OBJECTIVE

To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride.

RESEARCH DESIGN AND METHODS

Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I–III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events.

RESULTS

In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively).

CONCLUSIONS

Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study.

Patients with type 2 diabetes have an increased risk of bone fractures compared with individuals without diabetes (13) for a number of possible reasons, including the effects of diabetes on bone macroarchitecture and microarchitecture and turnover and the presence of complications that may increase the risk of falls (4). Bone safety profiles of glucose-lowering agents may need to be considered in the management of patients with type 2 diabetes at risk for fractures (4,5). Some sodium–glucose cotransporter 2 (SGLT2) inhibitors increase concentrations of serum phosphate, likely as a result of increased tubular reabsorption, which may have adverse effects on bone (6), and an increased risk of bone fracture is listed as a side effect of the SGLT2 inhibitor canagliflozin (7).

Empagliflozin is a potent and selective SGLT2 inhibitor that is used for the treatment of type 2 diabetes. In phase III trials, empagliflozin 10 mg and 25 mg as monotherapy or as add-on therapy significantly reduced HbA1c level, weight, and systolic blood pressure in patients with type 2 diabetes (811). There was no increase in bone fracture adverse events (AEs) with empagliflozin 10 mg or 25 mg compared with placebo in patients with type 2 diabetes and chronic kidney disease (12) or in patients with type 2 diabetes and high cardiovascular risk (13). There was no increase in bone fracture AEs with empagliflozin 25 mg compared with glimepiride in patients with type 2 diabetes in a 104-week head-to-head study (EMPA-REG H2H-SU trial) (14). We present the effect of empagliflozin on bone fractures in patients with type 2 diabetes using pooled data from placebo-controlled clinical trials and 4-year data from the head-to-head study versus glimepiride (EMPA-REG H2H-SU trial), and the effect of empagliflozin on bone mineral density in a substudy of the EMPA-REG H2H-SU trial.

Study Populations

Data on bone fractures were pooled from patients with type 2 diabetes who were randomized in a 1:1:1 ratio to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I–III clinical trials. This comprised 14 phase I–III trials with a duration of 8 days to 78 weeks (812,1523); the 52-week extension to the phase III trials of empagliflozin given as monotherapy or as add-on therapy to metformin, metformin plus sulphonylurea, and pioglitazone with or without metformin (2427); and the phase III cardiovascular outcomes trial EMPA-REG OUTCOME (median duration of treatment 2.6 years) (13).

Bone fractures were also analyzed in the EMPA-REG H2H-SU trial, where patients received empagliflozin 25 mg once daily or glimepiride 1–4 mg once daily, in addition to metformin and diet and exercise counseling for 104 weeks, and could participate in a 104-week extension (14). Patients were required to be receiving an unchanged dose of metformin immediate release (≥1,500 mg/day, maximum tolerated dose, or maximum dose according to the local label) for at least 12 weeks before randomization. Patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 at screening or during the placebo run-in period were excluded. Glimepiride was initiated at a dose of 1 mg/day, with a recommendation for uptitration if the fasting plasma glucose concentration (assessed with home monitoring) was >6.1 mmol/L to 2 mg/day at week 4, 3 mg/day at week 8, and 4 mg/day at week 12. In this study, sites could choose whether to participate in a dedicated body composition substudy in which whole-body DXA scans, regional DXA scans, and/or MRI scans were performed. Patients who chose to participate were required to sign an additional informed consent form. Patients with regional DXA scans of the lumbar spine (total L1–L4) or proximal femur (including total femur or femoral neck regions) with a baseline T-score of less than or equal to −2.5 were to be treated for osteoporosis at the discretion of the investigator and were to be excluded from participation in the bone mineral density part of the substudy. Patients who had received a diagnosis of osteoporosis during the study were treated at the discretion of the investigator and could continue in the substudy.

End Points

Investigators in the trials that were included in this analysis reported AEs, which were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 18.0. Bone fracture AEs were not adjudicated. Bone fracture AEs were assessed through a search of 62 preferred terms related to fractures, including terms related to vertebral fractures. The assessment was based on AEs that occurred during treatment or within 7 days after the last dose of study drug. AEs classified as serious were as reported by the investigator. A serious AE was one that resulted in death, was immediately life threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, was a congenital anomaly/birth defect, or was deemed serious for any other reason based on appropriate medical judgment.

Bone markers were measured from urine samples (N-terminal telopeptides of type I collagen expressed as a ratio to creatinine) and blood samples (alkaline phosphatase, total protein, albumin, intact parathyroid hormone, 25-OH vitamin D, calcium, and phosphate) taken during study visits. We present changes from baseline to the last value obtained during treatment.

In the EMPA-REG H2H-SU trial, DXA scans of the femoral neck and lumbar spine were taken at weeks 52, 104, 156, and 208. The right proximal femur was the preferred side (the left side was acceptable if the right side was not evaluable), and the same side was to be imaged for each patient at each time point. Bone mineral density was analyzed from DXA scans of the lumbar spine and femoral neck. Bone mineral content was analyzed from whole-body DXA scans. DXA scans were to be performed using Lunar Prodigy, Lunar Prodigy Advance, Lunar iDXA, or Hologic scanners and were analyzed by a central imaging laboratory. A spine phantom was measured before, during, and after acquiring data, and measurements during the trial were required to be within quality control limits calculated at baseline. The data presented are cross-calibration–corrected values.

