Empagliflozin reduces albuminuria—a promise for better cardiorenal protection from the EMPA-REG OUTCOME trial
Editorial

Empagliflozin reduces albuminuria—a promise for better cardiorenal protection from the EMPA-REG OUTCOME trial

Rikke Borg1,2, Frederik Persson3

1Department of Nephrology, Zealand University Hospital, Roskilde, Denmark; 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 3Steno Diabetes Center Copenhagen, Gentofte, Denmark

Correspondence to: Frederik Persson. Steno Diabetes Center Copenhagen, Niels Steensensvej 1, DK-2820 Gentofte, Denmark. Email: Frederik.ivar.persson@regionh.dk.

Provenance: This is an invited Editorial commissioned by Section Editor Dr. Kaiping Zhang, PhD (AME College, AME Group, Hangzhou, China).

Comment on: Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:610-21.


Submitted Oct 25, 2017. Accepted for publication Oct 30, 2017.

doi: 10.21037/atm.2017.11.02


Nowadays, type 2 diabetes care covers much more than lowering of blood glucose. To prevent and treat both micro- and macrovascular complications, risk factors like blood pressure and dyslipidemia are equally important treatment targets.

Over the last 3 or 4 decades albuminuria has become recognized as both a risk marker and a treatment target in diabetes care, with a strong association to both renal and cardiovascular outcome (1). This has led to albuminuria-lowering treatment as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) becoming a part of standard treatment in diabetes care, especially following significant clinical studies in patients with microalbuminuria (2) [urinary albumin creatinine ratio (UACR) >30 mg/g] and macroalbuminuria (3,4) (>300 mg/g). In addition, post-hoc analyses from these studies demonstrated higher benefit in patients that achieved the largest reduction in albuminuria, both in relation to renal outcome (5) and cardiovascular outcome (6). Following this, a series of studies investigated different modes of combination treatment seeking to further reduce albuminuria and obtain improved renal and cardiovascular protection (7-9). This approach was however not successful as adverse events as hyperkalemia, hypotension and acute kidney injury offset the benefits of combining two agents blocking the renin-angiotensin system.

In 2015 treatment of type 2 diabetes changed markedly with the publication of the EMPA-REG OUTCOME trial (10), for the first time demonstrating a reduction in cardiovascular outcome in a trial comparing sodium glucose co-transporter (SGLT2) inhibitors to placebo added to standard care.

The SGLT2 inhibitor class lowers blood glucose by blocking the sodium glucose co-transporter on the luminal side of the renal tubuli, thereby causing glucosuria, resulting in up to 70 gram glucose to be excreted daily. It is an oral agent, taken once daily.

It was evident from the EMPA-REG study that the lower occurrence of cardiovascular death and hospitalization for heart failure seen early in the empagliflozin treated group could not exclusively be attributed to lowering of blood glucose levels and several theories regarding the mechanism of effect started to emerge (11-13). Following the primary publication, a secondary analysis of the EMPA-REG OUTCOME trial (14) also found substantial benefit on progression of kidney outcome, with an interesting and apparent protective effect on estimated glomerular filtration rate (eGFR), which displayed a lower rate of decline in the empagliflozin group compared to placebo.

Recently, an EMPA-REG OUTCOME report investigating the effect of empagliflozin on albuminuria levels was published by Cherney et al. (15). Of the 7,028 patients included in the study, baseline UACR was available for this post-hoc analysis in 6,953 patients. Of the treated patients 59% had normoalbuminuria at baseline, 29% had microalbuminuria and 11% had macroalbuminuria. Reductions in UACR of 7%, 25% and 32% were seen after 12 weeks of treatment in the normo-, micro- and macroalbuminuria group, respectively. These reductions were maintained after a median follow-up of 3.1 years. The reduction in UACR in the micro-and macroalbuminuria groups were consistent across strata of changes in HbA1c, blood pressure, weight and eGFR. As an interesting exploratory analysis, a group of participants had UACR measured at baseline, at end of treatment and then again at 34–35 days after stopping treatment. In the normoalbuminuria group UACR values returned to baseline levels, but in the micro-and macroalbuminuria group UACR levels in the empagliflozin treated group UACR levels only partly returned to baseline levels. In the microalbuminuria part of the group the albuminuria reduction on empagliflozin was 42% lower versus placebo after 3.1 years, but increased to being 22% lower than placebo after 34 days off treatment, still statistically significantly lower than placebo. For macroalbuminuria the corresponding numbers were 49% and 29%, respectively. This finding indicates that the effect seen after approximately 3 years of treatment is more than just hemodynamic, and that structural changes may also play a role after long term treatment. If the effect on albuminuria was predominately due to hemodynamic effects, UACR levels would be expected to return to baseline levels after a few days. The authors state however that it is difficult to determine whether diabetes-related structural effects as glomerulosclerosis or tubulointerstitial fibrosis could have been attenuated, as there are no human renal biopsy data after SGLT2 treatment available.

