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01-08-2018 | Ertugliflozin | Article

Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study

Journal: Diabetes Therapy

Authors: Sam Miller, Tania Krumins, Haojin Zhou, Susan Huyck, Jeremy Johnson, Gregory Golm, Steven G. Terra, James P. Mancuso, Samuel S. Engel, Brett Lauring

Publisher: Springer Healthcare

Abstract

Introduction

Ertugliflozin is an oral sodium-glucose cotransporter 2 inhibitor that is being developed to treat type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of co-initiation of ertugliflozin and sitagliptin compared with placebo in patients with T2DM inadequately controlled on diet and exercise.

Methods

In this phase III, randomized, double-blind, multicenter, placebo-controlled 26-week study (NCT02226003), patients with T2DM and glycated hemoglobin (HbA1c) 8.0–10.5% on diet/exercise were randomized 1:1:1 to ertugliflozin 5 mg once daily (QD) and sitagliptin 100 mg QD (E5/S100), ertugliflozin 15 mg QD and sitagliptin 100 mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26.

Results

The mean baseline HbA1c of the randomized patients (n = 291) was 8.9%. At week 26, both ertugliflozin/sitagliptin treatments provided significant reductions from baseline in HbA1c compared with placebo [least squares mean HbA1c change (95% confidence intervals) from baseline was − 0.4% (− 0.7, − 0.2), − 1.6% (− 1.8, − 1.4), and − 1.7% (− 1.9, − 1.5) for placebo, E5/S100, and E15/S100, respectively]. At week 26, 8.3%, 35.7%, and 31.3% of patients receiving placebo, E5/S100, and E15/S100, respectively, had HbA1c < 7.0%. Significant reductions in fasting plasma glucose, 2-h post-prandial glucose, body weight, and systolic blood pressure were observed with both ertugliflozin/sitagliptin groups compared with placebo. The incidence of adverse events (AEs) was similar across the groups. The incidences of the pre-specified AEs of urinary tract infection, genital mycotic infection, symptomatic hypoglycemia, and hypovolemia were low and not meaningfully different across groups.

Conclusion

Co-initiation of ertugliflozin with sitagliptin in patients with T2DM inadequately controlled on diet and exercise provided a clinically meaningful improvement in glycemic control over 26 weeks.

Clinical Trial Registration

Clinicaltrials.gov NCT02226003.
Literature
1.
American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40:S64–74.CrossRef
2.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9.CrossRefPubMed
3.
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2017 executive summary. Endocr Pract. 2017;23:207–38.CrossRefPubMed
4.
Harper W, Clement M, Goldenberg R, Hanna A, Main A, Retnakaran R, et al. Pharmacologic management of type 2 diabetes. Can J Diabetes. 2013;37:S61–8.CrossRefPubMed
5.
Korytkowski MT, Brooks M, Lombardero M, DeAlmeida D, Kanter J, Magaji V, et al. Use of an electronic medical record (EMR) to identify glycemic intensification strategies in type 2 diabetes. J Diabetes Sci Technol. 2015;9:593–601.CrossRefPubMed
6.
Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36:3411–7.CrossRefPubMedPubMedCentral
7.
Fu AZ, Qiu Y, Davies MJ, Radican L, Engel SS. Treatment intensification in patients with type 2 diabetes who failed metformin monotherapy. Diabetes Obes Metab. 2011;13:765–9.CrossRefPubMed
8.
Olansky L, Reasner C, Seck TL, Williams-Herman DE, Chen M, Terranella L, et al. A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycemic agents. Diabetes Obes Metab. 2011;13:841–9.CrossRefPubMed
9.
Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med. 2013;368:1613–24.CrossRefPubMed
10.
Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 2002;287:360–72.CrossRefPubMed
11.
Amin NB, Wang X, Jain SM, Lee DS, Nucci G, Rusnak JM. Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin. Diabetes Obes Metab. 2015;17:591–8.CrossRefPubMed
12.
Amin NB, Wang X, Mitchell JR, Lee DS, Nucci G, Rusnak JM. Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension. Diabetes Obes Metab. 2015;17:805–8.CrossRefPubMed
13.
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;75:33–59.CrossRefPubMed
14.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.CrossRefPubMed
15.
Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008;24:489–96.CrossRefPubMed
16.
Terra SG, Focht K, Davies M, Frias J, Derosa G, Darekar A, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19:721–8.CrossRefPubMed
17.
Rosenstock J, Frias J, Pall D, Charbonnel B, Pascu R, Saur D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab. 2017. https://​doi.​org/​10.​1111/​dom.​13103.
18.
Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: the VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab. 2017. https://​doi.​org/​10.​1111/​dom.​13116.
19.
Eldor R, Pratley R, Golm G, et al. Effect of ertugliflozin plus sitagliptin on glycemic control versus either treatment alone in subjects with T2DM inadequately controlled with metformin (poster number 125-LB). In: 76th American Diabetes Association Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA.
20.
Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Dev Ther. 2017;11:2905–19.CrossRef
21.
Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564–71.CrossRefPubMed
22.
Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24:537–50.CrossRefPubMed
23.
U.S. Department of Health and Human Services. Guidance for industry diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. 2008. https://​www.​fda.​gov/​downloads/​Drugs/​…/​Guidances/​ucm071624.​pdf. Accessed 6 Dec 2017.
24.
Tura A, Kautzky-Willer A, Pacini G. Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT. Diabetes Res Clin Pract. 2006;72:298–301.CrossRefPubMed
25.
American Diabetes Association. Executive summary: standards of medical care in diabetes—2012. Diabetes Care. 2012;35:S4–10.CrossRef
26.
University of Oxford. HOMA calculator. 2004. http://​www.​dtu.​ox.​ac.​uk/​homacalculator/​. Accessed 6 Dec 2017.
27.
Liang K-Y, Zeger SL. Longitudinal data analysis of continuous and discrete responses for pre-post designs. Sankhya Ser B. 2000;62:134–48.
28.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4:213–26.CrossRefPubMed
29.
American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care. 2016;39:S1–112.CrossRef
30.
Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015;38:394–402.CrossRefPubMed
31.
Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–14.CrossRefPubMedPubMedCentral
32.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.CrossRefPubMedPubMedCentral
33.
Kalra S, Singh V, Nagrale D. Sodium-glucose cotransporter-2 inhibition and the glomerulus: a review. Adv Ther. 2016;33:1502–18.CrossRefPubMedPubMedCentral
34.
Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.CrossRefPubMed
35.
Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39(Suppl 2):S165–71.CrossRefPubMed
36.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
37.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.CrossRefPubMed

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