Abstract
In the last ten years, knowledge on pathophysiology of type 2 diabetes (T2DM) has significantly increased, with multiple failures (decreased incretin effect, increased lipolysis, increased glucagon secretion, neurotransmitters dysfunction) recognized as important contributors, together with decreased insulin secretion and reduced peripheral glucose uptake. As a consequence, the pharmacologic therapy of T2DM has been progressively enriched by several novel classes of drugs, trying to overcome these defects. The last, intriguing compounds come into the market are SGLT2 inhibitors, framing the kidney in a different scenario, not as site of a harmful disease complication, but rather as the means to correct hyperglycemia and fight the disease. This review aims to offer a short, updated overview of the role of these compounds in the treatment of T2DM, focusing on efficacy, ancillary albeit relevant clinical effects, safety, potential cardiovascular protection, positioning in common therapeutic algorithms.
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References
Wright E, Loo D, Hirayama B (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794
Dyer J, Daly K, Salmon KS et al (2007) Intestinal glucose sensing and regulation of intestinal glucose absorption. Biochem Soc Trans 35(Pt 5):1191–1194
Ferrannini E, Solini A (2012) SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 8:495–502
Tabatabai NM, Sharma M, Blumenthal SS et al (2009) Enhanced expressions of sodium–glucose cotransporters in the kidneys of diabetic Zucker rats. Diabetes Res Clin Pract 83:e27–e30
Freitas HS, Anhe GF, Melo KF et al (2008) Na(+)-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology 149:717–724
Rahmoune H, Thompson PW, Ward JM et al (2005) Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54:3427–3434
Campos C (2012) Chronic hyperglycemia and glucose toxicity: pathology and clinical sequelae. Postgrad Med 124:90–97
Ehrenkranz J, Lewis N, Kahn C et al (2005) Phlorizin: a review. Diabetes Metab Res Rev 21:31–38
Rossetti L, Smith D, Shulman GI et al (1987) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79:1510–1515
Scheen AJ (2014) Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 10:647–663
Komoroski B, Vachharajani N, Boulton D et al (2009) Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 85:520–526
Devineni D, Curtin CR, Polidori D et al (2013) Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol 53:601–610
Heise T, Seewaldt-Becker E, Macha S et al (2013) Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab 15:613–621
Kasichayanula S, Chang M, Hasegawa M et al (2011) Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium–glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes Metab 13:357–365
List JF, Whaley JM (2011) Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int 120(Suppl):S20–27
Liu JJ, Lee T, DeFronzo RA (2012) Why do SGLT2 inhibitors inhibit only 30–50 % of renal glucose reabsorption in humans? Diabetes 61:2199–2204
Weinstein AM (2015) A mathematical model of the rat nephron: glucose transport. Am J Physiol Ren Physiol 308:F1098–F1118
Gavin JR 3rd, Davies MJ, Davies M et al (2015) The efficacy and safety of canagliflozin across racial groups in patients with type 2 diabetes mellitus. Curr Med Res Opin 31:1693–1702
Riggs MM, Staab A, Seman L et al (2013) Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. J Clin Pharmacol 53:1028–1038
Macha S, Lang B, Pinnetti S et al (2014) Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther 52:973–980
Devineni D, Manitpisitkul P, Vaccaro N et al (2015) Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants. Int J Clin Pharmacol Ther 53:41–53
Berhan A, Barker A (2013) Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord 13:58
Ferrannini E, Ramos SJ, Salsali A et al (2010) Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 33:2217–2224
Stenlof K, Cefalu WT, Kim KA et al (2013) Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 15:372–382
Roden M, Weng J, Eilbracht J et al (2013) Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 1:208–219
Wilding JP, Woo V, Rohwedder K et al (2014) Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 16:124–136
Ahmann A (2015) Combination therapy in type 2 diabetes mellitus: adding empagliflozin to basal insulin. Drugs Context 4:212288
Ridderstråle M, Andersen KR, Zeller C et al (2014) Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2:691–700
Leiter LA, Yoon KH, Arias P et al (2015) Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 38:355–364
Del Prato S, Nauck M, Durán-Garcia S et al (2015) Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab 17:581–590
Merovci A, Mari A, Solis C et al (2015) Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J Clin Endocrinol Metab 100:1927–1932
Polidori D, Mari A, Ferrannini E (2014) Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia 57:891–901