In a categorical analysis the authors also looked at “class shifts”, i.e., the progression from normo- to micro-or macroalbuminuria, indicating a worse cardiorenal prognosis, or the regression to normoalbuminuria from the other classes which is associated with improved prognosis. Progression was less frequent in empagliflozin treated participants and a greater proportion of patients in the empagliflozin group experienced regression. In all three groups of albuminuria and eGFR was stable over the course of the study, while it displayed a decline in the placebo group. This difference was most prominent in the macroalbuminuria group.

This paper is indeed of special interest as it adds to understanding of the multifactorial potential of SGLT2 inhibition, as the treatment also lowers blood pressure, weight, blood glucose and can stabilize kidney function. It also represents evidence that empagliflozin has a clear albuminuria lowering potential, probably by increased sodium delivery to the macula densa, which leads to vasoconstriction of the afferent arteriole followed by a reduction in intraglomerular pressure resulting in a reduced filtration of albumin (11).

The two other major compounds in the SGLT2 inhibitor class, canagliflozin and dapagliflozin, have also demonstrated this potential. Canagliflozin was recently found to lower albuminuria and delay progression of albuminuria (class shift) in the CANVAS program (16), as a secondary outcome. In the ongoing CREDENCE (NCT02065791) study, canagliflozin is investigated in relation to a renal primary endpoint, and this will provide further evidence regarding the compound. Dapagliflozin has demonstrated similar potential in pooled analyses of trials as well as in a study in patients with type 2 diabetes and renal impairment. The ongoing DECLARE-TIMI-58 study (NCT01730534), a cardiovascular outcome trial, will also include a secondary renal analysis. Furthermore, the recently initiated DAPA-CKD study (NCT03036150) investigates dapagliflozin in relation to renal outcome in patients with albuminuria and impaired renal function, including both patients with type 2 diabetes and non-diabetic patients with proteinuria. A similar study in heart failure has been initiated, and both these studies will explore the potential of SGLT2 inhibition outside diabetes.


Why is it important to lower albuminuria?

The general hypothesis is that a reduction of albuminuria following an intervention is primarily reflecting a reduction in intraglomerular pressure, thereby decreasing filtration of large proteins such as albumin (17). This in turn leads to a reduction in inflammation, endothelial dysfunction, oxidative stress and fibrosis, leading to less long-term damage to the kidney. Although renin-angiotensin system blockade is thought to dilate the efferent arterioles and SGLT2 inhibition leads to vasoconstriction of the afferent arteriole, these and other albuminuria lowering compounds are often referred to as having other local structural effects in the kidney, i.e., anti-fibrotic or anti-inflammatory effects, although complicated to demonstrate in vivo. In a large metanalysis, Heerspink et al. (18) explored available clinical trials on albuminuria lowering in relation to hard renal outcome and concluded that for each 30% reduction in albuminuria, ESRD risk is reduced by 24%, an association that is consistent regardless of drug class used.


Other antidiabetic treatment and albuminuria

Not all glucose-lowering treatments have the potential to lower albumin excretion. However, treatment with glucagon-like peptide 1 (GLP-1) agonists, have shown reduction in albuminuria (19). So far, only liraglutide has shown renal benefit in a large outcome trial. In a secondary analysis of the LEADER trial (20), a lower proportion of liraglutide treated patients displayed progression to macroalbuminuria, making up the major part of the combined renal endpoint which occurred in 15 versus 19 patients per 1,000 patient-years of observation in the liraglutide and the placebo group, respectively.

