The Effect of Trandolapril and Its Fixed- Dose Combination with Verapamil on Proteinuria in Normotensive Adults with Type 2 Diabetes

Pathophysiology/Complications ORIGINAL ARTICLE

The Effect of Trandolapril and Its Fixed- Dose Combination With Verapamil on Proteinuria in Normotensive Adults With Type 2 Diabetes

1,2 ALBERTO FRANCISCO RUBIO-GUERRA, MD, LETICIA RODRIGUEZ-LOPEZ, MD to cardiovascular mortality, and in Mex- 1,2 1,2 FACP JOSE JUAN LOZANO-NUEVO, MD ico, proteinuria has a prevalence of 9.3% 2 1 ADALBERTO ARCEO-NAVARRO, MD CARLOS TREVINO˜ GOMEZ-HARPER, MD 1,2 in type 2 diabetic normotensive patients GERMAN VARGAS-AYALA, MD (3). In turn, reduction of proteinuria or delay in its progression may delay the on- set of end-stage renal disease. Recent clinical studies have shown that several therapeutic strategies are OBJECTIVE — To compare the effect of fixed-dose trandolapril-verapamil (FDTV) with that of trandolapril on proteinuria in normotensive, type 2 diabetic patients. available to delay the progression of diabetic nephropathy: rigorous glycemic RESEARCH DESIGN AND METHODS — A total of 60 normotensive, type 2 diabetic control, aggressive antihypertensive con- patients with 24-h proteinuria Ͼ300 mg were randomly assigned to two groups for open-label trol to achieve blood pressure values treatment. One group received 2 mg trandolapril/180 mg verapamil FDTV once daily; the other Ͻ130/80 mmHg, and blockade of the re- group received 2 mg trandolapril once daily. Study drugs were administered for 6 months in nin-angiotensin system (1). both groups. Creatinine clearance and 24-h urinary protein excretion were measured at the To decrease morbidity and mortality beginning and the end of the study. Patients were evaluated monthly for blood pressure, fasting due to diabetic nephropathy, early detec- blood glucose level, heart rate, and adverse events. Statistical analysis was performed using ANOVA. tion of patients at risk is critical, as is the application of all necessary therapeutic RESULTS — Both groups experienced a statistically significant (P Ͻ 0.005) mean decrease in measures. The 2003 European Society of mean proteinuria from baseline: FDTV ([mean Ϯ SD] 1,200 Ϯ 200 to 540 Ϯ 79 mg; P Ͻ 0.001) Hypertension–European Society of Car- and trandolapril (1,105 Ϯ 212 to 750.9 Ϯ 134 mg; P Ͻ 0.005). A significantly greater reduction diology guidelines for the management of from baseline in proteinuria was observed in the FDTV group compared with the trandolapril arterial hypertension recommend antihy- group. Patients who received trandolapril experienced a statistically significant (P Ͻ 0.05) pertensive therapy with a blocker of the decrease in mean creatinine clearance (91.1 Ϯ 3.4 to 75.3 Ϯ 3 ml/min; P Ͻ 0.05) compared with Ϯ Ϯ Ͼ renin-angiotensin system in type 2 dia- patients who received FDTV (88.3 3.6 to 82.9 3.5 ml/min; P 0.05). Final fasting blood betic patients who have microalbumin- glucose was significantly lower in the FDTV group (139 Ϯ 19) compared with the trandolapril group (154 Ϯ 22; P Ͻ 0.001). No significant differences were observed between the two groups uria, irrespective of blood pressure values in mean baseline or final measurements of blood pressure, mean heart rate, or frequency of (4). However, enough evidence exists adverse events. from clinical trials that both angiotensin II receptor blockers and ACE inhibitors are CONCLUSIONS — Our results suggest that FDTV is more effective than trandolapril in useful in reducing proteinuria in hyper- reducing proteinuria in normotensive, type 2 diabetic patients. This effect on proteinuria is not tensive and normotensive patients with related with blood pressure reduction. type 2 diabetes (4–6). It has been shown that the combina- Diabetes Care 27:1688–1691, 2004 tion of an ACE inhibitor and verapamil produces greater decreases in proteinuria and smaller declines in renal function he prevalence of diabetic nephropa- disease and increases the mortality rate in compared with ACE inhibitor therapy ϳ thy is 30% in patients with type 2 those patients (1,2). In diabetic patients, alone in hypertensive type 2 diabetic pa- T diabetes after 20–30 years. It is the proteinuria levels are related not only to tients with nephropathy. And in those hy- most common cause of end-stage renal the progression of nephropathy but also pertensive type 2 diabetic patients who ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● did not respond to monotherapy with an ACE inhibitor (7,8). However, we could From the 1Hypertension Clinic, Hospital General de Ticomań, Health Ministry, Mexico City, Mexico; and the 2Ticomań Group for Hypertension Research, Mexico DF, Mexico. not distinguish whether this response was Address correspondence and reprint requests to Alberto Francisco Rubio-Guerra, MD, Hospital General due to the reduction in blood pressure or de Ticoman, Plan de San Luis S/N Esq Bandera, Mexico DF CP 07330, Mexico. E-mail: [email protected]. a direct nephroprotective effect of the Received for publication 16 October 2003 and accepted in revised form 26 March 2004. drug combination. The nephroprotective Abbreviations: FDTV, fixed-dose trandolapril-verapamil; GFR, glomerular filtration rate. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion effect of fixed-dose trandolapril-verapamil factors for many substances. (FDTV) has been demonstrated in exper- © 2004 by the American Diabetes Association. imental animal studies, in which the

