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Effects of SGLT2 inhibitors on fractures and bone mineral
density in type 2 diabetes: An updated meta‐analysis
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Download the PDF here
Download the PDF here
Based on existing trials, SGLT2 inhibitor treatments neither increased the risk of bone fracture nor decreased the BMD compared with that of the placebos. However, given that bone health damage is a relatively long-term process and may be affected by several external factors, SGLT2 inhibitors may not have adverse effects on bone health, but more long-term detailed data are needed to validate this conclusion.
SGLT2 inhibitor treatment did not decrease the BMD at four skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm), and the overall WMD was 0.08 (95% CI [-0.09, 0.26]). No significant publication bias was detected.
Conclusions
No increased risk for bone fracture was detected in patients with T2DM treated with SGLT2 inhibitors in this meta-analysis. SGLT2 inhibitor therapy did not appear to affect bone health, but more long-term detailed data are needed to validate this conclusion.
INTRODUCTION
Diabetes mellitus (DM) is a global public health problem. In 2017, 8.8% adults 20 to 79 years of age suffered from DM. Following this trend, approximately 629 million people 20 to 79 years of age will have DM by 2045.1 Currently, several therapies are available for type 2 diabetes mellitus (T2DM), including metformin (MET), sulfonylurea (SU), thiazolidinedione (TZD), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase IV (DPP4) inhibitors, and insulin, but these therapies have common side effects that cannot be ignored.2
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of novel hypoglycaemic drug that alters calcium and phosphate homeostasis and acts on the kidneys to promote urinary glucose excretion, thereby decreasing the plasma glucose level.3 Many drugs belong to the SGLT2 inhibitors, including dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, and luseogliflozin. Physiologically, SGLT2 and sodium glucose cotransporter 1 (SGLT1) together reabsorb filtered glucose, with the former accounting for the majority of this function (80%-90%). In patients with poorly controlled T2DM, the kidneys improve the threshold of glucosuria and reabsorb more glucose, resulting in an increase in the maximum glucose reabsorptive capacity (TmG). Accordingly, SGLT2 inhibitors can reduce the threshold of glucosuria and TmG, decrease reabsorption, and alleviate glucotoxicity.3
SGLT2 inhibitors have been proven to have protective effects on the blood pressure (BP), cardiovascular issues,4 lipid spectrum, and body weight.3 Inevitably, SGLT2 inhibitors also have numerous safety problems. Genital infections, urinary tract infections, and reduced intravascular volume-related diseases appear to be the major adverse reactions to SGLT2 inhibitor therapy. In addition, equal importance should be attached to hyperkalaemia for canagliflozin and bladder cancer for dapagliflozin.3
In 2014, Kohan et al5 reported a clinical trial of 252 patients with inadequately controlled T2DM and moderate renal impairment. Bone fracture events occurred in five patients receiving 5 mg/day of dapagliflozin, eight patients receiving 10 mg/day of dapagliflozin, and no patient receiving the placebo. An increased bone fracture risk was also detected in canagliflozin-treated patients who were older, had cardiovascular diseases, and had a lower baseline estimated glomerular filtration rate (eGFR) and higher baseline diuretic use.6 In particular, it has been well demonstrated that several antidiabetic agents can impair the bone health7 in addition to the negative effect of diabetes itself to the skeleton.8 However, a large number of trials have shown different results for canagliflozin, dapagliflozin, and empagliflozin; SGLT2 inhibitors do not affect bone health.9-11 Kohler et al reported that the incidence of bone fracture was similar between the empagliflozin and placebo treatment groups and even within renal function (eGFR) subgroups.12 Two meta-analyses that previously reviewed trials on SGLT2 inhibitors together with bone fractures reported that evidence of an association was lacking.13, 14 In general, whether SGLT2 inhibitors can increase the risk of bone fractures is debatable and needs further discussion.15 Newer, larger sample and longer term studies with relatively complete data need to be included, and the preliminary conclusion needs to be updated.15, 16 For this purpose, we once again reviewed trials on SGLT2 inhibitors to reach a more comprehensive and reliable conclusion.
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Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis
Abstract
Background
The aim of the study is to update and determine the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor therapy on fracture and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM).
Methods
We identified 27 eligible randomized controlled trials (RCTs) that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20 895 T2DM participants, with an average duration of 64.22 weeks. The relative risk (RR) of bone fracture and weighted mean difference (WMD) of changes in the BMD from baseline were determined to evaluate the risk of fracture. The degree of heterogeneity was evaluated by the I2 statistic, and publication bias was estimated using a funnel plot and Egger test.
Results
The pooled RR was 1.02 (95% CI [0.81, 1.28]) with low heterogeneity, indicating that SGLT2 inhibitor treatment was not correlated with a higher risk of fracture. Additionally, no increased risk was found for patients with different ages, sexes, and levels of HbA1c and some biochemical indicators. Three trials with 1303 patients reported a change in the BMD from baseline. SGLT2 inhibitor treatment did not decrease the BMD at four skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm), and the overall WMD was 0.08 (95% CI [-0.09, 0.26]). No significant publication bias was detected.
Conclusions
No increased risk for bone fracture was detected in patients with T2DM treated with SGLT2 inhibitors in this meta-analysis. SGLT2 inhibitor therapy did not appear to affect bone health, but more long-term detailed data are needed to validate this conclusion.
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Pdf attached
In this nationwide propensity score-matched Medicare cohort of older adults with T2D, the use of SGLT-2i was not associated with an increased risk of nontraumatic fractures compared with DPP-4i or GLP-1RA. Results were consistent across categories of sex, frailty, age, and insulin use. Our results add to the evidence base evaluating the safety profile of SGLT-2i in older adults outside of RCTs and further characterize the risk-benefit balance of SGLT-2i in clinical practice.
