Top

Published in:

01-12-2016 | Review Article

Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus

Author: Anna Solini

Published in: Acta Diabetologica | Issue 6/2016

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.

Wright E, Loo D, Hirayama B (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794CrossRefPubMed

Dyer J, Daly K, Salmon KS et al (2007) Intestinal glucose sensing and regulation of intestinal glucose absorption. Biochem Soc Trans 35(Pt 5):1191–1194CrossRefPubMed

Ferrannini E, Solini A (2012) SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 8:495–502CrossRefPubMed

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–e30CrossRefPubMed

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 149:717–724CrossRefPubMed

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 54:3427–3434CrossRefPubMed

Campos C (2012) Chronic hyperglycemia and glucose toxicity: pathology and clinical sequelae. Postgrad Med 124:90–97CrossRefPubMed

Ehrenkranz J, Lewis N, Kahn C et al (2005) Phlorizin: a review. Diabetes Metab Res Rev 21:31–38CrossRefPubMed

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 79:1510–1515CrossRefPubMedPubMedCentral

10.

Scheen AJ (2014) Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 10:647–663CrossRefPubMed

11.

Komoroski B, Vachharajani N, Boulton D et al (2009) Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 85:520–526CrossRefPubMed

12.

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 53:601–610CrossRefPubMed

13.

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 15:613–621CrossRefPubMed

14.

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 13:357–365CrossRefPubMed

15.

List JF, Whaley JM (2011) Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int 120(Suppl):S20–27CrossRef

16.

Liu JJ, Lee T, DeFronzo RA (2012) Why do SGLT2 inhibitors inhibit only 30–50 % of renal glucose reabsorption in humans? Diabetes 61:2199–2204CrossRefPubMed

17.

Weinstein AM (2015) A mathematical model of the rat nephron: glucose transport. Am J Physiol Ren Physiol 308:F1098–F1118CrossRef

18.

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 31:1693–1702CrossRefPubMed

19.

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 53:1028–1038CrossRefPubMed

20.

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 52:973–980CrossRefPubMed

21.

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 53:41–53CrossRefPubMed

22.

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 13:58CrossRefPubMedPubMedCentral

23.

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 33:2217–2224CrossRefPubMedPubMedCentral

24.

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 15:372–382CrossRefPubMedPubMedCentral

25.

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 1:208–219CrossRefPubMed

26.

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 16:124–136CrossRefPubMed

27.

Ahmann A (2015) Combination therapy in type 2 diabetes mellitus: adding empagliflozin to basal insulin. Drugs Context 4:212288PubMedPubMedCentral

28.

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 2:691–700CrossRefPubMed

29.

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 38:355–364CrossRefPubMed

30.

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 17:581–590CrossRefPubMed

31.

Merovci A, Mari A, Solis C et al (2015) Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J Clin Endocrinol Metab 100:1927–1932CrossRefPubMedPubMedCentral

32.

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 57:891–901CrossRefPubMedPubMedCentral

33.

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

34.

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 32:531–541CrossRefPubMed

35.

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 37:1650–1659CrossRefPubMed

36.

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 5:267–283CrossRefPubMedPubMedCentral

37.

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 16:147–158CrossRefPubMed

38.

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 17:809–812CrossRefPubMed

39.

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 70:1149–1158CrossRefPubMed

40.

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 37:1815–1823CrossRefPubMed

41.

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 97:1020–1031CrossRefPubMed

42.

Ferrannini G, Hach T, Crowe S et al (2015) Energy balance after sodium–glucose cotransporter 2 inhibition. Diabetes Care 38:1730–1735CrossRefPubMedPubMedCentral

43.

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 58:1183–1187CrossRefPubMedPubMedCentral

44.

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 12:352–358CrossRefPubMed

45.

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 129:587–597CrossRefPubMed

46.

Tikkanen I, Narko K, Zeller C et al (2015) Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38:420–428CrossRefPubMed

47.

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) 18:43–52CrossRef

48.

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

49.

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 17:1075–1084CrossRefPubMed

50.

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 30:163–175CrossRefPubMed

51.

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 32:1085–1103CrossRefPubMedPubMedCentral

52.

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 23:61–68CrossRef

53.

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 35:391–404CrossRefPubMedPubMedCentral

54.

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 16:433–442CrossRefPubMed

55.

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 16:984–993CrossRefPubMed

56.

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 14:37CrossRefPubMedPubMedCentral

57.

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 15:853–862CrossRefPubMed

58.

Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38:1638–1642CrossRefPubMed

59.

Taylor SI, Blau JE, Rother KI (2015) Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 3:8–10CrossRefPubMed

60.

Quarles LD (2012) Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8:276–286CrossRefPubMedPubMedCentral

61.

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 101:157–166CrossRefPubMed

62.

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

63.

Lin HW, Tseng CH (2014) A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol 2014:719578PubMedPubMedCentral

64.

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 62:1252–1262CrossRefPubMed

65.

Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128CrossRefPubMed

66.

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 36:1260–1265CrossRefPubMedPubMedCentral

67.

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 2:369–384CrossRefPubMed

68.

Solini A (2016) Extra-glycaemic properties of empagliflozin. Diabetes Metab Res Rev 32:230–237

69.

Ruggenenti P, Porrini EL, Gaspari F et al (2012) Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35:2061–2068CrossRefPubMedPubMedCentral

70.

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 85:962–971CrossRefPubMed

71.

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 38:1372–1382CrossRefPubMed

Title: Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus
Author: Anna Solini
Publication date: 01-12-2016
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 6/2016
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-016-0856-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2016

Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma

Acute-phase proteins and incidence of diabetes: a population-based cohort study

Sex ratio at birth is associated with type 1 diabetes characteristics

Lipid and inflammatory biomarker profiles in early insulin resistance

Biventricular takotsubo cardiomyopathy in an elderly woman with uncontrolled type 2 diabetes: the biphasic echocardiographic and clinical pattern

Muscle dysfunction in type 2 diabetes: a major threat to patient’s mobility and independence

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page