Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Abstract

Background Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Boehringer Ingelheim, Ingelheim, Germany/Eli Lilly and Company, Indianapolis, IN, USA), in monotherapy in people who cannot take metformin. Sources MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Merck Sharp & Dohme Limited, Kenilworth, NJ, USA). Funding The National Institute for Health Research Health Technology Assessment programme.

Evidence-Based Consensus on Positioning of SGLT2i in Type 2 Diabetes Mellitus in Indians

“…Moreover, GTI episodes (odds ratios [OR] 4–6) are reported to be higher with SGLT2i compared to placebo [ 44 ]. Recently, a systematic review and NMA by Johnston et al reported that SGLT2i as monotherapy significantly improved glycaemic parameters, induced weight loss, and reduced BP [ 45 ]. All RCTs included in this study were of ≥ 24 weeks.…”

“…All RCTs included in this study were of ≥ 24 weeks. Compared to placebo or active comparator, SGLT2i reduced A1C ( P < 0.001), body weight ( P < 0.001), lipid level ( P < 0.01), and BP ( P < 0.001) in patients with T2DM [ 45 ]. All RCTs reported a 4–9% increase in urinary tract infections (UTIs) and GTIs with SGLT2i treatment mainly in women.…”

Ertugliflozin Compared to Other Anti-hyperglycemic Agents as Monotherapy and Add-on Therapy in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis

“…This evidence synthesis represents the first published NMA that compares the effectiveness and safety of ertugliflozin to other SGLT2is. Previous NMAs of the SGLT2i class conducted prior to the availability of ertugliflozin suggested differences in effectiveness, generally favoring canagliflozin [ 11 , 23 , 24 ].…”

“…This study was excluded initially as the low threshold of HbA1c for inclusion was 6.5% HbA1c, versus our inclusion criteria of ≥ 7.0%. However, despite potential heterogeneity previous SGLT2i NMAs have included this study, and therefore a sensitivity analysis was considered appropriate [ 23 , 24 ]. In the second sensitivity analysis, studies that were not linked to the network via a common comparator (placebo) arm (Hadjadj [ 25 ]; Lewin [ 26 ]; Rosenstock [ 27 ]) were dropped from the network and analyses run.…”

The management of type 2 diabetes with fixed‐ratio combination insulin degludec/liraglutide (IDegLira) versus basal‐bolus therapy (insulin glargine U100 plus insulin aspart): A short‐term cost‐effectiveness analysis in the UK setting

“…However, it is common practice to adapt clinical trial data from multinational cohorts to country-specific analyses, with this methodology found throughout the published literature. 45,46,[50][51][52] Moreover, the effect of IDegLira and BBT would not be expected to vary across the different country settings included in the DUAL VII trial and the UK.…”