Abstract
Background & Introduction: The advent of the sodium-glucose cotransporter-2 inhibitors [SGLT-2i] provides an additional tool to combat diabetes and complications. The use of SGLT-2i leads to effective and durable glycemic control with important reductions in body weight/fat and blood pressure. These agents may delay beta-cell deterioration and improve tissue insulin sensitivity, which might slow the progression of the disease.
Methods & Results: In response to glycosuria, a compensatory rise in endogenous glucose production, sustained by a decrease in plasma insulin with an increase in glucagon has been described. Other possible mediators have been implicated and preliminary findings suggest that a sympathoadrenal discharge and/or rapid elevation in circulating substrates (i.e., fatty acids) or some yet unidentified humoral factors may have a role in a renal-hepatic inter-organ relationship. A possible contribution of enhanced renal gluconeogenesis to glucose entry into the systemic circulation has not yet been ruled out. Additionally, tissue glucose utilization decreases, whereas adipose tissue lipolysis is stimulated and, there is a switch to lipid oxidation with the formation of ketone bodies; the risk for keto-acidosis may limit the use of SGLT-2i. These metabolic adaptations are part of a counter-regulatory response to avoid hypoglycemia and, as a result, limit the SGLT-2i therapeutic efficacy. Recent trials revealed important cardiovascular [CV] beneficial effects of SGLT-2i drugs when used in T2DM patients with CV disease. Although the underlying mechanisms are not fully understood, there appears to be “class effect”. Changes in hemodynamics and electrolyte/body fluid distribution are likely involved, but there is no evidence for anti-atherosclerotic effects.
Conclusion: It is anticipated that, by providing durable diabetes control and reducing CV morbidity and mortality, the SGLT-2i class of drugs is destined to become a priority choice in diabetes management.
Keywords: SGLT-2i agents, glycosuria, type 2 diabetes, cardiovascular disease, keto-acidosis, glucose kinetics.
[1]
Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycemia of diabetes mellitus: therapeutic implications. Diabet Med 2010; 27: 136-42.
[3]
Forst T, Heise T, Plum-Morschel L. Pharmacological interventions in type 2 diabetes mellitus – a pathophysiological reasoned approach. Curr Diabetes Rev 2016; 12(4): 429-39.
[4]
Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005; 54(12): 3427-34.
[5]
Morgensen CE. Renal tubular transport activity in type 1 diabetes. Scand J Clin Lab Invest 1971; 28: 101-9.
[6]
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124(2): 509-14.
[7]
Cersosimo E. Renal glucose handling and the kidney as a target for anti-diabetic medication. Curr Trends Endocrinol 2014; 7: 81-94.
[8]
Wilding JPH, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: A randomised trial. Int J Clin Pract 2013; 67(12): 1267-82.
[9]
Mathieu C, Ranetti AE, Li D, et al. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care 2015; 38(11): 2009-17.
[10]
Mathews JC. Empagliflozin for type 2 diabetes mellitus: An overview of phase 3 clinical trials. Curr Diabetes Rev 2017; 13(4): 405-23.
[11]
Cahill GF Jr, Herrera MG, Morgan AP. Hormone-fuel interrelationships during fasting. J Clin Invest 1966; 45: 1751-69.
[12]
Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr. Liver and kidney metabolism during prolonged starvation. J Clin Invest 1969; 45: 574-83.
[13]
Cersosimo E, Judd R, Miles JM. Insulin regulation of renal glucose metabolism in conscious dogs. J Clin Invest 1994; 93: 2584-9.
[14]
Gianchandani RY, Neupane S, Iyengar JJ, Heung M. Pathophysiology and management of hypoglycemia in end stage renal disease patients: a review. Endocr Pract 2017; 23: 353-62.
[15]
Cersosimo E, Molina PE, Abumrad NN. Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia. Diabetes 1998; 46: 643-6.
[16]
Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich JE. Uptake and release of glucose by the human kidney: post-absorptive rates and responses to epinephrine. J Clin Invest 1995; 96: 2528-33.
