Jenny E. Blau

SGLT2 Inhibitors May Predispose to Ketoacidosis

CONTEXT Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. EVIDENCE ACQUISITION Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. EVIDENCE SYNTHESIS SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. CONCLUSIONS Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

Possible adverse effects of SGLT2 inhibitors on bone

SGLT2 inhibitors decrease plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney.1 The attractive efficacy profile of glucose-lowering plus weight loss must be balanced against possible side effects, including an increase in the incidence of treatment-emergent bone fractures observed in clinical studies. In a study of moderate renal impairment, 9.4% of patients treated with dapagliflozin (10 mg) experienced bone fractures while no fractures were observed in placebo-treated patients.2 Furthermore, a ~30% increase in bone fractures was observed in canagliflozin-treated patients in eight pooled clinical trials with longer mean duration (68 weeks).3 Although these data suggest the possibility that SGLT2 inhibitors might increase the risk of bone fractures, additional data will be required before drawing a firm conclusion. SGLT2 inhibitors increase tubular reabsorption of phosphate, thereby increasing serum phosphate levels3,4 (Fig. 1A). The body has evolved complex homeostatic mechanisms to regulate phosphate, and an increase in serum phosphate has the potential to exert an adverse impact upon bone (Fig. 1B). For example, phosphate administration increases PTH secretion.6 Furthermore, SGLT2 inhibitors increase levels of both phosphate and PTH.3,4 While canagliflozin caused a small increase in mean PTH (+7.9%), the standard deviation (SD) was relatively large (39.3%).3 Thus, a substantial number of canagliflozin-treated patients might experience a >50% increase in PTH levels – a change that could be clinically significant. In addition, phosphate administration has been reported to increase FGF23 levels in healthy volunteers,7 which would decrease 1,25-dihydroxyvitamin D levels. However, the mechanisms whereby phosphate regulates FGF23 remain controversial.8 In in vitro studies, phosphate exerts a direct effect to increase FGF23 mRNA levels in primary human fetal bone cells.9 In contrast, some evidence suggests phosphate decreases FGF23 expression by an indirect mechanism – possibly mediated by PTH.8 In light of the controversy, it is critical to conduct clinical studies to assess the effect of SGLT2 inhibitors upon FGF23 levels. Figure 1 Proposed mechanisms whereby SGTL2 inhibitors exert adverse effects on bone Phosphate administration increases both PTH and FGF23, two hormones that exert opposing effects upon vitamin D metabolism8 with PTH increasing and FGF23 decreasing 1,25-dihydroxyvitamin D levels. Accordingly, if SGLT2 inhibitors increase levels of both PTH and FGF23, one could not predict a priori the net impact upon 1,25-dihydroxyvitamin D. Nevertheless, available data suggest that SGLT2 inhibitors decrease mean 1,25-dihydroxyvitamin D levels.3 Canagliflozin caused a small decrease in mean 1,25-dihydroxyvitamin D levels (−12%), but the SD was relatively large (42.4%).3 Thus, a significant percentage of canagliflozin-treated patients could experience a clinically significant ~50% decrease in 1,25-dihydroxyvitamin D levels. In contrast to clinical data suggesting an increase in PTH, suprapharmacological doses of dapagliflozin decreased PTH in rats.10 An investigative toxicology study elucidated the mechanism.10 Dapagliflozin is relatively selective for SGLT2, but high doses administered in toxicology experiments were sufficient to inhibit intestinal SGLT1, which led to glucose malabsorption. Colonic bacteria fermented the unabsorbed glucose, which acidified the intestinal contents. Acid pH increased solubility of calcium, promoted calcium absorption, suppressed PTH, and promoted ectopic calcification. These suprapharmacologic doses of SGLT2 inhibitor are unlikely to be relevant to human pharmacology with approved doses of selective SGLT2 inhbitors.10 Sustained increases in PTH enhance bone resorption, and increase the risk of bone fractures. Similarly, increased levels of FGF23 have been associated with bone disease.8 Finally, decreased levels of 1,25-dihydroxyvitamin D may decrease absorption of Ca+2 from the GI tract, and impair bone calcification. Consistent with these mechanisms, canagliflozin was observed to increase bone turnover as reflected by increases in levels of both collagen type 1 beta-carboxy-telopeptide levels and osteocalcin (biomarkers for bone resorption and bone formation, respectively). In addition, both DXA and quantitative CT detected a decrease in bone mineral density in the lumbar spine