Abstract
Introduction: Diabetes mellitus (DM) is one of the most common diseases worldwide. Its adverse effects on several body organs, have made treatment of DM a priority. One of the most serious complications of DM is diabetic nephropathy (DN).
Objective: The aim of this review is to critically discuss available data on the pharmacological management of DN.
Methods: A comprehensive review of the literature was performed to identify studies assessing the impact of several drug classes on DN.
Results: Several studies have been conducted in order to find a novel and effective treatment of DN. So far, the cornerstone therapy of DN consists of renin-angiotensin system (RAS) inhibitors, agents that decrease the synthesis of intrarenal angiotensin II or block its receptors. Their antiproteinuric and antihypertensive effects can not only decelerate the progress of DN but prevent its onset as well. Novel antidiabetic drugs, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide- 1 receptor agonists (GLP-1 RA), are promising agents in the therapy of DN, due to their positive effect on renal and cardiovascular adverse events. From lipid-lowering agents, atorvastatin improves DN up to stage 3 and substantially reduces CVD.
Conclusion: RAS inhibitors, SGLT-2i and GLP-1 agonists were found to be beneficial for the treatment of DN. Larger renal trials are needed in order to incorporate these drugs into the first line treatment of DN.
Keywords: Diabetic nephropathy, pharmacological management, renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists.
Graphical Abstract
[1]
American Diabetes Association. Microvascular complications and foot care: Standards of medical care in diabetes-2018. Diabetes Care 2018; 41(Suppl. 1): 105-18.
[2]
Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 2018; 71: 884-95.
[3]
Yakush WJK. Management strategies for patients with diabetic kidney disease and chronic kidney disease in diabetes. Nurs Clin North Am 2017; 52: 575-87.
[4]
Molitch ME, Adler AI, Flyvbjerg A, et al. Diabetic kidney disease- a clinical update from kidney disease: improving global outcomes (KDIGO). Kidney Int 2015; 87(1): 20-30.
[5]
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3: 1-150.
[6]
Viazzi F, Bonino B, Ratto E, et al. Early renal abnormalities as an indicator of cardiovascular risk in type 2 diabetes. High Blood Press Cardiovasc Prev 2014; 21: 257-60.
[7]
American Diabetes Association. Cardiovascular disease and risk management: Standards of medical care in diabetes-2018. Diabetes Care 2018; 41(Suppl. 1): 86-104.
[8]
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009; 53: 298-304.
[9]
American Diabetes Association. Lifestyle management: Standards of medical care in diabetes-2018. Diabetes Care 2018; 41: 38-50.
[10]
American Diabetes Association. Glycemic targets: Standards of medical care in diabetes-2018. Diabetes Care 2018; 41: 55-64.
[11]
Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-53.
[12]
Nathan DM, Bayless M, Cleary P, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes 2013; 62: 3976-86.
[13]
Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-89.
[14]
Patel A, MacMahon S, et al. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-72.
[15]
Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010; 376: 419-30.
[16]
Gerstein HC, Miller ME, et al. Action to control cardiovascular risk in diabetes study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
[17]
Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014; 371: 1392-406.
[18]
Duckworth W, Abraira C, Moritz T, et al. VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.
[19]
Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular eanoutcomes in type 2 diabetes. N Engl J Med 2015; 372: 2197-206.
[20]
Van Biesen W, Van de Velde T, Slabbaert M, et al. Blood pressure management in patients with chronic kidney disease: an appraisal and summary of existing guidelines. Acta Clin Belg 2013; 68: 394-8.
[21]
Williams B, Mancia G, Spiering W, et al. Task Force Members. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens 2018; 36: 1953-2041.
[22]
Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the evention, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2018; 71: 2199-269.
[23]
ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575-85.
[24]
Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: The ACCORD randomized trial. Diabetes Care 2014; 37: 1721-8.
[25]
Athyros VG, Karagiannis A, Katsiki N, et al. Statins in patients with renal dysfunction. Am J Cardiol 2012; 109: 1537.
