tests for comparisons if appropriate.
Results Demography and Follow-Up A total of 2504 hypertensive patients with arterial hypertension and type 2 diabetes mellitus were included in our study. Of this group, 328 patients had a serum creatinine ⬎ 1.3 mg/dL or proteinuria and were included in the subgroup of hypertensive patients with type 2 diabetes mellitus and nephropathy. Further demographic details are given in Table 1. In the group of patients without renal disease, 531 patients were lost to follow-up. In the group with nephropathy, 71 patients were lost to follow-up (eg, they no longer visited the physicians who enrolled them into the outcome survey, for whatever reasons). Of the patients that could be followed-up for the whole survey period of 12 months, drug-related cough occurred in 8.2% of patients. In an additional 0.4% of this population, angioneurotic edema was diagnosed. These latter patients and 4% of the patients with cough had to be switched back to other antihypertensive drugs. The main medical problems to be taken care of related to pre-existing cardiovascular disease, mainly coronary heart disease and congestive heart failure. In patients with type 2 diabetes mellitus with nephropathy, the ACE inhibitor caused a ⬎ 50% increase in baseline serum creatinine in only 2 patients, and increases
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Table 1. Demographic data on patients with type 2 diabetes mellitus and hypertension* Normal Kidney Function Mean ⫾ SD Number Age (y) Male/female(%) Median Known duration of hypertension (y) Known duration of diabetes (y) Known duration of nephropathy (y)
Nephropathy
2176 62.7 ⫾ 10 44/56
531 65.7 ⫾ 10 43/47
6
5.3
7.2
4.8 2.8
* No significant differences could be detected between the groups.
in ⬎ 0.2 mg/dL were seen in 19%. In patients with type 2 diabetes mellitus without nephropathy, treatment with the ACE inhibitor did not cause a 50% increase in baseline serum creatinine in any of the patients. In contrast, 9% exhibited a nonsignificant decline in renal function within the first 6 months. In all, 0.7% of the patients with type 2 diabetes mellitus (n ⫽ 18) in the outcome survey died, mainly as a consequence of heart disease. None of the deaths were judged by the review board to be related to the ACE inhibitor. Control of Blood Pressure Mean systolic/diastolic blood pressure was 169 ⫾ 12/97 ⫾ 9 mm Hg in patients without nephropathy at the beginning of the study and 144 ⫾ 16/83 ⫾ 11 mm Hg at the last visit. The respective values for patients with renal involvement were 170 ⫾ 12/96 ⫾ 11 mm Hg v 143 ⫾ 13/82 ⫾ 5 mm Hg at the end of the outcome survey. Fig. 1A and 1B as well as Fig. 2A and 2B display a stratified time course for systolic and diastolic blood pressure in patients both with and without diabetic nephropathy. Although most patients had diastolic blood pressure values ⬍ 140/90 mm Hg, 11% of the patients had still diastolic blood pressure ⬎ 95 mm Hg. The primary study goal (control of diastolic blood pressure ⱕ 90 mm Hg) was achieved in 56.4% without and 53.3% with diabetic nephropathy at the end of the study. Of the remaining patients, 44% had a drop in diastolic blood pressure of ⱖ 10 mm Hg, thus fulfilling the second main response criterion. Renal Function and Proteinuria The mean serum creatinine on inclusion was 2.1 ⫾ 1.6 mg/dL for patients with nephropathy and 1.0 ⫾ 0.2 mg/dL for patients without renal involvement. Serum creatinine improved in 26% of patients with nephropathy and in 12% of patients without concomitant renal disease. The mean serum creatinine at the last study visit was 1.7 ⫾ 1.4
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FIG. 1. Stratified time course of the development of diastolic blood pressure (DBP) in patients with type 2 diabetes and normal kidney function (A) and diabetic nephropathy (B). At the end of the outcome survey the vast majority of the patients exhibited a diastolic blood pressure below 85 mm Hg.
