Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin

Mamidi, Rao N. V. S.; Proctor, Jim; Jonghe, Sandra De; Feyen, Bianca; Moesen, Esther; Vinken, Petra; Jing, Ying; Bryant, Stewart; Snook, Sandra; Louden, Calvert; Lammens, G; Ways, Kirk; Kelley, Michael F.; Johnson, Mark D.

doi:10.1016/j.cbi.2014.08.001

Cited by 18 publications

(31 citation statements)

References 11 publications

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“…A significant reduction in 3-OMG plasma levels was seen in rats treated with canagliflozin ( Figure 1). An increase in mean + standard error (SE) cecal glucose content was seen after a 2-week treatment with canagliflozin 100 mg/kg/day Mamidi et al 2014). Results from these studies confirm that in rats, under the conditions of canagliflozin treatment, glucose malabsorption occurs presumably through inhibition of intestinal SGLT1.…”

Section: Carbohydrate Malabsorption In Rats Treated With Canagliflozinsupporting

confidence: 56%

Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

et al. 2014

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Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM.

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Section: Carbohydrate Malabsorption In Rats Treated With Canagliflozinsupporting

confidence: 56%

Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

et al. 2014

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“…In preclinical studies in rats, canagliflozin and other SGLT2 and SGLT1 inhibitors have been associated with increased intestinal calcium absorption, hypercalciuria, decreases in PTH and 1,25-dihydroxyvitamin D levels, and hyperostosis 16,[18][19][20][21] . Based on mechanistic studies demonstrating that removal of glucose from the diet in the presence of canagliflozin can prevent these effects, these alterations in calcium homeostasis in rats are likely secondary to glucose malabsorption due to transient inhibition of intestinal SGLT1-mediated glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

“…Reductions in hormones regulating calcium metabolism and bone turnover, including parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, were observed in rats treated with canagliflozin 18,19 . Canagliflozin treatment was associated with hyperostosis (an increase in bone mass) in rats, but not in dogs or mice 19 .…”

Section: Preclinical Findings and Relevance To Humansmentioning

confidence: 99%

“…Increases in serum calcium and hyperostosis have also been observed in rats treated with the SGLT2 inhibitors dapagliflozin and empagliflozin and a selective SGLT1 inhibitor 15,16,20,21 . Avoidance of carbohydrate malabsorption by substituting dietary fructose (transported by glucose transporter 5 [GLUT5] and not by SGLT1 22 ) for glucose prevented canagliflozin-induced hypercalciuria and hyperostosis in rats 18 . Thus, canagliflozininduced carbohydrate malabsorption in rats was likely due to inhibition of intestinal SGLT1-mediated glucose uptake [17][18][19] .…”

Section: Preclinical Findings and Relevance To Humansmentioning

confidence: 99%

“…Avoidance of carbohydrate malabsorption by substituting dietary fructose (transported by glucose transporter 5 [GLUT5] and not by SGLT1 22 ) for glucose prevented canagliflozin-induced hypercalciuria and hyperostosis in rats 18 . Thus, canagliflozininduced carbohydrate malabsorption in rats was likely due to inhibition of intestinal SGLT1-mediated glucose uptake [17][18][19] . There was no evidence of carbohydrate malabsorption in humans treated with canagliflozin (measured by hydrogen breath content and radiolabeled oral glucose ingestion), suggesting that the bone and mineral findings in rats were species-specific and unlikely to be clinically relevant 16,17,21 .…”

Section: Preclinical Findings and Relevance To Humansmentioning

confidence: 99%

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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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Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin

Cited by 18 publications

References 11 publications

Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

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

Diabetes pharmacotherapy and effects on the musculoskeletal system

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