Skip to main content

The Effects of Novel Antidiabetic Drugs on Albuminuria in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract

Background and Objective

The effects of novel antidiabetic drugs, including sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors, on albuminuria in patients with type 2 diabetes mellitus (T2DM) are still controversial. Therefore, we performed a meta-analysis to evaluate the effects of novel antidiabetic drugs on albuminuria in patients with T2DM.

Methods

We conducted a random-effects meta-analysis of randomized controlled trials (RCTs) by searching the MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases up to 16 August 2018. The effects of novel antidiabetic drugs on albuminuria were evaluated as percent changes from baseline to follow-up urinary albumin excretion/urinary albumin to creatinine ratio (UAE/UACR) levels in both the intervention and control groups. Data regarding percent changes were used to generate weighted mean differences (WMDs) and 95% confidence intervals (CIs).

Results

In this meta-analysis, 26 RCTs involving 14,929 patients were included. Pooled analysis suggested that SGLT-2 inhibitors (WMD − 26.23%, 95% CI − 35.90 to − 16.56; p < 0.00001) and GLP-1 receptor agonists (WMD − 13.85%, 95% CI − 15.96 to − 11.74; p < 0.00001) were associated with a significant reduction in albuminuria compared with other conventional therapies or placebo. DPP-4 inhibitors (WMD − 6.19%, 95% CI − 14.03 to 1.66; p = 0.12) were not significantly associated with lower albuminuria than other conventional therapies or placebo.

Conclusion

This meta-analysis indicates that SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a reduction in albuminuria compared with other conventional therapies or placebo, while DPP-4 inhibitors were not associated with albuminuria-reducing effects compared with other conventional therapies or placebo.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376:1407–18.

    Article  Google Scholar 

  2. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37:2864–83.

    Article  Google Scholar 

  3. Liyanage T, Ninomiya T, Jha V, et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015;385:1975–82.

    Article  Google Scholar 

  4. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008;57:1446–54.

    CAS  Article  Google Scholar 

  5. Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid Med Cell Longev. 2010;3:101–8.

    Article  Google Scholar 

  6. Schmieder RE, Mann JF, Schumacher H, et al. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol. 2011;22:1353–64.

    Article  Google Scholar 

  7. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421–6.

    CAS  Article  Google Scholar 

  8. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–21.

    Article  Google Scholar 

  9. Norris KC, Smoyer KE, Rolland C, et al. Albuminuria, serum creatinine, and estimated glomerular filtration rate as predictors of cardio-renal outcomes in patients with type 2 diabetes mellitus and kidney disease: a systematic literature review. BMC Nephrol. 2018;19:36.

    Article  Google Scholar 

  10. Viazzi F, Muiesan ML, Schillaci G, et al. Changes in albuminuria and cardiovascular risk under antihypertensive treatment: a systematic review and meta-regression analysis. J Hypertens. 2016;34:1689–97.

    CAS  Article  Google Scholar 

  11. Heerspink HJ, Kröpelin TF, Hoekman J, de Zeeuw D. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol. 2015;26:2055–64.

    CAS  Article  Google Scholar 

  12. De Zeeuw D. The end of dual therapy with renin–angiotensin–aldosterone system blockade. N Engl J Med. 2013;369:1960–2.

    Article  Google Scholar 

  13. 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.

    CAS  Article  Google Scholar 

  14. Maione A, Navaneethan SD, Graziano G, et al. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials. Nephrol Dial Transpl. 2011;26:2827–47.

    CAS  Article  Google Scholar 

  15. Abdul-Ghani M, DeFronzo RA. Is it time to change the type 2 diabetes treatment paradigm? Yes! GLP-1RAs should replace metformin in the type 2 diabetes algorithm. Diabetes Care. 2017;40:1121–7.

    CAS  Article  Google Scholar 

  16. De Boer IH. A new chapter for diabetic kidney disease. N Engl J Med. 2017;377:885–7.

    Article  Google Scholar 

  17. Cherney DZ, 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.

    CAS  Article  Google Scholar 

  18. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:369–84.

    CAS  Article  Google Scholar 

  19. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–50.

    CAS  Article  Google Scholar 

  20. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16:1016–27.

    CAS  Article  Google Scholar 

  21. Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin–angiotensin blockers. Diabetes Obes Metab. 2016;18:590–7.

