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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 3  |  Page : 512-518
The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy


1 Department of Internal Medicine, Faculty of Medicine, Atatürk University, Erzurum, Turkey
2 Department of Nephrology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
3 Department of Nephrology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
4 Department of Internal Medicine, Erzurum Regional Training and Research Hospital, Erzurum, Turkey

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Date of Web Publication13-May-2016
 

   Abstract 

Diabetic nephropathy (DN) is one of the most important causes of the end-stage renal failure and its prevalence is found to be increasing. The presence of hypertension and progressive proteinuria is among the important findings. In this study, the effects of double and triple combinations of trandolapril, telmisartan, and verapamil on proteinuria were investigated in diabetic patients with nephropathy. Seventy-eight patients (mean age: 56.11 ± 11.26 years; 47 females and 31 males) with overt proteinuria and DN were included in this study. The patients were divided into four groups: Group I (n: 18, trandolapril + telmisartan), Group II (n: 20, trando- lapril + verapamil), Group III (n: 20, trandolapril +telmisartan + verapamil), and Group IV (n: 20, telmisartan + verapamil). At the end of a three-month therapy, within and between group compa- risons were done about the effects of the use of double or triple drug combinations on proteinuria, glomerular filtration rate (GFR), electrolytes, serum albumin, low-density lipoprotein (LDL)- cholesterol, and HbA1C. There was no significant difference among groups in terms of age, gender, diabetes duration, body mass index, and retinopathy frequency. The decreases in protei- nuria and mean arterial blood pressure (MABP) were significant in all groups. The decrease in proteinuria was independent of the decrease in MABP [the reduction rate in proteinuria was 39% (P <0.001) in Group I, 37% (P <0.001) in Group II, 42% (P <0.001) in Group III, and 43% (P <0.001) in Group IV; the reduction rate in MABP was 10.6% (P <0.001) in Group I, 13.7% (P <0.001) in Group II, 17.5% (P <0.001) in Group III, and 15.4% (P <0.001) in Group IV]. Decrease in HbA1C (before and after treatment) was significant in Groups III and IV when com- pared to Groups I and II. Any adverse event, like hyperkalemia, was not observed. There was no significant difference among the groups in terms of GFR, LDL-cholesterol, albumin, and potassium. All the patients tolerated the drugs well. In conclusion, in patients with DN, both double or triple combinations of trandolapril, telmisartan and verapamil resulted in signi- ficant decreases in proteinuria and MABP. Triple combinations did not have any supe- riority over double combinations. Therefore, the suitable drug combinations may be chosen according to the clinical status of a patient.

How to cite this article:
Albayrak B, Çankaya E, Çetinkaya R, Cerrah S, Bilen Y. The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy. Saudi J Kidney Dis Transpl 2016;27:512-8

How to cite this URL:
Albayrak B, Çankaya E, Çetinkaya R, Cerrah S, Bilen Y. The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Sep 25];27:512-8. Available from: http://www.sjkdt.org/text.asp?2016/27/3/512/182385

   Introduction Top


Diabetic nephropathy (DN) is one of the most important causes of the end-stage renal failure (ESRF) and its prevalence has increased rapidly.[1]The incidence of DN is 30-50% in Type 1 diabetes and 10-15% in Type 2 dia- betes. However, Type 2 diabetes accounts for the vast majority of patients who are placed on a therapy for ESRF due to the fact that Type 2 diabetes accounts for 90% of all patients with diabetes.[2]

With the development of overt nephropathy, overt proteinuria also occurs in patients with both Type 1 and type 2 diabetes mellitus (DM) and it is one of the major causes of the acce- lerated progression of nephropathy. If protei- nuria cannot be circumvented and lasts for a long time in patients with DN, progression to ESRF is inevitable due to the glomerular and tubular injury caused by proteinuria. It is therefore necessary to prevent or at least mini- mize proteinuria in patients with DN. Many recent studies showed that angiotensin (AT) converting enzyme inhibitors (ACE inhibitors) and AT receptor blockers (ARBs), in addition to their blood-pressure-lowering effects, re- duced proteinuria and exerted renoprotective effects by decreasing intraglomerular pressure and through other effects. Recent studies have also suggested the combined use of ACE inhi- bitors and ARBs in order to reduce proteinuria in patients with DN. This combination the- rapy is based on the fact that ACE inhibitors cause incomplete inhibition of AT II produc- tion, and the main purpose of this therapy is to inhibit the effects of AT II produced by acces- sory pathways using ARBs.[3],[4]

As an important cause of ESRF, prevention or reduction of proteinuria in DN is particu- larly important for a better prognosis. Many recent studies showed that ACE inhibitors, ARBs, and nondihydropyridine (non-DHP) calcium channel blockers (CCBs) reduced pro- teinuria and exerted renoprotective effects by decreasing intraglomerular pressure and through other effects in addition to their blood-pressure- lowering effects.[5]

The aim of the present study was to compa- ratively evaluate renoprotective effects of dual and triple combinations of ACE inhibitors, ARBs, and non-DHP CCBs in diabetic the patients with overt nephropathy. Therefore, we attempted to find the ideal drug combination that could prevent development or slow down the progression of DN.