Merovci A, Solis-Herrera C, Daniele G et al (2014) Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 124:509–514. Erratum in: J Clin Invest 2014;124:2287
Bailey CJ, Morales Villegas EC, Woo V et al (2015) Efficacy and safety of dapagliflozin monotherapy in people with type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial. Diabet Med 32:531–541
Häring HU, Merker L, Seewaldt-Becker E et al (2014) Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 37:1650–1659
Strojek K, Yoon KH, Hruba V et al (2014) Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther 5:267–283
Kovacs CS, Seshiah V, Swallow R et al (2014) Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 16:147–158
Sjöström CD, Hashemi M, Sugg J et al (2015) Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab 17:809–812
Yang XP, Lai D, Zhong XY et al (2014) Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur J Clin Pharmacol 70:1149–1158
Rosenstock J, Jelaska A, Frappin G et al (2014) Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37:1815–1823
Bolinder J, Ljunggren Ö, Kullberg J et al (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97:1020–1031
Ferrannini G, Hach T, Crowe S et al (2015) Energy balance after sodium–glucose cotransporter 2 inhibition. Diabetes Care 38:1730–1735
Cefalu WT, Stenlöf K, Leiter LA et al (2015) Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia 58:1183–1187
Sjöström CD, Johansson P, Ptaszynska A et al (2015) Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res 12:352–358
Cherney DZI, Perkins BA, Soleymanlou N et al (2014) Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:587–597
Tikkanen I, Narko K, Zeller C et al (2015) Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38:420–428
Townsend RR, Machin I, Ren J et al (2016) Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich) 18:43–52
Baker WL, Smyth LR, Riche DM et al (2014) Effects of sodium–glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens 8(262–275):e9
Matthaei S, Bowering K, Rohwedder K et al (2015) Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab 17:1075–1084
Stenlöf K, Cefalu WT, Kim KA et al (2014) Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin 30:163–175
Inagaki N, Goda M, Yokota S et al (2015) Effects of baseline blood pressure and low-density lipoprotein cholesterol on safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus. Adv Ther 32:1085–1103
Zhao G, Huang L, Song M et al (2013) Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis 23:61–68
Chino Y, Samukawa Y, Sakai S et al (2014) SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 35:391–404
Goring S, Hawkins N, Wygant G et al (2014) Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis. Diabetes Obes Metab 16:433–442
Liakos A, Karagiannis T, Athanasiadou E et al (2014) Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 16:984–993
Sinclair A, Bode B, Harris S et al (2014) Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord 14:37
Lambers Heerspink HJ, de Zeeuw D, Wie L et al (2013) Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15:853–862
Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38:1638–1642
Taylor SI, Blau JE, Rother KI (2015) Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 3:8–10
Quarles LD (2012) Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8:276–286
Watts NB, Bilezikian JP, Usiskin K et al (2016) Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 101:157–166
Grandy S, Sternhufvud C, Ryden A et al (2016) Patient-reported outcomes among type 2 diabetes mellitus patients treated with dapagliflozin in triple therapy regimen for 52 weeks. Diabetes Obes Metab 18:306–309
Lin HW, Tseng CH (2014) A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol 2014:719578
Leiter LA, Cefalu WT, de Bruin TW et al (2014) Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc 62:1252–1262
Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128
Ferrannini E, Veltkamp SA, Smulders RA et al (2013) Renal glucose handling: impact of chronic kidney disease and sodium–glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 36:1260–1265
Barnett AH, Mithal A, Manassie J et al (2014) 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 2:369–384
Solini A (2016) Extra-glycaemic properties of empagliflozin. Diabetes Metab Res Rev 32:230–237
Ruggenenti P, Porrini EL, Gaspari F et al (2012) Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35:2061–2068
Kohan DE, Fioretto P, Tang W et al (2014) 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 85:962–971
Powers MA, Bardsley J, Cypress M et al (2015) Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Care 38:1372–1382
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Solini, A. Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Acta Diabetol 53, 863–870 (2016). https://doi.org/10.1007/s00592-016-0856-y
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DOI: https://doi.org/10.1007/s00592-016-0856-y