FIG. 2. Stratified time course of the development of systolic blood pressure (SBP) in patients with type 2 diabetes and normal kidney function (A) and diabetic nephropathy (B). At the end of the outcome survey the vast majority of the patients exhibited a systolic blood pressure between 140 –160 mm Hg.
mg/dL for patients with nephropathy (P ⬍ .05 before versus after medication) and 1.0 ⫾ 0.1 mg/dL for patients without renal involvement. Fig. 3 displays the time course of renal function stratified according to serum creatinine in patients with diabetic nephropathy. Clearly, the antihypertensive treatment with cilazapril led to a decrease of proteinuria in patients with diabetic nephropathy (P ⬍ .05) (see Table 2). Hence, despite some cases with progression toward renal failure, overall, patients with renal involvement did benefit from treatment with the ACE inhibitor.
values had significantly improved to 131 ⫾ 40 mg/dL and 134 ⫾ 40 mg/dL, respectively (P ⬍ .05). Values for HbA1c were 8.2% ⫾ 2.6% in patients with nephropathy and 7.8% ⫾ 1.7% in the group without renal involvement. At the end of the study, these values had slightly improved to 8.0% ⫾ 2.7% and 7.2% ⫾ 2.6%, respectively (P ⬍ .05). Hence, in general, the metabolic control improved in patients with type 2 diabetes mellitus.
Metabolic Follow-Up and Type 2 Diabetes Mellitus Body mass index was 28.3 ⫾ 4 kg/m2 at the beginning and 27.2 ⫾ 4 kg/m2 at the end of the study, taking into account all of the patients. It therefore did not change significantly. No differences between patients with and without nephropathy could be detected. Blood glucose levels were 165 ⫾ 57 mg/dL in patients with nephropathy and 158 ⫾ 51 mg/dL in the group without renal involvement. At the end of the study, these
FIG. 3. Stratified time course of the development of serum SCrea (serum creatinine) in patients with type 2 diabetes and nephropathy. At the end of the outcome survey an increased number of the patients exhibited a serum creatinine below 1,2 mg/dL.
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Table 2. Proteinuria in patients with hypertension and type 2 diabetes mellitus with diabetic nephropathy Proteinuria
Initial Visit (%)
Last Visit (%)
0 ⫹ ⫹⫹ ⫹⫹⫹
17.9 80.8 0.7 0.6
36.5* 63.0* 0.5 0
* P ⬍ .05. FIG. 4. Stratified time course of the development of excertion dyspnea in patients with type 2 diabetes. Already after 6 months all patients showed improved physical fitness as assessed with the help of the 2 test.
Edema Formation and Fitness Clinical evidence of edema in all patients declined at the end of the study (P ⬍ .05) (Table 3). The decreasing incidence of edema formation suggests an improved overall cardiovascular status. Similarly, cardiovascular fitness also improved (Fig. 4). Hence, cardiovascular fitness was favorably influenced in these patients, suggesting an improvement in quality of life.
Discussion Our outcome survey, carried out with the help of German general practitioners, analyzed the efficacy of ACE inhibition in patients with type 2 diabetes mellitus and arterial hypertension, either with or without diabetic nephropathy. According to our study design, no further inclusion or exclusion criteria were applied. Our results indicate that the beneficial effects of ACE inhibition seen in doubleblind, prospective, controlled studies extend to unselected patients with type 2 diabetes mellitus. The lack of exclusion criteria and randomization imply that the results of our outcome survey could only be interpreted subsequent to and in light of controlled clinical trials, the putative shortcomings of which, for decision making in general practice, are that they underestimate the heterogeneity of an outpatient population.12,13 Furthermore, in contrast to controlled trials, no concomitant diseases influenced the eligibility of a patient to participate in this study. In all, 328 patients in this group had a serum creatinine ⬎ 1.2 mg/dL or proteinuria and were therefore
Table 3. Edema formation in patients with hypertension and type 2 diabetes mellitus with and without diabetic nephropathy Edema
Initial Visit
Last Visit
Normal kidney function (%) Nephropathy (%)
43.9 52.9
12.4* 16.0*
* P ⬍ .05.
