Nephrol Dial Transplant (2016) 31: 359–368 doi: 10.1093/ndt/gfu411 Advance Access publication 29 January 2015

Full Reviews Diabetic nephropathy: landmark clinical trials and tribulations Gary C.W. Chan and Sydney C.W. Tang Division of Nephrology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong

A B S T R AC T Diabetic nephropathy remains the most common cause of endstage renal disease worldwide. The current standard of therapy for diabetic nephropathy involves stringent blood pressure control via blockade of the renin–angiotensin system and control of hyperglycemia. Despite these strategies, diabetic nephropathy is still seen to progress relentlessly. A pressing need for novel therapeutic agents has fueled endless basic science research projects and clinical trials in the quest for a more specific therapy. Throughout the process, only a handful of ancillary agents have shown experimental promise and even fewer have demonstrated an impact in human trials. This review article aims to summarize the available data from landmark studies for the main therapeutic approaches investigated. Keywords: clinical trials, diabetic nephropathy, humans

INTRODUCTION The burden of diabetes mellitus (DM) is rapidly rising. Current projections estimate the global prevalence of diabetic individuals to rise from 6.4% (285 million) in 2010 to 7.7% (439 million) in 2030 [1]. The main problem with this disease entity is its propensity to incur macro- and microvascular complications over time, crippling both the individual and our resource restricted healthcare system. Diabetic nephropathy (DN) is estimated to affect one-third of individuals with DM and is associated with considerable cardiovascular morbidity and mortality. It is the leading cause of end-stage renal disease (ESRD) worldwide, accounting for 42% of all patients on renal replacement therapy (RRT) in the USA [2]. Unfortunately, the magnitude of this clinical entity continues to grow in association with an expanding diabetic © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

population and remarkably the excess mortality risk of DM is associated almost entirely with the presence of DN [3, 4]. Thus, the search for therapeutic modalities to stem this inexorable tide remains a pressing matter. Although no cure is available at present, treatment options to prevent or slow disease progression are available. In this update, we aim to address the current armamentarium in the clinical management of DN and highlight the potential novel therapies under development. The results from major clinical trials, summarized in Table 1, are presented and critically reviewed. Current established therapies, novel treatments on the horizon and investigational strategies in their infancy are illustrated in Figure 1.

C U R R E N T S TA N D A R D O F A P P R O AC H T O D N Glycemic optimization Direct evidence demonstrating the beneficial effect of glycemic control is derived from isolated pancreatic transplantation in patients with DN. Metabolic normalization resulted in histological regression in this cohort at 10 years following transplantation [29]. Clinical trials have consistently reverberated this notable finding in both type 1 and type 2 DM, and validate the favorable effects of stringent glycemic regulation in delaying the onset and progression of DN. The DCCT (Diabetes Control and Complications Trial) recruited 1441 patients with type 1 DM. Glycemic optimization to achieve hemoglobin A1c (HbA1c) 7.3 versus 9.1% reduced incident micro- and macro-albuminuria by 39 and 54%, respectively, at a mean follow-up of 6.5 years [5]. Furthermore, extended observational data from the EDIC (Epidemiology of Diabetes Interventions and Complications) study on the original DCCT cohort clearly exhibited durability of early intensive diabetic regulation beyond 18 years [6, 30, 31]. Comprehensive prospective data are also available for type 2 DM. The UKPDS: 33 (United Kingdom Prospective Diabetes Study: 33) randomized 3867 newly diagnosed type 2 DM 359

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Correspondence and offprint requests to: Sydney C.W. Tang; E-mail: [email protected]

Table 1. Main results of major RCTs of various therapeutic approaches in diabetic kidney disease Trial

n

DCCT [5]

1441 T1DM

EDIC/DCCT [6] UKPDS 33 [7] ADVANCE [8]

ACCORD [9] RENAAL [10, 11]

MARVAL [12]

IDNT [14]

DETAIL [15]

FULL REVIEW

ROADMAP [16]

CALM [17]

ONTARGET [18]

VA NEPHRON-D [19]

AVOID [20]

ALTITUDE [21]

BEAM [22]

BEACON [23] Di.N.A.S. [24]

Sun-MACRO [25] VITAL [26]

CANTATA-SU [27]

ASCEND [28]