For the widely used dipeptidyl peptidase IV (DPPIV) inhibitor class, there are conflicting results as to potential to lower albuminuria. The recently published MARLINA study (21), displayed a placebo-adjusted 6% reduction with linagliptin, which was not statistically or clinically significant, but a secondary analysis of the large saxagliptin study SAVOR-TIMI-53 (22) did report a significant reduction in UACR, however without influencing renal or cardiovascular outcome. More studies investigating the renoprotective potential in the DPPIV class are ongoing.

For now, SGLT2 inhibitors seem to be the obvious addition to standard renin-angiotensin system blocking treatment with the potential to lower residual albuminuria and enhance protection of the kidney and the heart in high risk patients. The EMPA-REG OUTCOME albuminuria analysis discussed here is indicating the potential, and the forthcoming studies will provide the answers needed. In addition, it is expected that global treatment guidelines will change in the coming years considering the recent developments in evidence.


Acknowledgements

None.


Footnote

Conflicts of Interest: R Borg reports having received lecture fees from Novartis, Amgen, Gambro, and Novo Nordisk and having served as a consultant for Boehringer Ingelheim and Astra Zeneca. F Persson reports having received research grants from AstraZeneca and Novartis and lecture fees from Novartis, Eli Lilly, MSD, AstraZeneca, Sanofi and Boehringer Ingelheim and having served as a consultant for Astra Zeneca, Bayer, Amgen, Novo Nordisk and MSD.


References

  1. Parving HH, Persson F, Rossing P. Microalbuminuria: a parameter that has changed diabetes care. Diabetes Res Clin Pract 2015;107:1-8. [Crossref] [PubMed]
  2. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8. [Crossref] [PubMed]
  3. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9. [Crossref] [PubMed]
  4. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60. [Crossref] [PubMed]
  5. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-20. [Crossref] [PubMed]
  6. de Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004;110:921-7. [Crossref] [PubMed]
  7. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-13. [Crossref] [PubMed]
  8. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-903. [Crossref] [PubMed]
  9. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53. [Crossref] [PubMed]
  10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-28. [Crossref] [PubMed]
  11. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation 2016;134:752-72. [Crossref] [PubMed]
  12. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG outcome Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care 2016;39:1108-14. [Crossref] [PubMed]
  13. Verma S, McMurray JJV, Cherney DZI. The Metabolodiuretic Promise of Sodium-Dependent Glucose Cotransporter 2 Inhibition: The Search for the Sweet Spot in Heart Failure. JAMA Cardiol 2017;2:939-40. [Crossref] [PubMed]
  14. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375:323-34. [Crossref] [PubMed]
  15. Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:610-21. [Crossref] [PubMed]
  16. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57. [Crossref] [PubMed]
  17. Rossing P, Fioretto P, Feldt-Rasmussen B, et al. Diabetic Nephropathy. In: Skorecki KL, Chertow GM, Marsden PA, et al. editors. Brenner and Rector’s The Kidney. 10th edition. Philadelphia: Elsevier, 2016:1283-321.
  18. Heerspink HJ, Kropelin TF, Hoekman J, et al. Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis. J Am Soc Nephrol 2015;26:2055-64. [Crossref] [PubMed]
  19. von Scholten BJ, Persson F, Rosenlund S, et al. The effect of liraglutide on renal function: A randomized clinical trial. Diabetes Obes Metab 2017;19:239-47. [Crossref] [PubMed]
  20. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:839-48. [Crossref] [PubMed]
  21. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab 2017;19:1610-9. [Crossref] [PubMed]
  22. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care 2017;40:69-76. [Crossref] [PubMed]
Cite this article as: Borg R, Persson F. Empagliflozin reduces albuminuria—a promise for better cardiorenal protection from the EMPA-REG OUTCOME trial. Ann Transl Med 2017;5(23):478. doi: 10.21037/atm.2017.11.02

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