and total hip after 52 weeks of therapy with canagliflozin (300 mg).3 In contrast, there was no statistically significant change in bone mineral density at the distal forearm and femoral neck. Additional data could place these observations into context – including a correlation of clinical outcomes (i.e., fractures) with changes in bone biomarkers and bone mineral density in individual patients. The existence of numerous homeostatic mechanisms creates challenges in interpretation of studies of mechanisms whereby SGLT2 inhibitors could affect bone health. For example, an increase in serum phosphate is predicted to increase FGF23 and PTH – both of which promote phosphaturia. Because of this negative feedback, the maximum increase in mean serum phosphate may be transient and/or small in magnitude. Nevertheless, even small changes may significantly affect bone health over years of drug exposure. Finally, it is important to recognize that most drug-treated patients do not experience bone fractures. Bone fractures may be most likely to occur in the subpopulation of “outlier” patients with above average changes in bone-related parameters. In short, mean data may not provide a full picture of the impact upon bone. Patients with type 2 diabetes are especially susceptible to adverse effects of drugs upon bone because of coexisting bone diseases (including post-menopausal osteoporosis, renal osteodystrophy, and diabetes-associated bone fragility). As reported in the ADOPT trial, thiazolidinediones increase the risk of bone fractures.11 After a one year lag, rosiglitazone-treated patients experienced an increase in bone fractures (hazard ratio, 1.6). Similarly, the fracture rate was not increased during the first year of treatment with canagliflozin, but patients experienced more fractures during the second year of therapy.3 The median follow-up for rosiglitazone-treated patients was four years, suggesting that the average duration of the pooled canagliflozin studies (68 weeks) was likely too short to provide conclusive data on fracture risk. Fortunately, ongoing FDA-mandated cardiovascular outcome studies with SGLT2 inhibitors are of sufficient size and duration to assess the risk of bone fractures. Several arguments have been advanced suggesting that the observed increase in fracture rate might be a “chance phenomenon”.2 For example, some fractures occur in the feet, hands, and patella, which were stated not to be associated with bone health.2,3 At the time of the FDA’s Dapagliflozin Advisory Committee, eight fractures had been observed among patients treated with dapagliflozin (10 mg) in the special study of patients with moderate renal impairment. These included one patient with a fractured patella and one with a foot fracture. It is impossible to draw firm conclusions based upon these two patients – either about the distribution of fractures among anatomical sites or whether the increased number of fractures will ultimately be confirmed as a toxicity associated with SGLT2 inhibitors. In contrast to biomarker data suggesting canagliflozin increases bone turnover,3 it has been reported that dapagliflozin does not affect mean bone mineral density or biomarkers of bone turnover in patients with normal to mildly impaired renal function.3,4 These obervations raise the question of whether the bone effects might be a compound-specific rather than mechanism-based. However, the literature suggests that any differences among compounds may be the consequence of dose selection rather than an intrinsic difference between the two compounds. Whereas the 300 mg dose of canagliflozin delivers maximal inhibition of SGLT2,3 the 10 mg dose of dapagliflozin delivers only sub-maximal inhibition.12 Specifically, the 10 mg dose was reported to cause ~35 g/day of urinary glucose excretion – approximately 35% less than the urinary glucose excretion caused by maximally effective doses of dapagliflozin (50–100 mg).4 Thus, canagliflozin (300 mg) might be more efficacious than dapagliflozin (10 mg) with respect to all mechanism-based pharmacology (both mechanism-based toxicity and glucose-lowering). It would require head-to-head trials to draw firm conclusions about comparative benefit:risk profiles of individual SGLT2 inhibitors. In conclusion, SGLT2 inhibitors have been observed to increase the incidence of treatment-emergent bone fractures, and the risk of fractures appears to increase over time. We have hypothesized plausible pathophysiologic mechanisms with potential to mediate adverse effects upon bone. Future mechanistic research may identify patients who are most vulnerable to develop drug-induced bone fractures (e.g., post-menopausal women), and may suggest therapeutic approaches to minimize the risk.

The PTH-Vitamin D-FGF23 axis.

