Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes

Abstract

OBJECTIVE To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA 1c , endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS Forty-five patients with poorly controlled (HbA 1c 7–11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3- 3 H]glucose infusion, after which they were randomized to receive 1 ) liraglutide 1.2 mg/day (LIRA), 2 ) canagliflozin 100 mg/day (CANA), or 3 ) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS The mean decrease from baseline to 16 weeks in HbA 1c was −1.67 ± 0.29% ( P = 0.0001), −0.89 ± 0.24% ( P = 0.002), and −1.44 ± 0.39% ( P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was −6.0 ± 0.8 kg ( P < 0.0001), −3.5 ± 0.5 kg ( P < 0.0001), and −1.9 ± 0.8 kg ( P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP ( P < 0.05), which was accompanied by a 50% increase ( P < 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% ( P < 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA 1c .

Glucagon‐like peptide‐1 receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta‐analysis

“…Seven RCTs with 1913 patients were included in the systematic review and meta-analysis ( Figure 1). [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Of these, two studies were retrieved as conference abstracts and one study was identified in ClinicalTrials.gov (NCT02964247). 25,28 Of note, for one of these conference abstracts and for the trial from ClinicalTrials.gov, we utilized post hoc data from their respective journal articles, which were published shortly after our search date.…”

“…25,28 Of note, for one of these conference abstracts and for the trial from ClinicalTrials.gov, we utilized post hoc data from their respective journal articles, which were published shortly after our search date. 33,36 The characteristics of included studies and participants' baseline characteristics are shown in Table 1. All studies had a parallelgroup design.…”

“…All studies had a parallelgroup design. Five studies were double-blind, 22,24,[33][34][35] one was open-label, 36 while blinding status was not reported in one study. 28 Duration of intervention ranged from 12 to 30 weeks in all studies, except for the DURATION-8 trial, which reported outcome data at 28 23 , 52 22 and 104 21 weeks.…”

“…Three studies 22,28,36 evaluated the combination of GLP-1RA/ SGLT2i as simultaneous initiation therapy versus isolated GLP-1RA and SGLT2i. Three studies [33][34][35] compared a GLP-1RA with placebo as add-on therapy in patients already treated with an SGLT2i, while one study was a post hoc subgroup analysis 24…”

“…A secondary analysis using short-term (at 28 weeks) 23 instead of long-term (at 104 weeks) 21 data from the DURATION-8 trial also showed that combination therapy was more efficacious in reducing HbA1c compared with either GLP-1RA (WMD −0.60%, 95% CI −1.09 to −0.12, I 2 = 70%, four studies) or SGLT2i (WMD −0.85%, 95% CI −1.18 to −0.51, I 2 = 88%, six studies). Individual trial data from studies assessing the simultaneous initiation of GLP-1RA/SGLT2i [21][22][23]28,36 suggested that the effect of the combination therapy on the reduction of HbA1c was probably less than additive (Table S4).…”