included in the subgroup of hypertensive patients with type 2 diabetes mellitus and nephropathy. Because the blood pressure lowering potential of ACE inhibitors is established beyond doubt,17,18 it is important to ask whether these drugs have advantages for patients with diabetes mellitus, arterial hypertension, and, eventually, diabetic nephropathy. In a large controlled multicenter trial by the UK Prospective Diabetes Group in Great Britain, blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications.2,3 Captopril and atenolol reduced blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg, respectively, with a similar proportion of patients requiring three or more antihypertensive treatments. This study provided no evidence that either drug had any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used. The Hypertension Optimal Treatment (HOT) study showed that lowering the diastolic blood pressure to 82.6 mm Hg was especially beneficial for patients with arterial hypertension and diabetes mellitus.19 In the HOT trial, felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen, to achieve the required blood pressure level. Both studies stress the fact that substantial blood pressure reduction may be especially important for diabetic patients with arterial hypertension. In the Ramipril Efficacy in Nephropathy study trial, ACE inhibition proved to be effective and superior to other drugs in treating nondiabetic nephropathy with proteinuria and hypertension.20 With respect to type 1 diabetes mellitus, Lewis et al reported the beneficial effects of captopril on diabetic nephropathy and blood pressure control.21 The Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency trial suggested that ACE inhibition might be useful in the treatment of a variety of diseases with hypertension and nephropathy, including type 2 diabetes mellitus.22 However, the number of patients with type 2 diabetes mellitus included in this trial was relatively small. In conclusion, current evidence from controlled
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trials suggests that ACE inhibitors might be important antihypertensive agents in the treatment of type 2 diabetes mellitus with renal involvement, although data are still incomplete and inconclusive in this group of diabetic patients.11 The results of our outcome survey confirm and extend the data of the above-mentioned controlled trials. After 1 year of treatment with the ACE inhibitor cilazapril, regardless of previous history and blood pressure medication, the majority of patients included exhibited blood pressure values in the range of 140 to 160 mm Hg systolic and ⬍ 85 mm Hg diastolic. At the beginning of the surveillance period, the majority of patients exhibited blood pressure values of 160 to 180 mm Hg systolic and 95 to 105 mm Hg diastolic. Hence, diastolic blood pressure was lowered sufficiently, whereas systolic blood pressure was still too high, if we apply the lessons learned from controlled clinical trials to our outcome survey.2,3,19 –21 The effects of the ACE inhibitor treatment were beneficial for renal function in our patients. In the group with diabetic nephropathy, serum creatinine levels improved significantly and proteinuria decreased, both markers indicating a less severe degree of diabetic nephropathy. The fact that blood pressure was lowered to a more favorable range with respect to end-organ damage suggests that the patients had good compliance without the close monitoring seen in controlled trials, or that they were well instructed about the beneficial effects of treatment of high blood pressure on their health and quality of life. Apparently, in our survey population, the benefit from the treatment was seen as compensatory for any side effects of the medication, as the blood pressure lowering effect of the therapy in the majority of patients suggests a continuous adherence to the prescribed medication.23 The use of ACE inhibitors has been associated with increased insulin sensitivity in diabetic patients.24 These results could explain why long-term cilazapril therapy improved glucose metabolism in hypertensive patients with impaired glucose tolerance.25 However, tight blood pressure control in patients with arterial hypertension and type 2 diabetes mellitus itself achieved a clinically important reduction in the complications related to diabetes mellitus.3 We observed an improvement of the metabolic situation in our outcome survey. This might be due to several factors besides the influence on ACE inhibitors on insulin sensitivity: an improved cardiovascular fitness also as a consequence of ACE inhibition,26 and a subsequent increase in quality of life are likely to influence the patient’s lifestyle in various respects.23 The improvement of HbA1c in the study population might be due to the fact that doctors got better at managing diabetes, because they became more attentive while enrolling patients into the outcome survey. In summary, in the reported outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively low-
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ered blood pressure, which was associated with improved glucose metabolism and beneficial effects on cardiac function and diabetic nephropathy. The open study design proved to be useful to assess the effects of the drugs prescribed in the mostly unselected patient population in general practice. The treatment proved to be safe, without severe systemic or renal side effects.
Acknowledgment This study was supported by a grant-in-aid from Merck KGA, Darmstadt, Germany.
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