[17]
Cersosimo E, Garlick P, Ferretti J. Insulin regulation of renal glucose metabolism in humans. Am J Physiol Endocrinol Metab 1999; 276(39): E78-84.
[18]
Ekberg K, Landau BR, Wajngot A, et al. Contributions by the kidney and liver to glucose production in the post-absorptive state and after 60 h of fasting. Diabetes 1999; 48: 292-8.
[19]
Cersosimo E, Garlick P, Ferretti J. Abnormal glucose handling by the kidney in response to hypoglycemia in type 1 diabetes. Diabetes 2001; 50: 2087-93.
[20]
Krebs HA, Hems RA, Gascoyne T. Renal gluconeogenesis IV: gluconeogenesis from substrate combinations. Acta Biol Med Ger 1963; 11: 607-15.
[21]
Eid A, Bodin S, Ferrier B. Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats. J Am Soc Nephrol 2006; 17: 398-405.
[24]
Klein KL, Wang MS, Torikai W, Davidson D, Kenokawa K. Substrate oxidation by isolated single nephron segments in rat. Kidney Int 1981; 20: 29-35.
[26]
Weiderman MJ, Krebs HA. The fuel of respiration of rat renal cortex. Biochem J 1969; 20: 149-65.
[28]
Aronson PS, Sacktor B. The Na+ gradient-dependent transport of D-glucose in renal brush border membranes. J Biol Chem 1975; 250: 6032-9.
[29]
Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose co-transporters. Physiol Rev 1994; 74: 993-1026.
[31]
Lee WS, Kanai Y, Wells RG, et al. The high affinity Na+/glucose co-transporter: re-evaluation of function and distribution of expression. J Biol Chem 1994; 269: 12032-9.
[32]
Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human
kidney low-affinity Na+-glucose co-transporter SGLT2. Delineation
of the major renal reabsorptive mechanism for D-glucose J
Clin Invest 1994; 93: 397-404.
[33]
Gorboulev GV, Schlormann A, Vallon V, et al. Na+ D-glucose co-transporter SGLT-1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 2012; 61: 187-96.
[34]
Al-Jobori H, Daniele G, Cersosimo E. Triplitt C, Norton L, De-
Fronzo R, Abdul-Ghani M.Empagliflozin and Kinetics of Renal Glucose Transport in Healthy and Type 2 Diabetic Individuals. Diabetes 2017; 66: 1999-2006.
[35]
Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951; 30: 125-9.
[36]
Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971; 28: 101-9.
[37]
DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017; 13: 11-26.
[38]
DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 2013; 36: 3169-76.
[39]
Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycemia: the pleiotropic effects of SGLT-2 inhibition. Diabetologia 2017; 60: 215-25.
[40]
Wang Y, Wang C, Zhang X, Gu HF, Wu L. Common drugs for stabilization of renal function in the progression of diabetic nephropathy and their relations with hypertension therapy. Curr Diabetes Rev 2018; 14(2): 149-61.
[41]
Rosetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 1987; 80: 1037-44.
[42]
Ehrenkranz JRL, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev 2005; 21(1): 31-8.
[43]
Oku A, Ueta K, Arakawa K. T-1095, an inhibitor of renal Na+-glucose co-transporters may provide a novel approach to treating diabetes. Diabetes 1999; 48: 1794-800.
[44]
Isaji M. Sodium-glucose co-transporter inhibitors for diabetes. Curr Opin Investig Drugs 2007; 8(4): 285-92.
[45]
Tsujhara K. Na-glucose co-transporter (SGLT) inhibitors as anti-diabetic agents. Synthesis and pharmacological properties of 4′-dihydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999; 42(26): 5311-24.
[46]
Obermeier MT, Yao M, Khanna A, et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II (SGLT2) inhibitor, in animals and humans. Drug Metab Dispos 2010; 38(3): 405-14.
[47]
Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. New drug–drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus. Clin Pharmacokinet 2012; 52(4): 457-63.
