Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

Pinto, Lana C.; Rados, Dimitris V.; Remonti, Luciana R.; Viana, Marina V.; Leitão, Cristiane B.; Gross, Jorge L.

doi:10.20945/2359-3997000000440

Lana C. Pinto Correspondence to: Lana C. Pinto, lanacfp@gmail.com

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0003-0954-8622

Dimitris V. Rados

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0003-0819-5343

Luciana R. Remonti

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0003-3117-804X

Marina V. Viana

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0001-9564-4885

Cristiane B. Leitão

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0002-2106-309X

Jorge L. Gross

Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pósgraduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil

http://orcid.org/0000-0003-4721-4623

Correspondence to: Lana C. Pinto, lanacfp@gmail.com

Disclosure: J.L.G. reports holding grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) during the conduct of the study, grants and other from Eli Lilly, grants from Bristol-Myers Squibb, grants and other from Boehringer Ingelheim, grants from GlaxoSmithKline, grants and other from Novo Nordisk, and grants from Janssen, outside the submitted work. No other relationships or activities that could appear to have influenced the submitted work are reported. C.B.L. receives a scholarship from CNPq (PQ-2). L.C.P., D.V.R, L.R.R. and M.V.V. declare that they have no competing interests.

Author contributions: all authors revised the final version of the manuscript. L.C.P. retrieved the full texts, abstracted the data, performed statistical analysis and wrote the first draft of the manuscript; D.V.R. retrieved the full texts and abstracted the data; L.R.R. performed statistical analysis; M. V.V. performed statistical analysis; C.B.L. performed statistical analysis; J.L.G. conceived the study idea and performed statistical analysis. L.C.P. is the guarantor for the contents of the article, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Author Year	n	Follow-up (wk)	Men (%)	Mean age (y)	Mean diabetes duration (y)	Mean HbA_1c (%)	Mean weight (kg)	Background treatment	SGLT2 inhibitor/dose
Bailey 2013 (²⁶26 Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.)	546	24	53.48	59.9	NR	8.05	85.91	Metformin	Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
Wilding 2012 (²⁵25 Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405-15.)	808	48	47.28	59.3	13.6	8.53	93.82	Insulin and/or OAD	Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg
Wilding 2009 (²⁷27 Wilding JP, Norwood P, T'joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656-62.)	71	12	59.15	56.7	12.3	8.43	102.10	Insulin	Dapagliflozin 10 mg Dapagliflozin 20 mg
Rosenstock 2012 (²⁸28 Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35:1473-8.)	420	48	49.52	53.4	NR	8.37	86.30	Pioglitazone	Dapagliflozin 5 mg Dapagliflozin 10 mg
Bode 2013 (²⁹29 Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013;41(2):72-84.)	714	102	55.46	52.9	11.7	7.70	89.50	Naïve or OAD	Canagliflozin 100 mg Canagliflozin 300 mg
Wilding 2013 (³⁰30 Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, 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;67:1267-82.)	343	12	51.02	57.4	5.9	7.76	89.76	Metformin	Canagliflozin 100 mg Canagliflozin 300 mg
Zinman 2015 (⁸8 Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.)	7020	192	71.45	63.1	NR	8.07	86.3	Any	Empagliflozin 10 mg Empagliflozin 25 mg
Yang 2018 (³¹31 Yang W, Ma J, Li Y, Li Y, Zhou Z, Kim JH, et al. Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial. J Diabetes. 2018;10:589-99.)	275	24	47.8	57.5	12.5	8.55	71.8	Insulin ± OAD	Dapagliflozin 10 mg
Januzzi 2017 (³²32 Januzzi JL Jr, Butler J, Jarolim P, Sattar N, Vijapurkar U, Desai M, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol. 2017;70:704-12.)	714	26	55.4	63.6	NR	NR	NR	OAD	Canagliflozin 100 mg Canagliflozin 300 mg
Haering 2015 (³³33 Haering HU, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, et al. Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes. Diabetes Res Clin Pract. 2015;110:82-90.)	666	76	50.9	57.1	NR	8.1	76.9	Metformin + sulphonylurea	Empagliflozin 10 mg Empagliflozin 25 mg
Jabbour 2014 (³⁴34 Jabbour SA, Hardy E, Sugg J, Parikh S; Study 10 Group. Dapagliflozin Is Effective as add-on therapy to sitagliptin with or without metformin: A 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740-50.)	447	24	54.80	54.8	5.67	7.95	90.1	Sitagliptin ± metformin	Dapagliflozin 10 mg
Matthaei 2015 (³⁵35 Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E; Study 05 Group. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17:1075-84.)	216	24	49.07	61	9.4	8.16	89.35	Metformin + sulphnylurea	Dapagliflozin 10 mg
Leiter 2014 (³⁶36 Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. 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. 2014;62:1252-62.)	964	24	67.01	63.7	NR	8.0	93.8	OAD	Dapagliflozin 10 mg
Stenlöf 2013 (³⁷37 Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372-82.)	584	26	44.18	55.4	4.3	8.00	86.8	Diet + exercise	Canagliflozin 100 mg Canagliflozin 300 mg
Roden 2013 (³⁸38 Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. 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. 2013;1:208-19.)	899	24	61	55	NR	7.88	78.4	No treatment for at least 12 weeks	Empagliflozin 10 mg Empagliflozin 25 mg
Tikkanen 2015 (³⁹39 Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-8.)	823	12	60.1	60.2	NR	7.90	NR	Diet + exercise	Empagliflozin 10 mg Empagliflozin 25 mg
Yale 2014 (⁴⁰40 Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, 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(10):1016-27.)	269	52	60.59	68.5	16.3	8.00	NR	Insulin	Canagliflozin 100 mg Canagliflozin 300 mg
Fulcher 2016 (⁴¹41 Fulcher G, Matthews DR, Perkovic V, de Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:82-91.)	316	18	65.50	63.0	12.6	8.1	NR	DPP-4 inhibitor	Canagliflozin 100 mg Canagliflozin 300 mg

