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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2000  |  Volume : 11  |  Issue : 4  |  Page : 531-536
The Place for Calcium Channel Blockers in the Treatment of Hypertension in Patients with Diabetes Mellitus


1 Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Rush University Hypertension Center, Rush Presbyterian St. Luke’s Medical Center, Chicago, USA

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How to cite this article:
Tarif N, Bakris G. The Place for Calcium Channel Blockers in the Treatment of Hypertension in Patients with Diabetes Mellitus. Saudi J Kidney Dis Transpl 2000;11:531-6

How to cite this URL:
Tarif N, Bakris G. The Place for Calcium Channel Blockers in the Treatment of Hypertension in Patients with Diabetes Mellitus. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2019 Nov 18];11:531-6. Available from: http://www.sjkdt.org/text.asp?2000/11/4/531/36638
Calcium channel blockers (CCBs) are excellent anti-hypertensive agents which have, however, come into question recently regarding their efficacy or lack of it, in reducing cardiovascular (CV) events. Specifically, the dihydropyridine (DHP) CCBs [nifedipine, amlodipine, felodipine, etc] have failed to reduce CV risk, in spite of adequate blood pressure reduction, in clinical trials where they were used without angiotensin converting enzyme (ACE) inhibitors in a diabetic population. [1] Conversely, when DHPCCBs were used in concert with agents that reduce sympathetic neural output such as ACE inhibitors or beta-blockers, they reduced CV risk. This is exemplified by the results of the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), Hypertension Optimal Treatment (HOT) and Systolic Hypertension in Europe (SYST-Eur) trials. [2],[3],[4] In the PRAISE and HOT trials, 100 and 73% of the patients respectively, received an ACE inhibitor and/or beta-blocker along with a DHPCCB, while in the SYST-Eur trial only 43% received an ACE inhibitor in addition to a DHPCCB. However, in this latter trial the DHPCCB was administered at bedtime, thus, taking advantage of blood pressure control during the peak period for CV events, which is between six in the morning until noon. [2]

These observations suggest that CCBs should be considered as agents that yield excellent blood pressure control but at the expense of not fully reducing CV risk. Since this is the most common cause of death among people with renal disease, the role of CCBs in such high-risk patients should be reviewed. This editorial serves as an overview of this area and serves to put these agents into proper perspective with regard to renal disease progression, specifi­cally in the largest growing population of patients with renal disease i.e., those with diabetes.

Type-2 diabetes, earlier called as non-insulin dependent diabetes, is more common than, and differs in renal presentation from, Type-1 or insulin dependent diabetes. [5],[6] Specifically, people with Type-2 diabetes have a higher prevalence of hypertension; 50% more compared to normal controls and 20-30% more than the Type-1 diabetics. [5],[6] Presence of nephropathy increases the likelihood of hypertension; 80% of patients with nephropathy developed hypertension compared to 70% of those with no evidence of nephropathy. [5] In the recently concluded UKPDS study, out of 5102 patients, 39 % had hypertension and 22% had proteinuria at the time of diagnosis. [7]

There exists a complex relationship between blood pressure and glomerular injury which is dependent on the delicate balance of auto-regulation, level of blood pressure control and intra-renal structural changes that result from diabetes. Hypertension leads to rapid decline in renal function in these patients compared to normotensive individuals. [5] Furthermore, control of hyper­tension in such patients is not easy to achieve and requires multiple anti­hypertensive medications in more than half the people. [8] In the UKPDS study, almost one third of patients required at least three medications to control the blood pressure to a mean value of 144/82 mm Hg. [7]

Effective blood pressure control to a much lower level is required to help in attenuating the decline in renal function in diabetic patients. In the captopril trial on people with Type-1 diabetes, a 48% risk reduction in doubling of serum creatinine was demonstrated in the ACE inhibitor group. [9] However, the difference was not totally explainable by differences in blood pressure alone. In a sub-group analysis of study patients with proteinuria > 3.5 grams who had remission of proteinuria to < 1.0 gram per day, a significantly lower mean systolic pressure was demonstrated when compared with the non-remission group. [10] The Modi­fication of Dietary Protein and Renal Disease [MDRD] trial also showed that patients with proteinuria of >1.0 gram per day who were randomized to a mean arterial pressure of < 92 mm Hg, corresponding to < 125/75 mm Hg, had a slower decline in renal function. [11]

