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Renoprotection in LEADER and EMPA-REG OUTCOME

2016; Elsevier BV; Volume: 4; Issue: 10 Linguagem: Inglês

10.1016/s2213-8587(16)30214-5

2213-8595

Marcel H.A. Muskiet, Lennart Tonneijck, Erik J.M. van Bommel, Mark M. Smits, Daniël H. van Raalte,

Pancreatic function and diabetes

In their research digest, Sattar and Preiss1Sattar N Preiss D Research digest.Lancet Diabetes Endocrinol. 2016; 4: 651Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar highlight the beneficial renal outcomes in LEADER2Marso SP Daniels GH Brown-Frandsen K et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (4230) Google Scholar and EMPA-REG OUTCOME,3Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar two landmark, placebo-controlled trials that assessed the cardiovascular safety of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (LEADER) and sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA-REG OUTCOME) in patients with type 2 diabetes. In both trials, baseline blood pressure was well controlled (about 136/77 mm Hg), and about 80% of patients used renin–angiotensin system (RAS) inhibitors and lipid-lowering drugs; thus the renoprotective effects seem to complement prevailing treatment strategies.4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar Once-daily liraglutide (1·8 mg) for 3·8 years reduced incident or worsening nephropathy by 22%2Marso SP Daniels GH Brown-Frandsen K et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (4230) Google Scholar and once-daily empagliflozin (10 or 25 mg) for 3·1 years reduced the same composite outcome by 39%.3Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar However, the four separate exploratory components of this renal composite outcome were differently affected (table). In LEADER,2Marso SP Daniels GH Brown-Frandsen K et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (4230) Google Scholar results were predominantly driven by reductions in the potential surrogate renal endpoint of incident macroalbuminuria.4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar In EMPA-REG OUTCOME,3Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar additional profound changes in established surrogate and hard renal endpoints4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar were reported, although the US Food and Drug Administration remarked that these endpoints differed from those typically used in renoprotection trials in diabetic nephropathy (appendix). Remarkably, empagliflozin did not affect albuminuria occurrence in patients who were normoalbuminuric, suggesting that the drug's renoprotective potential principally affects individuals with established kidney damage or single-nephron hyperfiltration.TableEffects of liraglutide and empagliflozin on renal outcomesLiraglutide (LEADER; n=9340)Empagliflozin (EMPA-REG OUTCOME; n=7020)Incident or worsening nephropathy0·78 (0·67–0·92); p=0·0030·61 (0·53–0·70); p<0·001New-onset macroalbuminuria0·74 (0·60–0·91); NR0·62 (0·54–0·72); p<0·001Doubling of serum creatinine concentration and eGFR ≤45 mL/min/1·73m20·88 (0·66–1·18); NR0·56 (0·39–0·79); p<0·001Need for renal replacement therapy0·87 (0·61–1·24); NR0·45 (0·21–0·97); p=0·04Death due to renal disease1·59 (0·52–4·87); NR3 (empagliflozin) vs 0 (placebo);*No hazard ratio is reported for death due to renal disease in EMPA-REG OUTCOME. NRData are hazard ratio (95% CI); p value. Doubling of serum creatinine concentration did not require a second confirmatory measurement in both trials. Need for continuous renal replacement therapy in EMPA-REG OUTCOME included five cases of acute kidney injury requiring temporary dialysis (appendix). eGFR=estimated glomerular filtration rate. NR=not reported.* No hazard ratio is reported for death due to renal disease in EMPA-REG OUTCOME. Open table in a new tab Data are hazard ratio (95% CI); p value. Doubling of serum creatinine concentration did not require a second confirmatory measurement in both trials. Need for continuous renal replacement therapy in EMPA-REG OUTCOME included five cases of acute kidney injury requiring temporary dialysis (appendix). eGFR=estimated glomerular filtration rate. NR=not reported. Several mechanisms might underlie the renoprotection seen in both trials. First, as intensified glycaemic control in type 2 diabetes reduces microalbuminuria risk by 14% and macroalbuminuria risk by 26%,4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar the considerable between-group HbA1c differences (appendix) might—at least partly—explain the albuminuria benefit, particularly in LEADER. Notably, in the ELIXA trial,5Pfeffer MA Claggett B Diaz R et al.Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.N Engl J Med. 2015; 373: 2247-2257Crossref PubMed Scopus (1604) Google Scholar the favourable effect of the GLP-1 receptor agonist lixisenatide versus placebo on change in urinary albumin-to-creatinine ratio at week 108 (24% vs 34%) was attenuated (p=0·07) after correction for an initial HbA1c difference of about 0·3%. Therefore, the role of glycaemic control in current and ongoing trials should be explored to establish drug-specific benefits. Second, well documented glucose-independent actions of both drug classes on renal risk factors might also have contributed.4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar Modest improvements in bodyweight (about 2 kg), systolic blood pressure (about 1–3 mm Hg) and lipids were seen, while empagliflozin additionally reduced plasma uric acid concentrations (appendix). Finally, empagliflozin and liraglutide might have directly affected renal physiology. Both drugs decrease proximal tubular sodium reabsorption, leading to (initial) natriuresis.4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar This effect theoretically increases afferent arteriolar resistance and alleviates glomerular hydraulic pressure (PGLO) through tubuloglomerular feedback activation. 8 week empagliflozin treatment has been reported to reduce inulin-measured glomerular filtration rate by 19% and estimated PGLO by 10%, albeit only in patients with type 1 diabetes and baseline hyperfiltration.6Cherney DZ Perkins BA Soleymanlou N et al.Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597Crossref PubMed Scopus (906) Google Scholar Hence, in EMPA-REG OUTCOME, the initial roughly 5% fall in estimated glomerular filtration rate (eGFR) probably reflects acute reductions in single-nephron hyperfiltration, which is associated with subsequent long-term renal function preservation.4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar Such an eGFR trajectory, also reported in phase 3 trials of SGLT2 inhibitors dapagliflozin and canagliflozin in type 2 diabetes (appendix), is highly reminiscent of the trajectory that occurs after RAS inhibition (which decreases PGLO by relieving efferent arteriolar resistance).4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar The alleged beneficial renal haemodynamic nature of this response is further substantiated by the eGFR upsurge that was seen 34 days after discontinuation of empagliflozin.3Wanner C Inzucchi SE Lachin JM et al.for the EMPA-REG OUTCOME InvestigatorsEmpagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2069) Google Scholar For liraglutide, although suggested by an uncontrolled small study in type 2 diabetes (appendix),4Muskiet MH Tonneijck L Smits MM Kramer MH Heerspink HJ van Raalte DH Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.Lancet Diabetes Endocrinol. 2015; 3: 367-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar similar eGFR trajectories have not been reported in the large-scale phase 3 LEAD programme or the LIRA-RENAL trial (appendix). Furthermore, no renal haemodynamic alterations assessed by gold-standard clearance techniques were reported after 12 week liraglutide treatment in patients with type 2 diabetes who were overweight.7Tonneijck L Smits MM Muskiet MH et al.Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial.Diabetes Care. 2016; (published online Sep 1.)https://doi.org/10.2337/dc16-1371Crossref Scopus (73) Google Scholar Empagliflozin seems to address an important unmet need in diabetic nephropathy, probably improving relevant outcomes via multiple unique mechanisms. Glucose-independent renoprotective properties of liraglutide are more uncertain, and perhaps longer follow-up duration than was used in LEADER would have been necessary to see differences in hard endpoints. DHvR has received a research grant from AstraZeneca for his institution. All other authors declare no competing interests. This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on September 28, 2016 This online publication has been corrected. The corrected version first appeared at thelancet.com/diabetes-endocrinology on September 28, 2016 Download .pdf (.12 MB) Help with pdf files Supplementary appendix Research digestWith buses, we often wait for one for a long time, only for two to arrive together; so is the case, it seems, for trials. Following quickly on from the cardiovascular results of the EMPA-REG OUTCOME trial, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial investigators have now reported a 13% lower risk of cardiovascular events in 9340 patients with diabetes and high cardiovascular risk on once daily liraglutide injections compared with placebo over an average follow-up of 3·8 years. Full-Text PDF Correction to Lancet Diabetes Endocrinol 2016; 4: 812–14Muskiet MH, Tonneijck L, van Bommel EJ, Smits MM, van Raalte DH. Renoprotection in LEADER and EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 2016; 4: 812–14. The supplementary appendix has now been uploaded. This correction has been made to the online version as of Sept 28, 2016. Full-Text PDF