[48]
Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co‐transporter-2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol 2013; 53(6): 601-10.
[49]
Scheen AJ. Pharmacodynamics, efficacy and safety of Sodium–Glucose Co-Transporter Type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 2015; 75(1): 33-59.
[50]
Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of sglt2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet 2015; 54(7): 691-708.
[51]
Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion. Diabetes Care 2013; 36: 2154-6.
[52]
Liu JJ, Lee TW, DeFronzo RA. Why do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes 2012; 61: 2199-204.
[53]
Komoroski B, Vachharanji N, Boulton D. Dapagliflozin, a novel SGLT2 inhibitor induces dose-dependent glycosuria in healthy subjects. Clin Pharmacol Ther 2009; 85: 520-6.
[54]
Kipnes MS. Sodium-glucose co-transporter 2 inhibitor in the treatment of type 2 diabetes: a review of Phase II and III trials. Clin Invest 2011; 1: 145-56.
[55]
Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223-33.
[56]
Nauck M, Del PS, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin. Diabetes Care 2011; 34: 2015-22.
[57]
Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose co-transporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012; 35: 1232-8.
[58]
Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium–glucose co-transporter 2 inhibition. Diabetes Care 2015; 38: 1730-5.
[59]
Del Prato S. SGLT-2 Inhibitors Show Durability in Glycemic Control, Weight-Loss Maintenance After 4 Years. American Diabetes Association Annual Meeting. Chicago. 2016.
[60]
Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes with inadequate glycemic control on metformin. J Clin Endocrinol Metab 2012; 97: 1020-31.
[61]
Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med 2015; 66: 255-70.
[62]
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: F194-204.
[63]
Terami N, Ogawa D, Tachibana H, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One 2014; 9: e100777.
[64]
Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently
of glycemic effects. J Am Soc Nephrol 2016;
[http://dx.doi.org/doi:10.1681 /ASN.2016030278]
[http://dx.doi.org/doi:10.1681 /ASN.2016030278]
[65]
Cherney DZI, 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: 587-97.
[66]
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.
[67]
Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events. Circulation 2018; 137: 323-34.
[68]
Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose co-transporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124(2): 499-508.
[69]
Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 2008; 31: 643-7.
[70]
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose co-transporter 2 inhibition. Diabetes Care 2015; 38(9): 1687-93.
[71]
Handelsman Y. The american association of clinical endocrinologists and american college of endocrinology position statement on the association of sglt-2 inhibitors and diabetic ketoacidosis. Endocr Pract 2016; 22: 753-62.
[72]
Neal B, Perkovic V. Mahaffey KW on behalf of the CANVAS Program Collaborative Group. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018; 137: 323-34.
[73]
Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPA-Reg outcome study. Diabetes Care 2016; 39: 1-9.
[74]
Kosiborod M, Cavender MA, Fu AZ, et al. Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation 2017.
[http://dx.doi.org/0.1161/CIRCULATIONAHA.117.029190]
[http://dx.doi.org/0.1161/CIRCULATIONAHA.117.029190]
[75]
Bertero EP, Roma L, Ameri P, Maack C. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res 2018; 114(1): 12-8.
[76]
Aloia JF, Cohn SH, Abesamis C, Babu J, Zanzi I, Elllis K. Total body sodium and sodium excess. J Nucl Med 1980; 21(2): 130-4.
[77]
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG outcome trial: A “Thrifty substrate” hypothesis. Diabetes Care 2016; 39(7): 1108-14.
[78]
Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005; 85: 1093-29.
[79]
Kevin D, Hall KD, Chen KY, et al. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. Am J Clin Nutr 2016; 104: 324-34.
[80]
Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): A 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2016; 4: 1004-16.
[81]
Li D, Shi W, Wang T, Tang H. SGLT2 inhibitor plus DPP-4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2018; 20(8): 1972-6.
[82]
John M, Gopinath D, Jagesh R. Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives. Indian J Endocrinol Metab 2016; 20(1): 22-31.
Article Metrics
44
5
3
2