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Table 1—Baseline patient characteristics

Characteristic Trandolapril/verapamil Trandolapril P Age (years) 52.5 Ϯ 7.6 55 Ϯ 3.1 NS Sex (men/women) 9/21 8/22 NS Duration of diabetes (years) 8.8 Ϯ 6 8.7 Ϯ 8NS Weight (kg) 69.7 Ϯ 15 67.8 Ϯ 11.5 NS BMI (kg/m2) 28.8 Ϯ 5.6 28.8 Ϯ 4.5 NS Basal blood pressure (mmHg) 123 Ϯ 11/76 Ϯ4 122 Ϯ 10/78 Ϯ 6NS Basal fasting blood glucose level (mg/dl) 158 164 NS Basal heart rate (bpm) 73 71 NS Basal proteinuria (mg/24 hr) 1,200 Ϯ 200 1,105 Ϯ 212 NS Basal GFR (ml/min) 88.3 Ϯ 3.6 91.1 Ϯ 3.4 NS Data are n or means Ϯ SD.

FDTV combination prevented the expan- Patients with any of the following di- ml/min; P Ͼ 0.05). In patients who re- sion of the mesangial matrix and glomer- agnoses were excluded from the study: ceived trandolapril, proteinuria de- ulosclerosis (8). decompensated diabetes (fasting blood creased from 1,105 Ϯ 212 to 750.9 Ϯ This study was conducted to compare glucose level Ͼ250 mg/dl); type 1 or sec- 134 mg (P Ͻ 0.005), and GFR decreased the effect of FDTV with that of trandola- ondary diabetes; heart, hepatic, or renal from 91.1 Ϯ 3.4 to 75.3 Ϯ 3 ml/min (P Ͻ pril on proteinuria and glomerular filtra- failure; evidence of valvular heart disease; 0.05). We found a statistically greater re- tion rate (GFR) in normotensive, type 2 heart block or cardiac arrhythmia; sec- duction (P Ͻ 0.005) from baseline in pro- diabetic patients with nephropathy. ondary hypertension; acute coronary syn- teinuria in patients who received FDTV drome or cerebrovascular disease 6 compared with patients who received RESEARCH DESIGN AND months before initiation of the study; his- trandolapril. We also found a statistically METHODS — A total of 60 normoten- tory of abuse of alcohol and/or psycho- greater reduction (P Ͻ 0.05) in GFR in sive patients with type 2 diabetes (Ͼ12 tropic drugs. patients who received trandolapril com- months’ duration and with 24-h protein- Patients were not permitted to use pared with patients who received FDTV. uria Ͼ300 mg) were evenly randomized any of the following drugs: any type of No significant differences were found into two groups. All study patients were antihypertensive, tricyclic antidepressive, between the two study groups in baseline referred from primary care clinics and and/or monoamine oxidase inhibitor or or final blood pressure, initial glycemia, were not receiving antihypertensive ther- any other drug for research purposes or heart rate. Although baseline fasting apy. One group received 2 mg trandola- within the 30 days of initiation of the blood glucose level was comparable be- pril/180 mg verapamil FDTV daily; the study. tween groups, a significantly greater re- other group received 2 mg trandolapril Postmicturition ultrasonography was duction in final fasting blood glucose level daily. Study drugs were administered for performed before initiation of treatment was observed in patients who received 6 months in both groups. to detect urine retention from a neuro- FDTV (Table 2). Patients were evaluated monthly dur- genic bladder, which might have altered Compliance with treatment was ing the 6-month period. At each evalua- the results of proteinuria and creatinine Ͼ90%, i.e., the number of capsules re- tion, blood pressure was recorded in clearance. Patients with Ͼ100 ml of resid- turned by most patients on each visit was triplicate with a mercurial sphygmoma- ual urine as measured by ultrasonography Ͻ10% of those dispensed. nometer in the sitting position after a were excluded from the study. Three patients in each group reported 5-min rest and at 3-min intervals. An av- Data are presented as a means Ϯ SD; dizziness, and two patients had headache. erage of the three measurements was re- statistical analysis was performed with All adverse events were transient and recorded. Heart rate and fasting glycemia ANOVA. P Ͻ 0.05 was considered solved spontaneously, and treatment was (glycose oxidase) also were recorded at significant. not interrupted. each evaluation. At the beginning and end The study was conducted with the ap- of the study, 24-h albuminuria (nephe- proval of the Research and Medical Ethics CONCLUSIONS — Our study dem- lometry) was measured; creatinine clear- Committee of our hospital, in accordance onstrated that combination therapy tran- ance was also measured at these times. with the Helsinki Declaration. Partici- dolapril-verapamil is more effective than Each patient collected 24-h urine speci- pants gave their informed, written con- monotherapy with trandolapril for the mens, and the total volume was delivered sent before inclusion in the study control of proteinuria in normotensive, to the laboratory. protocol. type 2 diabetic patients with diabetic ne- To achieve the best possible compli- phropathy. Because mean blood pressure ance, a telegram was sent to each patient RESULTS — The basic features of the changed very little in both study groups, 24 h after a missed visit. We dispensed 30 patients are described in Table 1. the aforementioned effects would not capsules at each visit, and the count of In patients who received FDTV, pro- have been related to reduction in blood capsules returned by the patient was doc- teinuria decreased from 1,200 Ϯ 200 to pressure. However, no ambulatory regis- umented as a measure of compliance with 540 Ϯ 79 mg (P Ͻ 0.001), whereas GFR ters of blood pressure were obtained; the study drug. did not change (88.3 Ϯ 3.6 to 82.9 Ϯ 3.5 therefore, a nondipping condition or out-