Many other investigators have also observed this relationship between slowing the rate of decline of renal function and blood pressure control to low levels. [8] Walker observed a relationship between the level of blood pressure and deterioration of renal function. [12] A systolic blood pressure of < 140 mm Hg did not cause any further decline in renal function compared to a level > 140 mm Hg. A review of studies extending for more than three years in Type-2 diabetics having nephropathy and hypertension clearly showed an on going risk with the level of blood pressure; decline in glomerular filtration rate (GFR) doubled with the blood pressure levels > 140/90 mm Hg. [8] Lastly, a blood pressure level of < 130/85 mm Hg has been recom­mended for those with diabetes and/or renal disease by all guidelines around the world. [13],[14]

The type of anti-hypertensive agents used to achieve the blood pressure goal may also have an impact on altering both the rate of decline in renal function as well as CV events. Parving et al have shown in diabetic nephropathy, attenuation of decline in GFR by 77% with the use of beta-blockers and diuretics when the blood pressure was effectively controlled to 130/84 mm Hg. [15]

In a study of patients with Type-2 diabetes by our group, we found that, while all groups showed a slowed rate of decline of renal function, those who were randomized to an ACE inhibitor or non- DHPCCB, i.e., verapamil or diltiazem, had slower rates of decline after a six-year follow-up. [16] In the UKPDS study, atenolol was also shown to reduce the risk of developing micro­albuminuria; however, this group was assigned to the tight blood pressure control category in a fashion comparable to the ACE inhibitor group. [17] However, in this latter trial, side effects were much higher in the beta-blocker group. These data, taken together with the results of both the Heart Outcome in Prevention of Events (HOPE) trial and the recently published renal outcomes from the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, demonstrate that ACE inhibitors can reduce progression of renal disease and markedly reduce CV events with fewer side-effects than beta blockers. [18],[19]

Analysis of these studies has shown that blood pressure control alone may not be enough to mitigate against the development of glomerulosclerosis; an anti-proteinuric effect is necessary. [8] This beneficial anti­proteinuric effect has been shown clearly in patients with Type-1 diabetes. ACE inhibitors due to their anti-hypertensive and anti-proteinuric effects naturally are the drugs of choice for Type-2 diabetic nephro­pathy with hypertension. Side effects associated with ACE inhibitors such as cough, worsening of renal function, hyper­kalemia or the presence of bilateral renal artery stenosis may portend its use. In such cases, most often the second line of medications is the CCBs.

In experimental animals, CCBs have been shown to retard renal hypertrophy, attenuating the effects of growth factors and decreasing the mesangial entrapment of macromolecules. These and the anti­hypertensive effects are beneficial in reducing the progression of renal disease. [20]

Studies have shown that differences exist among different CCBs. Short or long acting DHPCCBs have not been found beneficial compared to the non-DHPCCBs, the latter having a beneficial effect on preservation of renal morphology and blunting the rise in proteinuria. [20],[21] These results may not only be true in animal models of renal insuf­ficiency and diabetes, but also in patients with such problems.

Differences between Type-1 and Type-2 diabetes may exist not only in clinical presentation, but also in the response to anti-hypertensive agents. ACE inhibitor use in Type-1 diabetics has shown improve­ment in proteinuria and pore-size selectivity whereas a recent study by Ruggenneti et al failed to show such an effect in Type-2 diabetics. [22] Perindopril, an ACE inhibitor, was compared to the DHPCCB, nitrendipine in 12 patients over a period of 10 weeks. Both these drugs failed to show an improvement in pore-size as evaluated by dextran clearance and proteinuria. All these patients had overt nephropathy and the level of renal dysfunction was comparable to similar studies in Type-1 diabetics. Ruggenenti et al, thus concluded that even the response to ACE inhibitors in Type-2 diabetes is different from that seen in people with Type-1 diabetes. [22] A few other studies using ACE inhibitors have shown similar findings. [23] Thus, it may not be as simple to use ACE inhibitors in Type-2 diabetics based on the results of studies in Type-1 diabetics.