Together, T2D and aging may have negative effects on bone metabolism.8-10 In addition, other comorbidities, such as osteoporosis and chronic kidney disease, also increase the risk of fracture in older adults.11-13 Thus, understanding the fracture risk associated with SGLT-2i in older adults with T2D is critical.
SGLT-2i lower blood glucose levels by promoting urinary glucose excretion.14 SGLT-2i also augment urinary phosphate reabsorption, triggering the parathyroid hormone and fibroblast growth factor 23; this action has the potential to harm bone health.15,16
Older adults with type 2 diabetes (T2D) are at an increased risk of death from cardiovascular disease compared with older adults without T2D.1 Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are oral diabetes medications that reduce the risk of atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death among adults with T2D.2,3,4,5,6 There is, however, a concern that SGLT-2i may be associated with an increased risk of fracture on the basis of findings in 1 randomized clinical trial (RCT).7 Together, T2D and aging may have negative effects on bone metabolism.8,9,10 In addition, other comorbidities, such as osteoporosis and chronic kidney disease, also increase the risk of fracture in older adults.11,12,13 Thus, understanding the fracture risk associated with SGLT-2i in older adults with T2D is critical.
SGLT-2i lower blood glucose levels by promoting urinary glucose excretion.14 SGLT-2i also augment urinary phosphate reabsorption, triggering the parathyroid hormone and fibroblast growth factor 23; this action has the potential to harm bone health.15,16 In the Canagliflozin Cardiovascular Assessment Study (CANVAS), the incidence rate (IR) of bone fractures among those taking canagliflozin, an SGLT-2i, was significantly higher than that among those taking placebo (15.4 vs 11.9 fractures per 1000 person-years; hazard ratio [HR], 1.26; 95% CI, 1.04-1.52).3 This increased risk of fracture, however, was not observed in other large RCTs of canagliflozin or other SGLT-2i.2,4,5,6,17 Fewer than one-half of participants in these RCTs were adults aged 65 years and older, leading to a lack of data on fracture incidence in older adults taking any SGLT-2i.2,4,5,6,17 The present study sought to determine whether taking any SGLT-2i vs other diabetes agents is associated with an increased risk of fracture for older adults.
The primary outcome was a composite of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days (eTable 2 in the Supplement).
Secondary outcomes included incidence of falls, hypoglycemia,22 and syncope. We also validated our findings against 2 positive control outcomes: diabetic ketoacidosis and heart failure hospitalization rates.23 Prior studies have shown that SGLT-2i are associated with a significantly higher risk of diabetic ketoacidosis24,25 and significantly lower risk of heart failure hospitalization compared with DPP-4i and GLP-1RA.26,27,28
Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes
Key Points
Question
Are sodium-glucose cotransporter-2 inhibitors (SGLT-2i) associated with increased risk of fracture in older adults with type 2 diabetes?
Findings
In this nationwide cohort study of 137 667 Medicare beneficiaries aged 65 years or older with type 2 diabetes without a previous fracture, after 1:1:1 propensity score matching, there was no difference in fracture risk among new users of SGLT-2i compared with users of dipeptidyl peptidase 4 inhibitors or glucagon-like peptide 1 receptor agonists. Results were consistent across categories of sex, frailty, age, and insulin use.
Meaning
The initiation of SGLT-2i was not associated with an increased risk of fracture in older adults with type 2 diabetes compared with other diabetes agents, and these findings add to the evidence base evaluating the safety profile of SGLT-2i in older adults.
Abstract
Importance
Whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are associated with an increased risk of fractures in older adults with type 2 diabetes (T2D) outside of clinical trials remains unknown.
Objective
To examine the association of incident fracture among older adults with T2D with initiating an SGLT-2i compared with initiating a dipeptidyl peptidase 4 inhibitor (DPP-4i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA).
Design, Setting, and Participants
This is a population-based, new-user cohort study including older adults (aged ≥65 years) with T2D enrolled in Medicare fee-for-service from April 2013 to December 2017. Data analysis was performed from October 2020 to April 2021.
Exposures
New users of an SGLT-2i, DPP-4i, or GLP-1RA without a previous fracture were matched in a 1:1:1 ratio using 3-way propensity score matching.
Main Outcomes and Measures
The primary outcome was a composite end point of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days. After 3-way 1:1:1 propensity score matching, multivariable Cox proportional hazards regression models were used to generate hazard ratios (HRs) for SGLT-2i compared with DPP-4i and GLP-1RA and Kaplan-Meier curves to visualize fracture risk over time across groups.
Results
Of 466 933 new initiators of study drugs, 62 454 patients were new SGLT-2i users. After 3-way matching, 45 889 (73%) new SGLT-2i users were matched to new users of DPP-4i and GLP-1RA, yielding a cohort of 137 667 patients (mean [SD] age, 72 [5] years; 64 126 men [47%]) matched 1:1:1 for analyses. There was no difference in the risk of fracture in SGLT-2i users compared with DPP-4i users (HR, 0.90; 95% CI, 0.73-1.11) or GLP-1RA users (HR, 1.00; 95% CI, 0.80-1.25). Results were consistent across categories of sex, frailty (nonfrail, prefrail, and frail), age (<75 and ≥75 years), and insulin use (baseline users and nonusers).
Conclusions and Relevance
In this nationwide Medicare cohort, initiating an SGLT-2i was not associated with an increased risk of fracture in older adults with T2D compared with initiating a DPP-4i or GLP-1RA, with consistent results across categories of frailty, age, and insulin use. These findings add to the evidence base evaluating the potential risks associated with SGLT-2i use for older adults outside of randomized clinical trials.
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