PracticeUpdate Diabetes March 2019

EXPERT OPINION 21

Effects of Dapagliflozin on CirculatingMarkers of Phosphate Homeostasis By Simeon I. Taylor MD, PhD

Dr. Taylor is Professor of Medicine at the University of Maryland School of Medicine and Director of the Mid-Atlantic Nutrition Obesity Research Center in Baltimore, Maryland.

S odiumglucose transporter-2 (SGLT2) inhibitors – themost recently approvedclass of diabetes drugs–providemultipleclinical benefits, including glucose-lowering, weight loss, cardiovascular benefit, and possibly renoprotection. These benefits must be balanced against a number of side effects. While dapagliflozin was reported to increase the risk of bone fractures in patients with moderately impaired renal function, 1 the drug has not been observed to exert an adverse effect on bone health in patients with normal renal function. Subsequently, canagliflozin was reported to accelerate the loss of bone mineral density 2 and also to increase the risk of bone fracture 3 in patients with normal renal function. A6-day clinical trial in healthy volunteers provided insights into pathophysiological mechanisms mediating the effects on bone. Cross-talk between SGLT2 and other sodium-dependent solute transporters triggers an increase in tubular reabsorption of phosphate. The resulting increase in serum phosphorus triggers an increase in FGF23, a decrease in 1,25-dihydroxyvitamin D, and an increase in PTH. Similar to the pathophysiology mediating adverse effects of chronic kidney disease on bone health, the combination of decreased 1,25-dihydroxyvitamin D and increased PTH is predicted to accelerate loss of bone mineral density. The recent publication by de Jong et al 4 is an important contribution that extends previous research. Most importantly, they demonstrate that dapagliflozin triggers sustained increases in FGF23 and PTH as well as a sustained decrease in 1,25-dihydroxyvitamin D in diabetic patients with early-stage diabetic kidney disease. The fact that similar endocrine changes are triggered by both canagliflozin and dapagliflozin suggests that this is a class effect – likely shared by all SGLT2 inhibitors. While large, multiyear clinical trials may be required to demonstrate effects on bone fracture rates, smaller and shorter studies are sufficient to demonstrate these endocrine changes and/or changes in bone mineral density. These insights into pathophysiology suggest a hypothesis that calcitriol replacement therapy might have potential to protect against adverse effects of SGLT2 inhibitors on bone health. Future research will be required to test this hypothesis. This commentary is based upon the article Effects of Dapagliflozin on Cir- culating Markers of Phosphate Homeostasis by de Jong et al. References 1. Kohan DE, Fioretto P, TangW, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85(4):962-971. 2. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab 2016;101(1):44-51. 3. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016;101(1):157-166. 4. de Jong MA, Petrykiv SI, Laverman GD, et al. Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol 2018;14(1):66-73. www.practiceupdate.com/c/78784

control, obese, and with poor treatment adherence, along with those with more depressive symptoms and poorer quality of life may especially need closer attention, as youth in this study with these behaviors had higher levels of DEB. One additional unique aspect of this study is that the researchers also exam- ined those with “moderate” behaviors based on the DEPS-R, as opposed to only those who met the established cut off of ≥20, warranting further evaluation. If youth with “moderate” behaviors can be targeted earlier in their progression of DEB, perhaps intervention can begin earlier, minimizing the impact on metabolic control and risk of short- and long-term compli- cations of poor control. This study further validates the importance of screening for DEB in adolescents with type 1 diabetes. The American Diabetes Association recommends using the same screening survey that was used in this study, the DEPS-R, to screen for these behaviors, to allow for earlier diagnosis and intervention. 4 This commentary is based upon the article Factors Associated With Disordered Eating Behaviours in Adolescents With Type 1 Diabe- tes by Cecilia-Costa et al. References 1. Cecilia-Costa R, Volkening LK, Laffel LM, et al. Factors associated with disordered eating behaviours in adolescents with type 1 diabetes. Diabet Med 2018 Dec 24;[EPub Ahead of Print]. 2. Markowitz JT, Butler DA, Volkening LK, et al. Brief screening tool for disordered eating behaviors in diabetes: Internal consistency and external validity in a contemporary sample of pediatric patients with type 1 diabetes. Diabetes Care 2010;33(3):495-500. 3. Goebel-Fabbri AE, Fikkan J, Franko DL, et al. Insulin restriction and associated morbidity and mortality in women with type 1 diabetes. Diabetes Care 2008;31(3):415-419. 4. American Diabetes Association. Children and adolescents: standards of medical care in diabetes-2019. Diabetes Care 2019;42(Suppl 1):S148-S164. www.practiceupdate.com/c/77992

VOL. 3 • NO. 1 • 2019