DHPCCBs have yielded variable results in experimental studies in terms of preventing glomerulosclerosis. Overall, these studies have shown a complete loss of renal auto-regulation with these drugs which is thought to be detrimental in transmitting the vascular pressure to the glomerular capillary wall, thereby worsening sclerosis. [21] Non­DHPCCBs on the other hand, have shown lesser effect on renal auto-regulation and possess other beneficial effects such as decreasing the mesangial expansion and glomerular permeability. [21] In a long-term clinical study involving 21 Type-2 diabetics with nephropathy, randomized to nifedipine slow-release formulation [n=10], or slow­release diltiazem [n=11], a difference in glomerular permeability was demonstrated. Both groups had equal blood pressure control and no effect on the GFR was noted. Significant differences were noted between the two groups however, in that the diltiazem group showed a decrease in proteinuria with improvement in size selectivity. [24] In another study by Nielson et al using an animal model of Type-1 diabetes i.e. streptozocin induced diabetes, nitrendipine failed to show a decline in proteinuria in hypertensive rats even though the blood pressure was adequately controlled. [25] In yet another animal study, Griffin et al used diltiazem, verapamil or felodipine to treat hyper­tension in the 1 and 5/6th renal ablation model. [21] Diltiazem was not as effective as felodipine or verapamil in controlling blood pressure. Complete loss of auto-regulation, however, was documented only in felodipine treated animals. Glomerulo­sclerosis was not statistically different among the groups, although a trend towards more glomerulosclerosis was obvious in felodipine treated rats. Further, it was noted that there was a significant positive correlation between the level of blood pressure and glomerulosclerosis. Separate experiments in similar animal models of renal insufficiency have also demonstrated failure to preserve renal function with amlodipine. [26] However, in these same studies, concomitant use of an ACE inhibitor preserved renal function at similar levels of blood pressure control.

Maki et al, in a meta-analysis of 14 randomized controlled trials of diabetic and non-diabetic renal disease, found that ACE inhibitors and non-DHPCCBs reduced the proteinuria and caused a relative improvement in renal function [0.18 ml/min/month] whereas DHPCCBs were seen to further worsen the renal function. [27] Smith et al in a randomized crossover study, compared the effects of extended release diltiazem and extended release nifedipine. Despite similar blood pressure control, proteinuria decreased by threefold in the diltiazem group. [29]

In summary, Type-2 diabetics have a higher incidence of hypertension that may lead to nephropathy and its progression. Tighter blood pressure control along with control of glycemia is the mainstay of therapy in attenuating the progression of nephropathy. ACE inhibitors have intrinsic beneficial effects in this regard and non­DHPCCBs are the second line of medications along with diuretics in patients intolerant to the ACE inhibitors. DHPCCBs and other anti-hypertensive medications, in most of the studies, have not been effective in slowing renal disease progression. However, a tighter control of blood pressure may over ride the detrimental effects of these agents. [28] Also, patients with diabetes mellitus may require multiple anti-hypertensives for adequate blood pressure control. In a multi­centered trial of patients with Type-2 diabetes, we have shown that the combination of an ACE inhibitor and a non-DHPCCB was more effective than either agent alone in preventing renal injury even when blood pressure was similarly controlled. [29] Thus, the combination of an ACE inhibitor and a non-DHPCCB may be a better initial choice to achieve the blood pressure goal of < 130/85 mm Hg, since these agents have additive beneficial effects than either single agent alone.

