EMERGING THERAPIES: DRUGS AND REGIMENS Diabetes Care 1 fl Tina Vilsbøll,1 Ella Ekholm,2 Eva Johnsson,2 Dapagli ozin Plus Saxagliptin Nalina Dronamraju,3 Serge Jabbour,4 and Add-on Therapy Compared With Marcus Lind5 Insulin in Patients With Type 2 Diabetes Poorly Controlled by Metformin With or Without Sulfonylurea Therapy: A Randomized Clinical Trial https://doi.org/10.2337/dc18-1988 OBJECTIVE This study evaluated whether an oral combination of a sodium–glucose cotrans- porter 2 inhibitor and a dipeptidyl peptidase 4 inhibitor achieved glycemic control similar to basal insulin in patients with type 2 diabetes, poorly controlled with metformin, without increasing hypoglycemia or body weight. RESEARCH DESIGN AND METHODS In a multinational, open-label, randomized, phase 3 trial (NCT02551874), adults with type 2 diabetes inadequately controlled on metformin, with or without sulfonyl- urea, were randomized (1:1) to receive dapagliflozin (DAPA) plus saxagliptin (SAXA) or titrated insulin glargine (INS). The primary end point was change in glycated hemoglobin A1c (HbA1c) from baseline to week 24. DAPA + SAXA treatment was tested for noninferiority versus INS. 1Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark 2 RESULTS AstraZeneca Gothenburg, Molndal,¨ Sweden 3 fi 6 6 6 AstraZeneca, Gaithersburg, MD The ef cacy data set included 643 patients (mean SD HbA1c, 9.1 1.0% [75 4Division of Endocrinology, Thomas Jefferson 11 mmol/mol]). At week 24, DAPA + SAXA treatment versus INS resulted in University Hospital, Philadelphia, PA 5Institute of Medicine, University of Gothenburg, noninferior reductions in HbA1c (adjusted mean 6 SE change, 21.7 6 0.1% vs. 21.5 6 0.1% [18.3 6 0.7 mmol/mol vs. 16.8 6 0.7 mmol/mol]; P = 0.118), Gothenburg, Sweden significantly different body weight change (between-group difference, 23.64 kg Corresponding author: Tina Vilsbøll, t.vilsboll @dadlnet.dk [95% CI 24.20 to 23.09]; P < 0.001), fewer patients with confirmed hypoglycemia P < < Received 20 September 2018 and accepted 10 (21.3% vs. 38.4%, 0.001), more patients achieving HbA1c 7.0% (53 mmol/mol) May 2019 P without hypoglycemia (20.9% vs. 13.1%, = 0.008), and a similar proportion of Clinical trial reg. no. NCT02551874, clinicaltrials patients achieving HbA1c <7.0% (33.2% vs. 33.5%, P = 0.924). Mean reductions in .gov 24-h glucose measurements from baseline to week 2 were greater with DAPA + This article contains Supplementary Data online SAXA than with INS (P < 0.0001). No patients in the DAPA + SAXA group and three at http://care.diabetesjournals.org/lookup/suppl/ patients (0.9%) in the INS group experienced severe hypoglycemia. doi:10.2337/dc18-1988/-/DC1. © 2019 by the American Diabetes Association. CONCLUSIONS Readers may use this article as long as the work Adding DAPA + SAXA to insulin-na¨ıve patients with poorly controlled type 2 dia- is properly cited, the use is educational and not for profit, and the work is not altered. More infor- betes achieved similar glycemic control, a lower risk of hypoglycemia, and a clin- mation is available at http://www.diabetesjournals ically relevant body weight difference compared with basal INS. .org/content/license. Diabetes Care Publish Ahead of Print, published online June 4, 2019 2 Dual Add-on Oral Therapy Versus Insulin Diabetes Care Most patients with type 2 diabetes are body weight gain, which may reduce or Independent Ethics Committee before treated with metformin as a first-line patient compliance (13). Furthermore, initiation of the study. glucose-lowering monotherapy, as rec- insulin is administered by injection, ommended by treatment guidelines and titration is mandatory to obtain Participants and Eligibility Criteria (1,2). However, patients receiving met- acceptable glycemic control. Many pa- Adults ($18 years) with type 2 diabetes formin monotherapy often require the tients are reluctant to use insulin owing and inadequate glycemic control (HbA1c subsequent addition of one or more to psychological barriers, and health care 8.0–12.0% [64–108 mmol/mol]), who further glucose-lowering agents to achieve providers must have specialist knowl- had been receiving a stable dose of and maintain glycemic control as the dis- edge and resources to initiate and guide metformin ($1,500 mg/day), with or ease progresses (2). Sulfonylureas are the patients in the use of insulin therapy. It is without a stable dose of sulfonylurea most commonly prescribed drug after likely that many clinicians perceive in- ($50% maximum dose) for at least metformin, although treatment with this sulin to be more efficacious than oral 8 weeks before screening, were eligible drug class is associated with an increased therapies in patients with high HbA1c for enrollment. Participants were re- risk of hypoglycemia and