Dapa 2.5	0.11 [-0.001; 0.22]	0.25 [0.14; 0.35]	-0.35 [-0.44; −0.25]	0.23 [0.12; 0.34]	0.29 [0.18; 0.40]	0.26 [0.16; 0.37]	0.44 [0.33; 0.54]
0.58 [0.02; 1.14]	Dapa 5	0.13 [0.04; 0.23]	-0.46 [-0.55; −0.38]	0.12 [0.02; 0.22]	0.18 [0.07; 0.28]	0.15 [0.05; 0.25]	0.33 [0.23; 0.42]
0.57 [0.06; 1.07]	-0.01 [-0.46; 0.44]	Dapa 10	-0.59 [-0.66; −0.54]	-0.01 [-0.09; 0.07]	0.04 [0.04; 0.12]	0.01 [-0.06; 0.09]	0.19 [0.12; 0.27]
-1.31 [-1.78; −0.84]	-1.89 [-2.32; −1.47]	-1.88 [-2.16; −1.60]	Placebo	0.58 [0.64; 0.52]	0.64 [0.69; 0.58]	0.61 [0.57; 0.66]	0.79 [0.75; 0.84]
0.46 [-0.11; 1.04]	-0.11 [-0.65; 0.42]	-0.10 [-0.54; 0.33]	1.77 [1.44; 2.11]	Empa 10	-0.05 [-0.00; 0.10]	0.03 [-0.10; 0.04]	0.21 [0.13; 0.28]
0.76 [0.18; 1.34]	0.18 [-0.35; 0.71]	0.19 [-0.24; 0.62]	2.07 [1.74; 2.41]	0.29 [0.01; 0.58]	Empa 25	-0.02 [-0.04; 0.09]	0.15 [0.08; 0.22]
0.64 [0.05; 1.23]	0.05 [-0.49; 0.60]	0.07 [-0.38; 0.52]	1.95 [1.60; 2.30]	0.17 [-0.31; 0.66]	-0.12 [-0.60; 0.36]	Cana 100	0.18 [0.13; 0.22]
1.04 [0.43; 1.65]	0.46 [-0.11; 1.03]	0.47 [0.001; 0.94]	2.35 [1.97; 2.73]	0.58 [0.07; 1.08]	0.28 [-0.22; 0.78]	0.40 [0.01; 0.79]	Cana 300

[1] Correspondence to: Lana C. Pinto, lanacfp@gmail.com

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Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

ABSTRACT