   Patients and Methods Top


A total of 78 volunteers with overt protei- nuria (above 300 mg/day/1.73 m[2] and aged between 18 and 75 years, who were admitted as an inpatients to the Department of Internal Medicine or treated as an outpatient at Atatürk University, Faculty of Medicine and diagnosed with Type 1 or Type 2 DM, were included in this study. The patients with an additional pro- blem apart from DM that could cause protei- nuria, secondary causes of hypertension other than DM, and the patients who received chro- nic renal replacement therapy and those who did not accept to participate in the study after being informed of the study were excluded.

The patients were divided into four groups: Group 1 received trandolapril 2 mg/day + telmisartan 80 mg/day, Group 2 received tran- dolapril 2 mg/day + verapamil 120 mg/day, Group 3 received trandolapril 2 mg/day + telmisartan 80 mg/day + verapamil 120 mg/ day, and Group 4 received telmisartan 80 mg/day + verapamil 120 mg/day [Table 1].
Table 1. Drug combinations according to groups

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During the course of the study, blood che- mistry, proteinuria (24 h urine collected) level, and mean arterial blood pressure (MABP) were obtained at 15 days and monthly there- after. Glomerular filtration rates (GFRs) of the participants were calculated based on 6-item MDRD (the modification of diet in renal disease) formula.

The effects of three-month course of therapy with antihypertensive drugs on proteinuria, MABP, GFR, electrolytes, serum albumin, low- density lipoprotein (LDL)-cholesterol, and HbA1C were evaluated with intragroup and intergroup comparisons.

Venous blood samples were collected in the morning after 10-12 h of fasting for the ana- lysis of blood glucose, blood urea nitrogen, creatinine, sodium, potassium, total protein, albumin, and LDL-cholesterol at biochemistry laboratory of our hospital, and all of these analyses were performed with Hitachi 717 autoanalyzer using spectrophotometric method. Proteinuria was assessed with 24 h urine col- lection method. Protein and creatinine levels were measured in spot urine sample using the same method. HbA1C was measured in all patients before and after therapy using high- performance liquid chromatography in Hi-auto A1C analyzer.

All drugs that could affect the efficiency of the study treatment and the use of albumin were avoided during the course of the treat- ment. The patients received a daily diet con- taining 0.8 g/kg/day protein and 100 mmol sodium. The blood pressure of the patients was measured after 15 min of rest in sitting posi- tion using ERKA blood pressure monitor and two subsequent measurements were obtained with 5 min intervals. The duration of DM and antidiabetic medications used by the patients were recorded. The presence and stage of reti- nopathy were determined by ophthalmoscopic examination after consultation by an ophthal- mologist.


   Statistical analysis Top


The results of the study were expressed as arithmetic mean and standard deviation. SPSS for Windows 11.5 software package was used in the analysis of the data. (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp). Nonparametric Wilcoxon rank test was used to calculate the intragroup differences separately for each parameter before and after the treat- ment. The relationship between the groups was analyzed using regression analysis, and non- parametric Kruskal-Wallis variance analysis was used to determine the differences in treat- ment outcomes between four groups. The Mann-Whitney U-test was used to evaluate treatment efficiency for parameters that yielded statistical significance. The level of statistical significance was set at P <0.05.


   Results Top


The demographic features of the study pa- tients are presented in [Table 2]. At the end of three months, proteinuria level was reduced from 3.27 ± 4.50 g/day to 1.98 ± 2.80 g/day in Group 1 (trandolapril + telmisartan), from 2.52 ± 2.55 g/day to 1.58 ± 1.71 g/day in Group 2 (trandolapril + verapamil), from 2.98 ± 2.79 g/day to 1.71 ± 1.79 g/day in Group 3, and from 3.88 ± 3.99 gr/day to 2.20 ± 2.24 g/day in Group 4. The reduction in proteinuria level was found to be statistically significant in all groups (P <0.001). Proteinuria levels before and after treatment are shown in [Figure 1].
Figure 1. Pretreatment and posttreatment proteinuria levels

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Table 2. Demographic properties of the patient groups

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Considering the reduction in the level of pro- teinuria at three months as an indication for treatment efficiency, all treatments resulted in a similar reduction in proteinuria level (Group 1, 39%; Group 2, 37%; and Group 3, 42%) and there was no statistically significant diffe- rence between the groups in terms of treatment efficiency (P = 0.974).