weight gain (2). levels, because studies comparing insulin quired to have a maximum BMI of 2 An ideal therapy should be efficacious, with oral agents have generally excluded 45.0 kg/m at screening and a maximum achieve glycated hemoglobin A1c (HbA1c) these patients. No studies to date have fasting plasma glucose (FPG) measure- targets without hypoglycemia through evaluated whether an oral combination ment of 270 mg/dL at baseline. All par- complementary mechanisms of actions, of two modern glucose-lowering agents ticipants provided written, informed and result in weight reduction. Sodium– may achieve a similar glucose reduction consent. glucose cotransporter 2 (SGLT-2) inhib- as initiation and titration of a once-daily Key exclusion criteria were type 1 di- itors, glucagon-like peptide 1 receptor basal insulin analog in patients with abetes, cardiovascular disease (including agonists (GLP-1RAs), and dipeptidyl pep- type 2 diabetes inadequately controlled myocardial infarction; cardiac surgery or tidase 4 inhibitors (DPP-4is) are glucose- with metformin. revascularizations; valvular disease or lowering drugs that are recommended by Here, we report the results from a repair; unstable angina; unstable conges- international guidelines for use in com- randomized, open-label, 24-week, phase tive heart failure; transient ischemic attack bination with metformin (3). SGLT-2 in- 3 trial evaluating the efficacy and safety or significant cerebrovascular disease; hibitors promote urinary excretion of of DAPA plus SAXA add-on therapy versus unstable or previously undiagnosed ar- excess glucose by inhibiting renal glucose titrated insulin in patients with type 2 rhythmia; congestive heart failure de- reabsorption and act independently of diabetes inadequately controlled by met- fined as New York Heart Association insulin (4), whereas DPP-4is and GLP- formin with or without sulfonylurea ther- Functional Classification III and IV; un- 1RAs enhance glucose-dependent insulin apy. The primary objective of this study stable or acute congestive heart failure; secretion and suppress glucagon secre- was to determine whether DAPA plus and/or known left ventricular ejection tion (5). GLP-1RAs are generally recom- SAXA treatment was noninferior to ti- fraction of #40%) within 3 months of fi mended by clinical guidelines as the first trated insulin in reducing HbA1c. Secondary screening, severe hepatic insuf ciency, injectable medication for patients with objectives included effects on hypogly- and a medical history of diabetic keto- type 2 diabetes (6). cemia and body weight. acidosis or renal impairment (defined as The SGLT-2 inhibitor dapagliflozin creatinine clearance ,60 mL/min or se- (DAPA) and the DPP-4i saxagliptin (SAXA) RESEARCH DESIGN AND METHODS rum creatinine $1.5 mg/dL in men improve glycemic control in patients with Study Design or $1.4 mg/dL in women). type 2 diabetes when used as mono- This international, multicenter, randomized, therapies (7–9) or in combination with open-label, active-controlled, parallel-group, Randomization metformin (10,11). Moreover, dual ad- 24-week phase 3b trial (clinicaltrials.gov Participants were randomized 1:1 using dition of DAPA plus SAXA to metformin identifier: NCT02551874) was conducted an interactive voice response system to resulted in greater reductions in HbA1c at 112 centers in 11 countries (Czech receive DAPA plus SAXA or titrated in- than either agent added to metformin Republic, Denmark, Germany, Hungary, sulin glargine (INS), stratified by use of alone (12). DAPA plus SAXA add-on to Mexico, Poland, Romania, South Africa, sulfonylurea with background metformin metformin is also associated with body Spain, Sweden, and U.S.). It consisted of a treatment, for 24 weeks (Supplementary weight reduction and a low risk of hy- 2-week lead-in period, during which par- Fig. 1). Randomization schedules were poglycemia and produces a similar safety ticipants received instruction on diet, exer- generated and kept by Bristol-Myers profile to that reported in previous stud- cise, and self-monitoring of glucose levels, Squibb. ies of these agents as monotherapy (7–9) followed by a 24-week treatment period. or as add-on therapy (10–12). The study was conducted in accor- Interventions Insulin is an effective glucose-lowering dance with the ethical principles outlined DAPA, 10 mg/day (Bristol-Myers Squibb, agent for patients with type 2 diabetes in the Declaration of Helsinki and Good New Brunswick, NJ), and SAXA, 5 mg/day and is recommended as one of several Clinical Practice guidelines of the Inter- (Bristol-Myers Squibb, Mount Vernon, options for second- or third-line glucose- national Conference on Harmonization. IN), were administered orally in tablet lowering therapy by many clinical guide- The