 
   References Top

1.Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338:645-52.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hyper­tension in Europe Trial Investigators. N Engl J Med 1999;340(9):677-84.  Back to cited text no. 2    
3.Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998;351:1755-62.  Back to cited text no. 3    
4.Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335:1107-14.  Back to cited text no. 4    
5.Ismail N, Becker B, Strzelczyk P, Ritz E. Renal disease and hypertension in non­Insulin-dependent diabetes mellitus. Kidney Int 1999;55:1-28.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Ritz E, Orth SR. Nephropathy in patients with Type 2 diabetes mellitus. N Engl J Med 1999;341(15):1127-33.  Back to cited text no. 6    
7.UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular compli­cations in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Sheinfeld GR, Bakris GL. Benefits of combination angiotensin converting enzyme inhibitor and calcium antagonist therapy for diabetic patients. Am J Hypertens 1999;12:80S-5S.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Lewis EJ, Hunsicker LG, Bain RP, Rhode RD. The effect of angiotensin-converting­enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62.  Back to cited text no. 9    
10.Hebert LA, Bain RP, Verme D, et al. Remission of nephrotic range proteinuria in Type 1 diabetes. Collaborative Study Group. Kidney Int 1994;46:1688-93.  Back to cited text no. 10    
11.Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995;123:754-62.  Back to cited text no. 11    
12.Walker WG. Hypertension-related renal injury: a major contributor to end stage renal disease. Am J Kidney Dis 1993; 22:164-73.  Back to cited text no. 12  [PUBMED]  
13.The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure [JNC VI]. Arch Intern Med 1997;157:2413-46.  Back to cited text no. 13    
14.1999 World Health Organization­International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens 1999;17(2):151-83.  Back to cited text no. 14    
15.Parving HH, Smidt UM, Hommel E, et al. Effective anti-hypertensive treatment post­pones renal insufficiency in diabetic nephro­pathy. Am J Kidney Dis 1993;22:188-95.  Back to cited text no. 15  [PUBMED]  
16.Bakris GL, Copley JB, Vicknair N, et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM-associated nephropathy. Kidney Int 1996;50(5):1641-50.  Back to cited text no. 16    
17.UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713-20.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and micro­vascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub-study. Lancet 2000; 355:253-9.  Back to cited text no. 18    
19.Estacio RO, Gifford N, Jeffers BW, Schrier RW. Effect of blood pressure control on diabetic microvascular comp-lications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23(Suppl 2):B54-B64.  Back to cited text no. 19  [PUBMED]  
20.Epstein M. Calcium antagonists and renal disease. Kidney Int 1998;54:1771-84.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Griffin KA, Picken MM, Bakris GL, Bidani AK. Class differences in the effect of calcium channel blockers in the rat remnant kidney model. Kidney Int 1999;55:1849-60.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Ruggenenti P, Mosconi L, Sangalli F, et al. Glomerular size selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade. Kidney Int 1999;55:984-94.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Lebovitz HE, Wiegmann TB, Cnaan A, et al. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl 1994;45: S150-S5.  Back to cited text no. 23  [PUBMED]  
24.Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int 1998;54:889-96.  Back to cited text no. 24  [PUBMED]  [FULLTEXT]
25.Nielsen B, Gronbaek H, Osterby R, Flyvbjerg A. Effect of the calcium channel blocker nitrendipine in normotensive and spontaneously hypertensive, diabetic rats on kidney morphology and urinary albumin excretion. J Hypertens 1999;17:973-81.  Back to cited text no. 25    
26.Bakris GL, Griffin KA, Picken MM, Bidani AK. Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury. J Hypertens 1997;15:1181-5.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Maki DD, Ma JZ, Louis TA, Kasiske BL. Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 1995;155:1073-80.  Back to cited text no. 27  [PUBMED]  
28.Tarif N, Bakris GL. Preservation of renal function: the spectrum of effects by calcium channel blockers. Nephrol Dial Transplant 1997;12:2244-50.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998;54:1283-9.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]

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George Bakris
Rush Medical Center, 1700 W. Van Buren St., Suite 470, Chicago, IL 60612
USA
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PMID: 18209340

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