    CAS  Article  Google Scholar 

  22. Fioretto P, Stefansson BV, Johnsson E, et al. Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia. 2016;59:2036–9.

    Article  Google Scholar 

  23. Petrykiv SI, Laverman GD, de Zeeuw D, Heerspink HJL. The albuminuria-lowering response to dapagliflozin is variable and reproducible among individual patients. Diabetes Obes Metab. 2017;19:1363–70.

    CAS  Article  Google Scholar 

  24. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314:687–99.

    CAS  Article  Google Scholar 

  25. Davies MJ, Bain SC, Atkin SL, et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care. 2016;39:222–30.

    CAS  Article  Google Scholar 

  26. Von SBJ, Persson F, Rosenlund S, et al. The effect of liraglutide on renal function: a randomized clinical trial. Diabetes Obes Metab. 2017;19:239–47.

    Article  Google Scholar 

  27. Von SBJ, Hansen TW, Goetze JP, et al. Glucagon-like peptide 1 receptor agonist (GLP-1 RA): long-term effect on kidney function in patients with type 2 diabetes. J Diabetes Complicat. 2015;29:670–4.

    Article  Google Scholar 

  28. Bouchi R, Nakano Y, Fukuda T, et al. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial. Endocr J. 2017;64:269–81.

    Article  Google Scholar 

  29. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376:431–9.

    Article  Google Scholar 

  30. Tonneijck L, Smits MM, Muskiet MHA, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016;59:1412–21.

    CAS  Article  Google Scholar 

  31. Zhang H, Zhang X, Hu C, Lu W. Exenatide reduces urinary transforming growth factor-β1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Kidney Blood Press Res. 2012;35:483–8.

    CAS  Article  Google Scholar 

  32. Derosa G, Cicero AF, Franzetti IG, et al. Effects of exenatide and metformin in combination on some adipocytokine levels: a comparison with metformin monotherapy. Can J Physiol Pharmacol. 2013;91:724–32.

    CAS  Article  Google Scholar 

  33. Mori H, Okada Y, Arao T, Tanaka Y. Sitagliptin improves albuminuria in patients with type 2 diabetes mellitus. J Diabetes Investig. 2014;5:313–9.

    CAS  Article  Google Scholar 

  34. Tonneijck 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;39:2042–50.

    CAS  Article  Google Scholar 

  35. 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.

    CAS  Article  Google Scholar 

  36. Yoon SA, Han BG, Kim SG, et al. Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: a 12-week, double-blind randomized study (the GUARD Study). Diabetes Obes Metab. 2017;19:590–8.

    CAS  Article  Google Scholar 

  37. Zografou I, Sampanis C, Gkaliagkousi E, et al. Effect of vildagliptin on hsCRP and arterial stiffness in patients with type 2 diabetes mellitus. Hormones (Athens). 2015;14:118–25.

    Google Scholar 

  38. Heerspink HJ, Desai M, Jardine M, et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017;28:368–75.

    CAS  Article  Google Scholar 

  39. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

    CAS  Article  Google Scholar 

  40. Tonneijck L, Muskiet MHA, Smits MM, et al. Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: an 8-week, randomised, open-label trial. Diabetes Obes Metab. 2017;19:1669–80.

    CAS  Article  Google Scholar 

  41. Mita T, Katakami N, Yoshii H, et al. Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A). Diabetes Care. 2016;39:139–48.

    CAS  Article  Google Scholar 

  42. Hong AR, Lee J, Ku EJ, et al. Comparison of vildagliptin as an add-on therapy and sulfonylurea dose-increasing therapy in patients with inadequately controlled type 2 diabetes using metformin and sulfonylurea (VISUAL study): a randomized trial. Diabetes Res Clin Pract. 2015;109:141–8.

    CAS  Article  Google Scholar 

  43. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.

    Article  Google Scholar 

  44. Jadad AR, Carroll D, Moore A, McQuay H. Developing a database of published reports of randomised clinical trials in pain research. Pain. 1996;66:239–46.

    CAS  Article  Google Scholar 

  45. Higgins JPT, Green S, et al. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. The Cochrane Collaboration; 2011. http://www.cochrane-handbook.org.

  46. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  Google Scholar 

  47. 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.

    CAS  Article  Google Scholar 

  48. Muskiet MHA, Tonneijck L, Smits MM, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017;13:605–28.

    CAS  Article  Google Scholar 

  49. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? PLoS One. 2013;8:e54442.

