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Daglutril for treatment of renal damage in hypertensive patients with type 2 diabetes: disappointment or hope?
Comment
Tek Image/Science Photo Library
Daglutril for treatment of renal damage in hypertensive patients with type 2 diabetes: disappointment or hope?
Published Online June 13, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70036-6 See Articles page19
2
Successful treatment of hypertension and effective regression of overt nephropathy in patients with type 2 diabetes is difficult, probably because the underlying pathophysiology does not respond to the most widely prescribed antihypertensive drugs, including antagonists of the renin–angiotensin system, dihydropyridine calcium channel blockers, and diuretics.1 Several newly described cell signalling pathways and pathophysiological mechanisms have provided new drug targets.2 Of the new classes of antihypertensive drugs in clinical development,3 dual inhibitors of endothelin-converting enzyme and neutral endopeptidase, are promising compounds.4 Inhibition of neutral endopeptidase—an enzyme involved in the degradation of natriuretic peptides— reduces blood pressure by potentiating the diuretic, natriuretic, and vasorelaxant effects of endogenous natriuretic peptides.5 Endothelin-converting enzyme is a key peptidase in the endothelin system: it cleaves inactive big endothelin 1 (big END1) to produce active END1, which binds to endothelin receptors EDNRA and EDNRB, and thereby exerts a vasoconstrictor effect. By combining inhibition of neutral endopeptidase and endothelin-converting enzyme, the objective is not only to better control blood pressure in patients with hypertension, but also to reduce target organ damage—particularly in patients with type 2 diabetes— through enhanced anti-proliferative, anti-fibrotic, and anti-inflammatory effects.6 Drugs that inhibit both neutral endopeptidase and endothelin-converting enzyme have several potential advantages over inhibitors of neutral endopeptidase or endothelin-converting enzyme alone.7 First, they block the pro-inflammatory and pro-fibrotic effects of END1 and enhance the plasma concentration of natriuretic peptides, which are known for their vasodilatory, anti-hypertrophic, and anti-fibrotic effects. Second, they overcome a limitation of sole neutral endopeptidase inhibition: because neutral endopeptidase also degrades END1, inhibition of neutral endopeptidase can lead to some vasoconstriction. Third, the natriuretic-promoting action of neutral endopeptidase can oppose the
salt and fluid retention attributed to nonselective antagonism of endothelin receptors. Combined neutral endopeptidase and endothelinconverting enzyme inhibitors might be especially useful for treatment of overt nephropathy and reduction of albuminuria in hypertensive patients with type 2 diabetes. END1 exaggerates proteinuria and contributes to glomerular capillary hypertension and excessive protein filtration.8,9 Furthermore, renal inflammation and production of TGFβ—which both exert a profibrotic effect—are mediated by EDNRA.8,9 Antagonists of EDNRA have been shown to provide nephroprotection.8,9 Although several potential dual or triple vasopeptidase inhibitors have been identified by basic research,6 few—such as daglutril—have reached clinical development. In The Lancet Diabetes & Endocrinology, Aneliya Parvanova and colleagues10 investigate whether inhibition of neutral endopeptidase and endothelinconverting enzyme can ease nephropathy and reduce albuminuria in addition to lowering blood pressure. In their double-blind, crossover trial, they treated 45 patients with daglutril 300 mg per day or placebo, plus losartan and other antihypertensive drugs, for 8 weeks for each treatment. The primary objective was not met: albuminuria did not differ significantly between the daglutril and placebo phases (difference in change –7·6 μg/min, IQR –78·7 to 19·0; p=0·559). This finding is disappointing—the study was designed to show a 40% mean difference in 24 h urinary albumin excretion rate between groups. Type 2 error is unlikely, not only because the study was well powered, but also because it was well designed. 45 patients were included, which is in the upper range for a crossover study, and gold standard measurements were used for assessment of ambulatory blood pressure and renal haemodynamics. However, their results do show that daglutril significantly reduces all measures of systolic blood pressure compared with placebo, as well as diastolic blood pressure for 24 h and night-time readings. Reduction in night-time systolic and diastolic blood pressures are usually difficult to obtain in patients with diabetic nephropathy who are www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
Comment