MABP was reduced from 118.11 ± 8.50 to 99.40 ± 9.65 mm Hg in Group 1, from 113.79 ± 11.36 to 98.12 ± 8.04 mm Hg in Group 2, from 128.46 ± 9.0 to 105.96 ± 8.76 mm Hg in Group 3, and from 116.79 ± 14.15 to 98.79 ± 7.81 mm Hg in Group 4. The reduction in MABP was found to be statistically significant in all groups (P <0.001).

Considering the decrease in MABP at three months as an indication for treatment effi- ciency, all treatments efficiently decreased MABP and there was no statistically signi- ficant difference between the groups in terms of treatment efficiency (P = 0.201). MABP values before and after treatment are shown in [Figure 2].
Figure 2. Pretreatment and posttreatment mean arterial blood pressure values

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The reduction in the level of proteinuria was evaluated if it was dependent on the decrease in MABP. The reduction in the level of proteinuria was found to be independent from the decrease in MABP in all groups (r = −0.32, P = 0.780, r = 0.40, P = 0.86, r = −0.216, P = 0.350, and r = 0.033, P = 0.890, respectively).

There was no statistically significant difference between the four groups in terms of GFRs before and after treatment. At three months, GFR was reduced from 59.15 ± 30.70 to 57.60 ± 28.60 mL/min in Group 1 (P = 0.586) and from 63.25 ± 30.24 to 58.71 ± 27.38 mL/min in Group 2 (P = 0.240). GFR was reduced from 54.17 ± 27.64 to 52.46 ± 24.61 mL/min in Group 3 at three months (P = 0.866). In Group 4, GFR was reduced from 56.57 ± 29.22 to 55.29 ± 28.51 mL/min at three months (P = 0.881) [Table 3].
Table 3. Differences between before and after therapy among proteinuria, GFR, mean arterial blood
pressure, creatinine, glucose, albumin, low-density lipoprotein, cholesterol, and HbA1c levels of groups


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Serum potassium levels were within normal ranges before and after treatment in all groups. None of the patients developed hyperpotas- semia that would require interruption of the treatment. In Group 1, mean serum potassium level increased from 4.57 ± 0.50 mEq/L to 4.61 ± 0.48 mEq/L, and the difference was found to be statistically significant (P = 0.690).In Group 2, mean serum potassium level decreased from 4.60 ± 0.45 to 4.58 ± 0.46 mEq/L, and the difference was not statistically significant (P = 0.793). Similarly, in Group 3 that received triple-drug combination, the mean serum po- tassium level decreased from 4.58 ± 0.44 to 4.49 ± 0.53 mEq/L, and the difference was not statistically significant (P = 0.342). In Group 4, the mean serum potassium level increased from 4.62 ± 0.45 to 4.70 ± 0.45 mEq/L, and the difference was not statistically significant (P = 0.154) [Table 3].

HbA1C, serum albumin, and LDL-choles- terol levels of the patients before and after treatment are present in [Table 3].


   Discussion Top


DN is a microvascular complication of DM and it causes a significant health problem due to the development of ESRD in an increasing number of patients. The treatment options such as strict blood pressure and blood glucose con- trol are effective means of therapy in preven- ting the development and progression of DN.[6],[7]Proteinuria is tubulotoxic and directly contri- butes to renal damage. Thus, proteinuria is the most important risk factor in impairing renal function.[8]After the development of overt nephropathy, significant correlation occurs between the elevated blood pressure and progression of nephropathy.[9]Both systolic and diastolic hypertension cause progression of nephropathy.[10]

Microalbuminuria is an early indicator of DN in the patients with DM and it must be taken into account in the first place in preventing the development of nephropathy. Many studies have shown that ACE inhibitors reduce micro- albuminuria and progression of renal disease.[11]Proteinuria is a sensitive and independent marker for cardiovascular disease and the progression of nephropathy.