[26]
Athyros VG, Katsiki N, Karagiannis A, et al. Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients, further reducing cardiovascular risk. Fact or fiction? Expert Opin Pharmacother 2015; 16: 1449-61.
[27]
Athyros VG, Karagiannis A, Liberopoulos EN, et al. Statin treatment may be beneficial to both the kidneys and the heart. Perit Dial Int 2007; 27: 215-6.
[28]
Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57: 728-34.
[29]
Athyros VG, Karagiannis A, Kakafika A, Elisaf M, et al. Statins and renal function. Is the compound and dose making a difference? Nephrol Dial Transplant 2007; 22: 963-4.
[30]
Shepherd J, Kastelein JJ, Bittner V, et al. TNT (Treating to New Targets) Investigators.Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol 2008; 51: 1448-54.
[31]
Athyros VG, Tziomalos K, Karagiannis A, et al. Statins and cardiovascular events in patients with end-stage renal disease on hemodialysis. The AURORA results suggest the need for earlier intervention. Curr Vasc Pharmacol 2009; 7: 264-6.
[32]
Afzali B, Goldsmith DJ. Beneficial effects of statins on the kidney. J Clin Pathol 2004; 57: 673-4.
[33]
Athyros VG, Papageorgiou AA, Elisaf M, et al. GREACE Study Collaborative Group. Statins and renal function in patients with diabetes mellitus. Curr Med Res Opin 2003; 19: 615-7.
[34]
Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol 2011; 22(7): 1335-41.
[35]
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387-97.
[36]
Sabatine MS, Giugliano RP, Keech AC, et al. FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
[37]
Standl E, Schnell O, McGuire DK, et al. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol 2017; 5: 391-402.
[38]
González Sanchidrián S, Labrador Gómez PJ, Aguilar Aguilar JC, et al. Evolocumab for the treatment of heterozygous familial hypercholesterolemia in end-stage chronic kidney disease and dialysis. Nefrologia 2019; 39: 218-20.
[39]
Schwartz GG, Steg PG, Szarek M, et al. ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097-107.
[40]
Pan R, Li Y, Zhou H. Efficacy and safety of different doses of alirocumab in reducing low-density lipoprotein cholesterol levels: a network meta-analysis. Pharmazie 2019; 74: 8-14.
[41]
ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1563-74.
[42]
Reyes-Soffer G1, Ngai CI, Lovato L, et al. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. Diabetes Care 2013; 36: 422-8.
[43]
Elam MB, Ginsberg HN, Lovato LC, et al. ACCORDION Study Investigators. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol 2017; 2: 370-80.
[44]
Ferro CJ, Mark PB, Kanbay M, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol 2018; 14: 727-49.
[45]
Papademetriou V, Lovato L, Doumas M, et al. Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int 2015; 87: 649-59.
[46]
Papademetriou V, Zaheer M, Doumas M, et al. Cardiovascular outcomes in action to control cardiovascular risk in diabetes: impact of blood pressure level and presence of kidney disease. Am J Nephrol 2016; 43: 271-80.
[47]
Papademetriou V, Lovato L, Tsioufis C, et al. Effects of high density lipoprotein raising therapies on cardiovascular outcomes in patients with type 2 diabetes mellitus, with or without renal impairment: the action to control cardiovascular risk in diabetes study. Am J Nephrol 2017; 45: 136-45.
[48]
Yacoub R, Campbell KN. Inhibition of RAS in diabetic nephropathy. Int J Nephrol Renovasc Dis 2015; 8: 29-40.
[49]
Parving HH, Lehnert H, Bröchner-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.
[50]
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.
[51]
Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am Soc Nephrol 2005; 16: 3027-37.
[52]
Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 1993; 329(20): 1456-62.
[53]
Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364: 907-17.
[54]
Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829-40.
[55]
Bangalore S, Fakheri R, Toklu B, et al. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: Systematic review and meta-analysis of randomized trials. BMJ 2016; 352: i438.
[56]
Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59.
[57]
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.
[58]
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.