FU

Renal outcome

Intensive glycemic control versus standard control (HbA1c 7.3 versus 9.1%) reduced incident micro- and macro-albuminuria by 39 and 54%. 1441 T1DM 18 years Renoprotective efficacy of intensive glycemic control persisted and resulted in 45% risk reduction of micro-albuminuria at 18 years 3867 T2DM 10 years Intensive glycemic control versus standard control (HbA1c 7.0 versus 7.9%) led to 33% risk reduction for micro-albuminuria. 11 140 T2DM 5 years Intensive glycemic control versus standard control (HbA1c 6.5 versus 7.3%) reduced risk of micro-, macro-albuminuria and ESRD by 9, 30 and 65%. For those with macro-albuminuria, number needed to treat to prevent one ESRD = 41. 10 251 T2DM Intensive versus standard Terminated Targeting HbA1c 6.0 versus 7.0–7.9% resulted in excess mortality (HR glycemic control at 3.5 years 1.22; 95% CI 1.01–1.46; P = 0.04). 1513 T2DM Losartan versus placebo 3.4 years Multivariate analysis: every 10 mmHg SBP rise increased risk of ESRD or death by 6.7%. Losartan led to decrement of proteinuria (35%; P < 0.001), risk reduction of serum creatinine doubling (25%; P = 0.006) and ESRD (28%; P = 0.002). 332 T2DM Valsartan versus 24 weeks Reduction of micro-albuminuria with valsartan (44%) greater than amlodipine amlodipine (8%). 590 T2DM Irbesartan versus placebo 2 years Irbesartan demonstrated renoprotective efficacy with reduction in disease progression compared with placebo (HR 0.3; 95% CI 0.14–0.61; P < 0.001 for 300 mg irbesartan). 1715 T2DM Irbesartan versus 2.6 years Irbesartan was renoprotective with lower risk of serum creatinine amlodipine versus placebo doubling (33%; P = 0.003) and ESRD (23%; P = 0.07) compared with placebo. 250 T2DM Telmisartan versus 5 years Telmisartan and enalapril fared equally. No significant differences in enalapril level of albuminuria, rate of GFR decline and ESRD. 4447 T2DM Olmesartan versus placebo 3.2 years Olmesartan resulted in a reduction in time to micro-albuminuria onset by 23% (HR 0.77; 95% CI 0.63–0.94; P = 0.01). Blood pressure was similarly controlled in both study arms. 199 T2DM Candesartan/lisinopril 12 weeks Combination therapy more effective with greater reduction in urinary combo versus candesartan albumin: creatinine ratio (50%) compared with candesartan (24%) or versus lisinopril lisinopril (39%) alone. 55 months Combination therapy was associated with increased composite outcome 25 620 T1&2DM Telmisartan/ramipril of dialysis, serum creatinine doubling and death (HR 1.09; 95% CI 1.01– combo versus telmisartan versus ramipril 1.18; P ≤ 0.037). 1448 T2DM Losartan/lisinopril combo Terminated Combination therapy offered no renal benefit but resulted in excessive versus losartan at 2.2 years risk of hyperkalemia (6.3 versus 2.6 events per 100 person years; P < 0.001) and acute kidney injury (12.2 versus 6.7 events per 100 person years; P < 0.001). 599 T2DM Losartan versus aliskiren/ 6 months Aliskiren (direct renin inhibitor)/losartan combo led to reduction of losartan combo urinary albumin: creatinine ratio by 20% (95% CI 9–30; P < 0.001) independent of blood pressure control. 8561 T2DM RAS blockade plus Terminated Addition of aliskiren to maximal ARB offered no additional benefit. aliskiren versus placebo at 2.7 years Hyperkalemia and hypotension were significantly increased in the aliskiren arm. 227 T2DM Bardoxolone methyl 52 weeks Bardoxolone methyl at 25, 75 and 150 mg resulted in a higher GFR versus placebo (5.8 ± 1.8, 10.5 ± 1.8 and 9.3 ± 1.9 mL/min/1.73 m2) compared with placebo at 52 weeks. 2185 T2DM Bardoxolone methyl Terminated Bardoxolone methyl led to a significant increase in cardiovascular versus placebo at 9 months morbidity (HR 1.83; 95% CI 1.32–2.55; P < 0.001). 223 T1&2DM Sulodexide versus placebo 8 months 4 months of sulodexide (200 mg/day) significantly reduced albuminuria. Effect persisted after 8 months with 62% reduction compared with placebo (P = 0.0001). 1248 T2DM Maximum ARB plus Terminated No significant benefit observed in end points of serum creatinine sulodexide versus placebo doubling and ESRD. 281 T2DM RAS inhibition plus 24 weeks Paricalcitol at 2 μg/day reduced albuminuria (20% compared with paricalcitol versus placebo placebo). However, 2 μg/day was poorly tolerated and patients often reduced the dosage. 1450 T2DM Canagliflozin versus 52 weeks Canagliflozin caused initial decrease in GFR but subsequently stabilized glimepiride while individuals in the glimepiride arm had progressive GFR decline (–1.7 versus –5.1 mL/min/1.73 m2 after 52 weeks). 1392 T2DM Avosentan versus placebo Terminated Avosentan reduced proteinuria compared with placebo, but, had excess at 4 months adverse cardiovascular events; especially fluid overload (4.6%; P = 0.225), congestive heart failure (3.6%; P = 0.194) and death (2.6%). Intensive versus standard glycemic control Intensive versus standard glycemic control Intensive versus standard glycemic control Intensive versus standard glycemic control

6.5 years

ARB, angiotensin receptor blocker; RAS, renin–angiotensin system; T1DM, type 1 diabetes mellitus.

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IRMA-2 [13]

Design

RCTs and tribulations in DN

thresholds for the safe use of metformin remain uncertain. In clinical practice, serum creatinine levels over 150 μmol/L have been suggested to be a contraindication [34], although this is an arbitrary limit. Some use an estimated GFR >30 mL/min/1.73 m2 as a safety threshold, and an estimated GFR between 30 and 60 mL/min/1.73 m2 as an indication for halving the dose. In any case, metformin should be withheld in patients who are about to receive intravenous iodinated contrast material (with potential for contrast-induced nephropathy) or undergo a surgical procedure (with potential for compromised circulation), irrespective of the baseline renal function. The dipeptidyl peptidase-4 inhibitors are structurally heterogeneous and differ in their metabolism and excretion. While sitagliptin, vildagliptin and saxagliptin have prominent renal excretion necessitating dosage reduction for GFR

Diabetic nephropathy: landmark clinical trials and tribulations.

Diabetic nephropathy remains the most common cause of end-stage renal disease worldwide. The current standard of therapy for diabetic nephropathy invo...
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