generally non-dippers (night-time blood pressure does not decrease as normal) and in whom blood pressure is well controlled with antihypertensive medication. In the study of Parvanova and co-workers the mean reductions in night-time blood pressures with daglutril were large; compared with placebo, the difference in systolic blood pressure was –7·5 mm Hg (SD 11·8) and in diastolic blood pressure it was –4·3 mm Hg (6·6). The negative results with respect to urinary albumin excretion are interesting from a pharmacodynamic point of view. The investigators have discussed mechanistic aspects that could explain why urinary albumin excretion rate was not reduced by daglutril: namely, a balance at the level of the glomeruli between the beneficial effects of reduced activation of endothelin receptors, and the deleterious effects of increased bioavailability of proatrial natriuretic peptide, which might have increased glomerular permeability to plasma macromolecules and induced preglomerular vasodilatation, thus maintaining glomerular perfusion and filtration despite lowered blood pressure. Further research is needed to establish whether higher doses of daglutril given for a longer period, or at higher doses, could reduce urinary albumin excretion. Whether other compounds with different ratios of neutral endopeptidase and endothelin-converting enzyme inhibition could provide better results, while minimising the deleterious effects when either endothelinconverting enzyme or neutral endopeptidase alone are inhibited, should also be investigated. Parvanova and colleagues provide a valuable contribution to research into novel antihypertensive drugs aimed at targeting specific cellular signalling pathways
to protect against renal damage. This study deserves the attention of doctors, at a time when they may be more attracted by novel devices than by modern pharmacology.3 Stéphane Laurent Department of Pharmacology and INSERM U970; Hôpital Européen Georges Pompidou; Assistance Publique—Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France [email protected] In the past 5 years, I have received relevant consultancies, honoraria, and speaker’s fees fromAstra-Zeneca, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, Menarini, Negma, Novartis, Recordati, and Servier; and research funding from Astra Zeneca, Daiichi Sankyo, Novartis, and Servier. 1
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3 4
5
6
7
8
9
10
Mancia G, de Backer G, Cifkova R, et al. Guidelines for the Management of Arterial Hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Cardiology (ESC) and of the European Society of Hypertension (ESH). J Hypertens 2007; 25: 1105–87. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888–904. Laurent S, Schlaich M, Esler M. New drugs, procedure, and devices for hypertension. Lancet 2012; 380: 591–600. Corti R, Burnett JC Jr, Rouleau JL, Ruschitzka F, Lüscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation 2001; 104: 1856–62. Dive V, Chang CF, Yiotakis A, Sturrock ED. Inhibition of zinc metallopeptidases in cardiovascular disease—from unity to trinity, or duality? Curr Pharm Des 2009; 15: 3606–21. Daull P, Jeng AY, Battistini B. Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. J Cardiovasc Pharmacol 2007; 50: 247–56. Kalk P, Sharkovska Y, Kashina E, et al. Endothelin-converting enzyme/ neutral endopeptidase inhibitor SLV338 prevents hypertensive cardiac remodeling in a blood pressure-independent manner. Hypertension 2011; 57: 755–63. Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov 2002; 1: 986–1001. Zoja C, Cattaneo S, Fiordaliso F, et al. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes. Am J Physiol Renal Physiol 2011; 301: F1114–23. Parvanova A, van der Meer I, Ililev I, et al, for the Daglutril in Diabetic Nephropathy Study Group. Lancet Diabetes Endocrinol 2013; published online June 13, 2013. http://dx.doi.org/10.1016/S2213-8587(13)70029-9.
Intensive insulin therapy for type 2 diabetes at diagnosis In The Lancet Diabetes & Endocrinology, Kramer and colleagues1 report a systematic review and metaanalysis of the effects of short-term intensive insulin therapy on β-cell function, insulin resistance, and remission of type 2 diabetes, with intriguing results. Pooling data from seven studies, treatment with intensive insulin therapy for 2–3 weeks, implemented soon after diagnosis, improved β-cell function by 13% (HR 1·13, 95% CI 1·02–1·25), and diminished insulin resistance by 43% (HR –0·57, –0·84 to –0·29), both www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
assessed using the Homeostasis Model Assessment (HOMA). Four studies also reported on type 2 diabetes remission rates, and with all pharmacological treatment stopped at the end of the intensive treatment period, 46·2% of patients were still in remission after 12 months.1 How can we explain these findings? As discussed by the investigators, removal of glucose toxicity improves β-cell function and insulin resistance. As to the diabetes remission rates, in addition to the removal of glucose
Published Online January 30, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70001-9 See Articles page 28
3
Tek Image/Science Photo Library
Daglutril for treatment of renal damage in hypertensive patients with type 2 diabetes: disappointment or hope?