Combination therapy with ACE inhibitors and ARBs has been shown to provide superior renal protection compared to monotherapy in patients with DN associated with Type 2 DM. On the other hand, few comparative studies have demonstrated pharmacological efficiency of combination therapies involving CCBs and ARBs and/or ACE inhibitors and ARBs.[12],[13]

In BENEDICT study, ACE inhibitor (trando- lapril) and nonhydropyridine calcium channel blocker (verapamil) were administered as a combination therapy or monotherapy in hyper- tensive patients with Type 2 DM and normal urine albumin excretion. Similar to our fin- dings, combination therapy reduced overt pro- teinuria, the drugs were well-tolerated, and no serious adverse events were observed.[14]In a meta-analysis of ten clinical studies with a primary end-point of 24 h urine albumin excretion that used combination of ACE inhi- bitors and ARBs, ACE inhibitor + ARB com- bination was found to be superior in reducing 24 h urine albumin excretion as compared to monotherapy with ACE inhibitors.[15]

The insulin resistance is often associated with increased oxidative stress. The combined use of CCBs and ARBs in Type 2 diabetic mice prevented insulin resistance by reducing super- oxide production in the muscles, and the combination therapy was found to be more effective compared to the monotherapy in the treatment of insulin resistance.[16]In the present study, combinations of verapamil with telmi- sartan (Groups 3 and 4) were associated with a significant reduction in HbA1C levels when compared to other groups. The observation of a more significant reduction with dual combi- nations of telmisartan and verapamil is a striking finding, and these results are consis- tent with the study conducted on mice.

Conclusion

The treatment of hypertension and protei- nuria is one of the basic steps in preventing the development and progression of DN, which is one of the most important causes of chronic renal disease and associated ESRD that has become a worldwide public health concern. ACE inhibitors, ARBs, and CCBs are among the first line medications to be used in anti- hypertensive and anti-proteinuric treatment. This was the first clinical study to evaluate the combinations of ACE inhibitors, ARBs, and non-DHP CCBs. The dual combination of these three drugs provides an effective decline in the blood pressure and proteinuria. The effi- ciency was similar across these three groups. Addition of the third medication to the dual therapy do not provide additional benefits in the control of hypertension and proteinuria. The findings of the present study suggest that one of the dual combinations of the above- mentioned three drugs can be preferred in the treatment of overt proteinuria in DN consi- dering individual patient characteristics, and further clinical studies are warranted on this subject.

 
   References Top

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2.
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Satman Ý. Epidemiology of Diabetes Mellitus. In: Imamoðlu ª, editor. Diabetes Mellitus 2006. Ýstanbul: Elif Ofset; 2006. p. 27-52.  Back to cited text no. 3
    
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Akalýn A. Hypertension and Diabetes Mellitus. In: Ýmamoðlu ª, editor. Diabetes Mellitus 2006. Ýstanbul: Elif Ofset; 2006. p. 457-65.  Back to cited text no. 4
    
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Eberhard R. Diabetic nephropathy. In: Feehally J, Floege J, Johnson RJ, eds. Clinical Nephro- logy. Philadelphia: Mosby; 2007. p. 353-73.  Back to cited text no. 5
    
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Cetinkaya R, Odabas AR, Selcuk Y. Anti- proteinuric effects of combination therapy with enalapril and losartan in patients with nephro- pathy due to type 2 diabetes. Int J Clin Pract 2004;58:432-5.  Back to cited text no. 8
    
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Bayliss G, Weinrauch LA, D'Elia JA. Resistant hypertension in diabetes mellitus. Curr Diab Rep 2014;14:516.  Back to cited text no. 9
    
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Sengul AM, Altuntas Y, Kürklü A, Aydin L. Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbumi- nuria and hypertension. Diabetes Res Clin Pract 2006;71:210-9.  Back to cited text no. 11
    
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Kuriyama S, Tomonari H, Tokudome G, et al. Antiproteinuric effects of combined antihyper- tensive therapies in patients with overt type 2 diabetic nephropathy. Hypertens Res 2002;25: 849-55.  Back to cited text no. 12
    
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PROCOPA Study Group. Dissociation bet- ween blood pressure reduction and fall in pro- teinuria in primary renal disease: A rando- mized double-blind trial. J Hypertens 2002; 20:729-37.  Back to cited text no. 13
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Remuzzi G, Macia M, Ruggenenti P. Preven- tion and treatment of diabetic renal disease in type 2 diabetes: The BENEDICT study. J Am Soc Nephrol 2006;17 4 Suppl 2:S90-7.  Back to cited text no. 14
    
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Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: A meta- analysis. Diabet Med 2007;24:486-93.  Back to cited text no. 15
    
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Iwai M, Li HS, Chen R, et al. Calcium channel blocker azelnidipine reduces glucose intole- rance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan. J Pharmacol Exp Ther 2006;319:1081-7.  Back to cited text no. 16
    

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Correspondence Address:
Erdem Çankaya
Department of Nephrology, Faculty of Medicine, Atatürk University, 25240 Erzurum
Turkey
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DOI: 10.4103/1319-2442.182385

PMID: 27215243

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