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Table 2—Comparative results

Trandolapril/ Parameter verapamil Trandolapril P Final blood pressure (mmHg) 122 Ϯ 9/75 Ϯ 4 122 Ϯ 8/75 Ϯ 5NS Final heart rate (bpm) 72 70 NS Final fasting blood glucose level (mg/dl) 139 154 Ͻ0.01 Final weight (kg) 69.5 Ϯ 15 67.7 Ϯ 11.5 NS BMI (kg/m2) 28.8 Ϯ 5.6 28.8 Ϯ 4.5 NS Final proteinuria (mg/24 hr) 540 Ϯ 79 750 Ϯ 134 Ͻ0.005 Mean change from basal in proteinuria (mg/24 hr) 660 355 Ͻ0.005 Final GFR (ml/min) 82.9 Ϯ 3.5 75.3 Ϯ 3 Ͻ0.05 Mean change from basal in GRF (ml/min) 5.4 15.8 Ͻ0.05 Data are n or means Ϯ SD. of-office changes not registered but in- sive drugs such as hydralazine or hydro- observed to be better (13). Indeed, the duced by verapamil may affect results. chlorothiazide (11). In addition, higher proteinuria level in the trandola- Further research is required to deter- nondihydropyridinic calcium antago- pril group may be due, in part, to the poor mine whether FDTV has additional bene- nists, unlike dihydropyridines, promote glycemic control in those patients. fits on renal function in normotensive, vasodilatation of the efferent arteriole, Patients with type 2 diabetes are at type 2 diabetic patients. Moreover, be- which renders them more effective to re- high risk for ischemic heart disease, espe- cause type 2 diabetes is risk equivalent to duce proteinuria (7,8). These actions of cially in the presence of albuminuria, coronary artery disease, research is also verapamil may account for the greater re- which is an indicator of endothelial dys- required to determine whether FDTV of- duction in proteinuria in the FDTV function. Both hyperglycemia and albu- fers better outcomes than monotherapy group, independent of blood pressure ef- minuria should be treated aggressively with ACE inhibitors in prevention of cor- fect. Therefore, FDTV may confer to these because both conditions are associated onary artery disease. patients a greater renoprotective effect with increased risk of macrovascular dis- Several hemodynamic and humoral than monotherapy with an ACE inhibitor ease and microvascular complications factors are involved in the pathophysiol- at the doses of the drugs studied. Higher (14). ogy of diabetic nephropathy, and most re- doses of an ACE inhibitor might lead to Our results suggest that FDTV is sult from angiotensin II activity: increased the same outcomes; this possibility re- more effective than trandolapril alone in intraglomerular pressure, vasoconstric- quires future study. reducing proteinuria in normotensive, tion of efferent arteriole, increased glo- In our study, heart rate did not type 2 diabetic patients. FDTV seems to merular membrane permeability for change in patients who took FDTV. We be a safe and effective option for manage- macromolecules, and mesangial cell pro- have no explanation for this, because ve- ment of patients with type 2 diabetes, liferation. ACE inhibitors can beneficially rapamil usually reduces this parameter. when they did not respond to mono- block all these effects (9). Overproduc- Similarly, in one of our previous studies therapy, or in diabetic normotensive pa- tion of endothelin-1 by the renal endothe- in hypertensive, type 2 diabetic patients, tients with proteinuria Ͼ1 g/dl. lium is a frequent occurrence in type 2 FDTV did not reduce heart rate (7). diabetic patients. Endothelin, a potent va- Although the final albumin levels in soconstrictor, has fibrotic effects on the all of our study patients were Ͻ50% of the Acknowledgments— For this study, tran- kidney and favors mesangial proliferation initial values in the FDTV group, further dolapril and trandolapril-verapamil were do- nated by Abbott Laboratories de Mexico. (10), as those actions are blocked by cal- reductions would likely be beneficial. cium antagonists (7,10). Then, the benefit This might be accomplished with longer of the trandolapril-verapamil combina- antihypertensive treatment as well as im- References tion in those patients may be due to the proved glycemic control. 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