Published Online June 13, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70036-6 See Articles page19
2
Successful treatment of hypertension and effective regression of overt nephropathy in patients with type 2 diabetes is difficult, probably because the underlying pathophysiology does not respond to the most widely prescribed antihypertensive drugs, including antagonists of the renin–angiotensin system, dihydropyridine calcium channel blockers, and diuretics.1 Several newly described cell signalling pathways and pathophysiological mechanisms have provided new drug targets.2 Of the new classes of antihypertensive drugs in clinical development,3 dual inhibitors of endothelin-converting enzyme and neutral endopeptidase, are promising compounds.4 Inhibition of neutral endopeptidase—an enzyme involved in the degradation of natriuretic peptides— reduces blood pressure by potentiating the diuretic, natriuretic, and vasorelaxant effects of endogenous natriuretic peptides.5 Endothelin-converting enzyme is a key peptidase in the endothelin system: it cleaves inactive big endothelin 1 (big END1) to produce active END1, which binds to endothelin receptors EDNRA and EDNRB, and thereby exerts a vasoconstrictor effect. By combining inhibition of neutral endopeptidase and endothelin-converting enzyme, the objective is not only to better control blood pressure in patients with hypertension, but also to reduce target organ damage—particularly in patients with type 2 diabetes— through enhanced anti-proliferative, anti-fibrotic, and anti-inflammatory effects.6 Drugs that inhibit both neutral endopeptidase and endothelin-converting enzyme have several potential advantages over inhibitors of neutral endopeptidase or endothelin-converting enzyme alone.7 First, they block the pro-inflammatory and pro-fibrotic effects of END1 and enhance the plasma concentration of natriuretic peptides, which are known for their vasodilatory, anti-hypertrophic, and anti-fibrotic effects. Second, they overcome a limitation of sole neutral endopeptidase inhibition: because neutral endopeptidase also degrades END1, inhibition of neutral endopeptidase can lead to some vasoconstriction. Third, the natriuretic-promoting action of neutral endopeptidase can oppose the
salt and fluid retention attributed to nonselective antagonism of endothelin receptors. Combined neutral endopeptidase and endothelinconverting enzyme inhibitors might be especially useful for treatment of overt nephropathy and reduction of albuminuria in hypertensive patients with type 2 diabetes. END1 exaggerates proteinuria and contributes to glomerular capillary hypertension and excessive protein filtration.8,9 Furthermore, renal inflammation and production of TGFβ—which both exert a profibrotic effect—are mediated by EDNRA.8,9 Antagonists of EDNRA have been shown to provide nephroprotection.8,9 Although several potential dual or triple vasopeptidase inhibitors have been identified by basic research,6 few—such as daglutril—have reached clinical development. In The Lancet Diabetes & Endocrinology, Aneliya Parvanova and colleagues10 investigate whether inhibition of neutral endopeptidase and endothelinconverting enzyme can ease nephropathy and reduce albuminuria in addition to lowering blood pressure. In their double-blind, crossover trial, they treated 45 patients with daglutril 300 mg per day or placebo, plus losartan and other antihypertensive drugs, for 8 weeks for each treatment. The primary objective was not met: albuminuria did not differ significantly between the daglutril and placebo phases (difference in change –7·6 μg/min, IQR –78·7 to 19·0; p=0·559). This finding is disappointing—the study was designed to show a 40% mean difference in 24 h urinary albumin excretion rate between groups. Type 2 error is unlikely, not only because the study was well powered, but also because it was well designed. 45 patients were included, which is in the upper range for a crossover study, and gold standard measurements were used for assessment of ambulatory blood pressure and renal haemodynamics. However, their results do show that daglutril significantly reduces all measures of systolic blood pressure compared with placebo, as well as diastolic blood pressure for 24 h and night-time readings. Reduction in night-time systolic and diastolic blood pressures are usually difficult to obtain in patients with diabetic nephropathy who are www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
Comment