Fibroblast growth factor 23 (FGF23) has emerged as an important regulator of phosphate and vitamin D homeostasis. It is important to understand how FGF23 interacts with vitamin D and parathyroid hormone (PTH) in a FGF23-Vitamin D-PTH axis to regulate mineral homeostasis. In this review, we discuss the genomic structure, and transcriptional, translational, and posttranslational regulation of FGF23. We describe its interaction with PTH and vitamin D, disorders of altered FGF23 states, and emerging therapies for diseases of FGF23 based upon these findings. This discussion helps redefine the role of PTH and vitamin D in relation to a complex bone-kidney-parathyroid loop, and points to areas within this complicated field in need of further clarification and research.

Nonnutritive Sweeteners in Breast Milk

Nonnutritive sweeteners (NNS), including saccharin, sucralose, aspartame, and acesulfame-potassium, are commonly consumed in the general population, and all except for saccharin are considered safe for use during pregnancy and lactation. Sucralose (Splenda) currently holds the majority of the NNS market share and is often combined with acesulfame-potassium in a wide variety of foods and beverages. To date, saccharin is the only NNS reported to be found in human breast milk after maternal consumption, while there is no apparent information on the other NNS. Breast milk samples were collected from 20 lactating volunteers, irrespective of their habitual NNS intake. Saccharin, sucralose, and acesulfame-potassium were present in 65% of participants’ milk samples, whereas aspartame was not detected. These data indicate that NNS are frequently ingested by nursing infants, and thus prospective clinical studies are necessary to determine whether early NNS exposure via breast milk may have clinical implications.

Understanding the Metabolic and Health Effects of Low-calorie Sweeteners: Methodological Considerations and Implications for Future Research.

Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socio-economic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS.

Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data

Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial.

Plasma Concentrations of Sucralose in Children and Adults.

ABSTRACT We aimed to measure concentrations of the commonly used artificial sweetener sucralose, following ingestion of doses reflecting a range of consumption and to compare concentrations in children and adults. Eleven adults consumed 355 mL water containing 0 mg (control), 68, 170, or 250 mg sucralose (equivalent to 1–4 diet sodas). A second group of adults (n = 11) consumed 355 mL Diet Rite Cola™ (68 mg sucralose and 41 mg acesulfame-potassium (ace-K)) or 68 mg sucralose and 41 mg ace-K in seltzer. Beverages were provided at separate visits in randomized order, prior to an oral glucose tolerance test. Eleven children consumed 0 or 68 mg sucralose in 240 mL water, in an identical study design. Blood was collected before beverage ingestion and serially for 120 min. Sucralose doses (corrected for weight) resulted in similar plasma concentrations in children and adults. Concentrations were comparable whether sucralose was administered in water, combined with ace-K, or in diet soda. Due to their lower body weight and blood volume, children have markedly higher plasma sucralose concentrations after the consumption of a typical diet soda, emphasizing the need to determine the clinical implications of sucralose use in children.

Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study

BACKGROUND Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health. METHODS We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours. RESULTS Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23. CONCLUSIONS Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk. TRIAL REGISTRATION ClinicalTrial.gov (NCT02404870). FUNDING Supported by the Intramural Program of NIDDK.

18F-NaF and 18F-FDG PET/CT in Gorham-Stout Disease

Gorham-Stout disease (GSD) is an extremely rare skeletal disorder of unknown etiology characterized by benign proliferation of vascular or lymphatic channels, leading to progressive bone resorption. We report on a patient diagnosed with GSD affecting the right scapula and the right ribs, who underwent PET/CT scans using F-FDG and F-NaF. The remnant upper portion of the affected scapula did not show F-FDG uptake but demonstrated markedly increased F-NaF activity. Furthermore, intense F-NaF activity was seen on the right posterior ribs, which were actively being resorbed, suggesting the potential application of F-NaF-PET/CT imaging in GSD diagnosis and follow-up.

Adverse effects of SGLT2 inhibitors on bone health

Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide metabolic and cardiorenal benefits for patients with type 2 diabetes but are associated with a number of safety issues. Here, we discuss evidence suggesting that indirect activation of the FGF23–1,25-dihydroxyvitamin D–parathyroid hormone axis by SGLT2 inhibition might contribute to adverse effects on bone health.