Canagliflozin: Effects in overweight and obese subjects without diabetes mellitus

Bays, Harold; Weinstein, Richard L.; Law, Gordon; Canovatchel, William

doi:10.1002/oby.20663

Cited by 143 publications

(123 citation statements)

References 23 publications

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“…SGLT-2 is the target of approved drugs for diabetes, which lower blood glucose (and body weight) by increasing renal glucose excretion. The SGLT-2 inhibitor canagliflozin caused weight loss over 12 weeks in nondiabetic obese subjects, but at the most effective dose this was only 1.6% greater than with placebo [60]. Thus, although like liraglutide there will be ample experience of SGLT-2 inhibitors from their use in diabetes, weight loss may prove insufficient for them to be used to treat obesity alone.…”

Section: Phase 2 Clinical Trials and Novel Targetsmentioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

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Abstract:Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.3

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Section: Phase 2 Clinical Trials and Novel Targetsmentioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

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“…Meaningful weight loss was seen with canagliflozin 100 and 300 mg across Phase III studies in patients with T2DM [29][30][31][32][35][36][37][38][39][40][41]; in a Phase II study, canagliflozin provided modest weight loss in overweight and obese patients without T2DM over 12 weeks [88]. However, weight loss with canagliflozin is less than would be predicted based on UGE alone; recent studies suggest that this may be attributable to a compensatory increase in food intake [59,89,90].…”

Section: Future Perspectivementioning

confidence: 99%

Canagliflozin for the treatment of adults with Type 2 diabetes

Meininger¹,

Canovatchel²,

Polidori³

et al. 2015

Diabetes Management

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Canagliflozin is an SGLT2 inhibitor approved for the treatment of adults with Type 2 diabetes mellitus (T2DM). A comprehensive Phase III program evaluated canagliflozin in a broad range of patients with T2DM on various background therapies; studies were also conducted in special populations, including older patients and those with moderate renal impairment. Canagliflozin provided clinically meaningful reductions in HbA1c, bodyweight and blood pressure versus placebo and active comparators in studies up to 104 weeks. Canagliflozin was generally well tolerated, with increased incidences of adverse events related to the mechanism of action, including genital mycotic infections and osmotic diuresisrelated adverse events. Overall, canagliflozin appears to be a useful treatment option for patients with inadequately controlled T2DM. Practice points• Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease, with growing prevalence worldwide.• SGLT2 inhibitors are a new class of oral antihyperglycemic agents with an insulin-independent mechanism of lowering the renal threshold for glucose and increasing urinary glucose excretion, thereby lowering plasma glucose.• Canagliflozin is an SGLT2 inhibitor approved in the USA, EU and other countries as adjunct to diet and exercise for the treatment of adults with hyperglycemia.• Canagliflozin has been evaluated in ~10,000 patients with T2DM in placebo-and active-controlled Phase III studies of up to 104 weeks, including special populations (e.g., older patients, patients with moderate renal impairment and patients with elevated cardiovascular risk).• In placebo-controlled, Phase III studies, canagliflozin improved glycemic control and lowered bodyweight and blood pressure in a broad range of patients with T2DM on a variety of background antihyperglycemic agents, including older patients, patients with moderate renal impairment and patients with elevated cardiovascular risk.• In active-controlled, Phase III studies, canagliflozin 300 mg demonstrated superiority to glimepiride and sitagliptin 100 mg in HbA1c lowering as add-on to metformin at 52 weeks; canagliflozin 300 mg also demonstrated superiority to sitagliptin 100 mg in HbA1c lowering as add-on to metformin and sulfonylurea over 52 weeks.• Canagliflozin was generally well tolerated, with increased incidences of adverse effects related to the mechanism of action (e.g., genital mycotic infections, urinary tract infections, osmotic diuresis-related adverse events, volume depletion-related adverse events); the incidence of hypoglycemia was low with canagliflozin in patients not on background sulfonylurea or insulin.

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“…Serum osteocalcin, a bone formation marker, also increased with canagliflozin treatment at 26 weeks and continued to increase through 52 weeks 36 . There were no significant changes in the bone formation marker amino-terminal type 1 procollagen (P1NP) with canagliflozin treatment 6,37 . Increases in beta-CTX were also seen with dapagliflozin (Supplemental Figure 1) 38 .…”

mentioning

confidence: 99%

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus

Alba

Xie

Fung

et al. 2016

Current Medical Research and Opinion

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(2016) The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus, Current Medical Research and Opinion, 32:8, 1375-1385, DOI: 10.1080/03007995.2016 Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. This review provides a comprehensive summary of preclinical and clinical data on the effects of the SGLT2 inhibitor canagliflozin on mineral balance and bone. Methods: Published articles and internal study reports through November 2015 were included.Results: In clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, parathyroid hormone, or vitamin D. Canagliflozin was associated with increases in serum magnesium and phosphate without changes in their urinary excretion. Increases in serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker, were observed with canagliflozin. Decreases in total hip bone mineral density (BMD) of up to 1.2% were seen with canagliflozin after 2 years; no changes in BMD were seen at other skeletal sites. Changes in total hip BMD and serum beta-CTX with canagliflozin correlated with decreases in body weight. In a clinical program-wide analysis, canagliflozin was associated with increased fracture risk that was driven by a higher incidence in the cardiovascular safety study (CANVAS), with no fracture imbalance seen in pooled data from other Phase 3 studies. The fracture imbalance occurred within 12 weeks after initiating treatment, most frequently in the distal portion of the upper and lower extremities. Conclusions: Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. Increases in bone turnover markers and decreases in BMD at the total hip, but not at other sites, that correlated with weight loss were seen with canagliflozin. Canagliflozin was associated with a higher fracture incidence within 12 weeks, primarily in distal extremities. Data from ongoing canagliflozin studies will provide additional information on fracture risk.

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Canagliflozin: Effects in overweight and obese subjects without diabetes mellitus

Cited by 143 publications

References 23 publications

Horizons in the Pharmacotherapy of Obesity

Horizons in the Pharmacotherapy of Obesity

Canagliflozin for the treatment of adults with Type 2 diabetes

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus

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