generally non-dippers (night-time blood pressure does not decrease as normal) and in whom blood pressure is well controlled with antihypertensive medication. In the study of Parvanova and co-workers the mean reductions in night-time blood pressures with daglutril were large; compared with placebo, the difference in systolic blood pressure was –7·5 mm Hg (SD 11·8) and in diastolic blood pressure it was –4·3 mm Hg (6·6). The negative results with respect to urinary albumin excretion are interesting from a pharmacodynamic point of view. The investigators have discussed mechanistic aspects that could explain why urinary albumin excretion rate was not reduced by daglutril: namely, a balance at the level of the glomeruli between the beneficial effects of reduced activation of endothelin receptors, and the deleterious effects of increased bioavailability of proatrial natriuretic peptide, which might have increased glomerular permeability to plasma macromolecules and induced preglomerular vasodilatation, thus maintaining glomerular perfusion and filtration despite lowered blood pressure. Further research is needed to establish whether higher doses of daglutril given for a longer period, or at higher doses, could reduce urinary albumin excretion. Whether other compounds with different ratios of neutral endopeptidase and endothelin-converting enzyme inhibition could provide better results, while minimising the deleterious effects when either endothelinconverting enzyme or neutral endopeptidase alone are inhibited, should also be investigated. Parvanova and colleagues provide a valuable contribution to research into novel antihypertensive drugs aimed at targeting specific cellular signalling pathways
to protect against renal damage. This study deserves the attention of doctors, at a time when they may be more attracted by novel devices than by modern pharmacology.3 Stéphane Laurent Department of Pharmacology and INSERM U970; Hôpital Européen Georges Pompidou; Assistance Publique—Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France [email protected] In the past 5 years, I have received relevant consultancies, honoraria, and speaker’s fees fromAstra-Zeneca, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, Menarini, Negma, Novartis, Recordati, and Servier; and research funding from Astra Zeneca, Daiichi Sankyo, Novartis, and Servier. 1
2
3 4
5
6
7
8
9
10
Mancia G, de Backer G, Cifkova R, et al. Guidelines for the Management of Arterial Hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Cardiology (ESC) and of the European Society of Hypertension (ESH). J Hypertens 2007; 25: 1105–87. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888–904. Laurent S, Schlaich M, Esler M. New drugs, procedure, and devices for hypertension. Lancet 2012; 380: 591–600. Corti R, Burnett JC Jr, Rouleau JL, Ruschitzka F, Lüscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation 2001; 104: 1856–62. Dive V, Chang CF, Yiotakis A, Sturrock ED. Inhibition of zinc metallopeptidases in cardiovascular disease—from unity to trinity, or duality? Curr Pharm Des 2009; 15: 3606–21. Daull P, Jeng AY, Battistini B. Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. J Cardiovasc Pharmacol 2007; 50: 247–56. Kalk P, Sharkovska Y, Kashina E, et al. Endothelin-converting enzyme/ neutral endopeptidase inhibitor SLV338 prevents hypertensive cardiac remodeling in a blood pressure-independent manner. Hypertension 2011; 57: 755–63. Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov 2002; 1: 986–1001. Zoja C, Cattaneo S, Fiordaliso F, et al. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes. Am J Physiol Renal Physiol 2011; 301: F1114–23. Parvanova A, van der Meer I, Ililev I, et al, for the Daglutril in Diabetic Nephropathy Study Group. Lancet Diabetes Endocrinol 2013; published online June 13, 2013. http://dx.doi.org/10.1016/S2213-8587(13)70029-9.
Intensive insulin therapy for type 2 diabetes at diagnosis In The Lancet Diabetes & Endocrinology, Kramer and colleagues1 report a systematic review and metaanalysis of the effects of short-term intensive insulin therapy on β-cell function, insulin resistance, and remission of type 2 diabetes, with intriguing results. Pooling data from seven studies, treatment with intensive insulin therapy for 2–3 weeks, implemented soon after diagnosis, improved β-cell function by 13% (HR 1·13, 95% CI 1·02–1·25), and diminished insulin resistance by 43% (HR –0·57, –0·84 to –0·29), both www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
assessed using the Homeostasis Model Assessment (HOMA). Four studies also reported on type 2 diabetes remission rates, and with all pharmacological treatment stopped at the end of the intensive treatment period, 46·2% of patients were still in remission after 12 months.1 How can we explain these findings? As discussed by the investigators, removal of glucose toxicity improves β-cell function and insulin resistance. As to the diabetes remission rates, in addition to the removal of glucose
Published Online January 30, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70001-9 See Articles page 28
3