    CAS  Article  Google Scholar 

  50. Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59(9):1860–70.

    CAS  Article  Google Scholar 

  51. Cherney 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(5):587–97.

    CAS  Article  Google Scholar 

  52. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302(1):R75–83.

    CAS  Article  Google Scholar 

  53. Wang Y, Xu L, Yuan L, et al. Sodium-glucose co-transporter-2 inhibitors suppress atrial natriuretic peptide secretion in patients with newly diagnosed Type 2 diabetes. Diabet Med. 2016;33(12):1732–6.

    CAS  Article  Google Scholar 

  54. Zhang PL, Mackenzie HS, Troy JL, Brenner BM. Effects of an atrial natriuretic peptide receptor antagonist on glomerular hyperfiltration in diabetic rats. J Am Soc Nephrol. 1994;4(8):1564–70.

    CAS  PubMed  Google Scholar 

  55. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6.

    CAS  Article  Google Scholar 

  56. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306(2):F194–204.

    CAS  Article  Google Scholar 

  57. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25.

    CAS  Article  Google Scholar 

  58. Nauck MA, Meier JJ, Cavender MA, et al. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136(9):849–70.

    CAS  Article  Google Scholar 

  59. Fujita H, Morii T, Fujishima H, et al. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int. 2014;85(3):579–89.

    CAS  Article  Google Scholar 

  60. Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol. 2011;301(2):F355–63.

    CAS  Article  Google Scholar 

  61. Tonneijck L, Smits MM, van Raalte DH, Muskiet MH. Incretin-based drugs and renoprotection-is hyperfiltration key. Kidney Int. 2015;87(3):660–1.

    Article  Google Scholar 

  62. Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia. 2011;54(4):965–78.

    CAS  Article  Google Scholar 

  63. Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012;61(10):1422–34.

    CAS  Article  Google Scholar 

  64. Mega C, de Lemos ET, Vala H, et al. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diabetes Res. 2011;2011:162092.

    Article  Google Scholar 

  65. Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther. 2012;340(2):248–55.

    CAS  Article  Google Scholar 

  66. Fujita H, Taniai H, Murayama H, et al. DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy. Endocr J. 2014;61(2):159–66.

    CAS  Article  Google Scholar 

  67. Mulvihill EE, Varin EM, Ussher JR, et al. Inhibition of dipeptidyl peptidase-4 impairs ventricular function and promotes cardiac fibrosis in high fat-fed diabetic mice. Diabetes. 2016;65(3):742–54.

    CAS  Article  Google Scholar 

  68. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.

    CAS  Article  Google Scholar 

  69. Xu L, Li Y, Lang J, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis. PeerJ. 2017;5:e3405.

    Article  Google Scholar 

  70. Oellgaard J, Gæde P, Rossing P, et al. Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits. Kidney Int. 2017;91(4):982–8.

    Article  Google Scholar 

  71. KDIGO. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3:19.

    Article  Google Scholar 

  72. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care. 2017;40(1):69–76.

    CAS  Article  Google Scholar 

  73. Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58(1):69–73.

    CAS  Article  Google Scholar 

  74. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.

    CAS  Article  Google Scholar 

  75. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.

    CAS  Article  Google Scholar 

  76. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

    CAS  Article  Google Scholar 

  77. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.

    CAS  Article  Google Scholar 

  78. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    CAS  Article  Google Scholar 

  79. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.

    CAS  Article  Google Scholar 

  80. Fei Y, Tsoi MF, Kumana CR, Cheung TT. BMY C. Network meta-analysis of cardiovascular outcomes in randomized controlled trials of new antidiabetic drugs. Int J Cardiol. 2018;254:291–6.

    Article  Google Scholar 

  81. Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580–91.

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiaoli Zhou.

Ethics declarations

Funding

No funding was received to conduct this study.

Conflict of interest

The authors (Xiaoli Zhou, Ya Luo, Kai Lu, Gang Liu, Jing Wang and Irakoze Laurent) declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 183 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Luo, Y., Lu, K., Liu, G. et al. The Effects of Novel Antidiabetic Drugs on Albuminuria in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Drug Investig 38, 1089–1108 (2018). https://doi.org/10.1007/s40261-018-0707-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-018-0707-4