[59]
Lacourcière Y, Bélanger A, Godin C, et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int 2000; 58: 762-9.
[60]
Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351: 1952-61.
[61]
Ozturk S, Sar F, Bengi-Bozkurt O, et al. Study of ACEi versus ARB in managing hypertensive overt diabetic nephropathy: long-term analysis. Kidney Blood Press Res 2009; 32: 268-75.
[62]
Egido J, Rojas-Rivera J, Mas S, et al. Atrasentan for the treatment of diabetic nephropathy. Expert Opin Investig Drugs 2017; 26: 741-50.
[63]
Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010; 21: 527-35.
[64]
Schievink B, de Zeeuw D, Smink PA, et al. Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers. Eur J Prev Cardiol 2016; 23: 758-68.
[65]
Heerspink HJL, Andress DL, Bakris G, et al. Rationale and protocol of the study of diabetic nephropathy with Atrasentan (SONAR) trial: a clinical trial design novel to diabetic nephropathy. Diabetes Obes Metab 2018; 20: 1369-76.
[66]
Stavropoulos K, Imprialos KP, Stavropoulos N, et al. Sodium-glucose cotransporter 2 inhibitors: nephroprotective impact on diabetic kidney disease. Cardiovasc Hematol Disord Drug Targets 2018; 18: 120-6.
[67]
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.
[68]
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.
[69]
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.
[70]
Jardine MJ, Mahaffey KW, Neal B, et al. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol 2017; 46: 462-72.
[71]
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.
[72]
Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014; 85: 962-71.
[73]
Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2017; 19: 1106-15.
[74]
de Vos LC, Hettige TS, Cooper ME. New glucose-lowering agents for diabetic kidney disease. Adv Chronic Kidney Dis 2018; 25: 149-57.
[75]
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[76]
Mann JFE, Ørsted DD, K. Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377: 839-48.
[77]
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375: 1834-44.
[78]
Tuttle KR, McKinney TD, Davidson JA, et al. Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. Diabetes Obes Metab 2017; 19: 436-41.
[79]
Tuttle KR, Lakshmann MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6: 605-17.
[80]
Lalau JD, Kajbaf F, Protti A, et al. Metformin-associated lactic acidosis (MALA): moving towards a new paradigm. Diabetes Obes Metab 2017; 19: 1502-12.
Call for Papers in Thematic Issues
07 May, 2024
Ischemic Cardiovascular Diseases: Mechanisms, Diagnosis and Therapy
Ischemic cardiovascular disease includes myocardial infarction, coronary atherosclerotic heart disease, angina pectoris, etc., constitute the leading cause of patient mortality by preventing tissues from getting sufficient oxygen and nutrients. Ischemic heart disease, as a clinical condition, is characterized by myocardial ischemia, causing an imbalance between myocardial blood supply and demand, ...read more
31 January, 2025
TREATMENT OF CARDIOVASCULAR DISEASE IN CHRONIC AND END STAGE KIDNEY DISEASE
Cardiovascular disease still remains the leading cause of death in Chronic and End Stage Kidney Disease, accounting for more than half of all deaths in dialysis patients. During the past decade, research has been focused on novel therapeutic agents that might delay or even reverse cardiovascular disease and vascular calcification, ...read more
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Cancer Drug Targets
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Current Drug Therapy
Related Books
Drug Addiction Mechanisms in the Brain
Software and Programming Tools in Pharmaceutical Research
Objective Pharmaceutics: A Comprehensive Compilation of Questions and Answers for Pharmaceutics Exam Prep
Medicinal Chemistry of Drugs Affecting Cardiovascular and Endocrine Systems
Advanced Pharmacy
Plant-derived Hepatoprotective Drugs
The Role of Chromenes in Drug Discovery and Development
New Avenues in Drug Discovery and Bioactive Natural Products
Practice and Re-Emergence of Herbal Medicine
Blood Oxidant Ties: The Evolving Concepts in Myocardial Injury and Cardiovascular Disease
Article Metrics
83
2