Analyses

Bone fractures and changes from baseline in bone markers were analyzed in randomized patients treated with one or more doses of study drug. We assessed the percentage of patients with bone fracture AEs (any, serious, leading to treatment discontinuation) and the event rate/100 patient-years in each treatment group. For any bone fracture AEs in all patients, we calculated incidence rate ratios and CIs for differences between empagliflozin and placebo or glimepiride. Kaplan-Meier estimates are presented for the time to first fracture. In the pooled analysis, we assessed the percentage of patients with any bone fracture AEs and event rates in subgroups by sex, baseline age (<50, 50 to <65, 65 to <75, and ≥75 years), baseline eGFR (according to the Modification of Diet in Renal Disease equation; ≥90, ≥60 to <90, ≥45 to <60, ≥30 to <45, and <30 mL/min/1.73 m2), time since diagnosis of type 2 diabetes (≤1, >1 to ≤5, >5 to ≤10, and >10 years), use of insulin at baseline (yes/no), diabetic nephropathy at baseline (yes/no), diabetic neuropathy at baseline (yes/no), and diabetic retinopathy at baseline (yes/no), and incidence rate ratios and CIs were calculated for differences between empagliflozin and placebo. We analyzed descriptively the percentage of patients with any bone fracture AE by fracture site (lower limb, upper limb, thoracic cage, spinal, skull and facial, pelvic, and other) based on grouping preferred terms. Serious bone fracture AEs, bone fracture AEs leading to treatment discontinuation, and changes from baseline in bone markers were analyzed descriptively.

Changes from baseline in bone mineral density parameters and bone mineral content were assessed using mixed-model repeated-measures analyses in patients who participated in the EMPA-REG H2H-SU body composition substudy who had valid baseline and on-treatment DXA or MRI scans. The mixed-model repeated-measures analyses were based on observed cases including values after the initiation of rescue medication. The models included the baseline value of the end point in question as a linear covariate and sex, age group, treatment, visit, visit by treatment interaction, and sex by age group interaction as fixed effects.

Study Populations

In the pooled analysis of data from >12,000 patients with type 2 diabetes in placebo-controlled trials, 4,221 patients received empagliflozin 10 mg, 4,196 patients received empagliflozin 25 mg, and 4,203 patients received placebo. Baseline characteristics were similar between the empagliflozin groups and the placebo group (Supplementary Table 1). At baseline, 13% of patients were not receiving any other glucose-lowering therapy, 29% were receiving one glucose-lowering therapy (mostly metformin or insulin), and 45% were receiving two glucose-lowering therapies (mostly metformin and sulphonylurea or metformin and insulin) (Supplementary Table 1). At baseline, 81% of patients were receiving antihypertensive therapy, 3% were receiving calcium supplements, 4% were receiving vitamin D, and <1% were receiving therapy for the treatment or prevention of bone diseases. Approximately 17% of patients had diabetic retinopathy, 25% had diabetic neuropathy, and 15% had diabetic nephropathy (Supplementary Table 1). The median exposure time (range) was 698 (1–1,546) days, 699 (1–1,632) days, and 658 (1–1,549) days in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively; 45% of patients were exposed to the study drug for ≥2 years, and 23% were exposed to the study drug for ≥3 years.

In the EMPA-REG H2H-SU trial, 769 and 780 patients were randomized to empagliflozin 25 mg and glimepiride 1–4 mg as add-on therapy to metformin, respectively, of whom 576 and 549 patients, respectively, completed 104 weeks of treatment and entered the 104-week extension period. Bone mineral density was analyzed in patients from the body composition substudy who provided analyzable data (50 and 39 patients at baseline, and 28 and 10 patients at week 208, in the empagliflozin and glimepiride groups, respectively), and bone mineral content was analyzed in patients from the substudy who provided analyzable data (46 and 38 patients at baseline, and 25 and 10 patients at week 208, in the empagliflozin and glimepiride groups, respectively). Baseline characteristics were balanced between the empagliflozin and glimepiride groups in the total study population (Supplementary Table 2) and in the body composition substudy (Supplementary Table 2). In the total study population, 61% of patients were receiving antihypertensive therapy, 4% were receiving calcium supplements, 2% were receiving vitamin D, and <1% were receiving therapy for the treatment/prevention of bone diseases. Approximately 5% of patients had diabetic retinopathy, 8% had diabetic neuropathy, and 3% had diabetic nephropathy (Supplementary Table 2).

Bone Fracture AEs in Placebo-Controlled Trials

Bone fracture AEs were reported in 119 patients (2.8%), 105 patients (2.5%), and 123 patients (2.9%) in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (Fig. 1 and Table 1). This corresponded to rates of 1.55, 1.36, and 1.69 events/100 patient-years, respectively. Kaplan-Meier estimates of the time to first fracture were similar between the empagliflozin and placebo groups, and there was no evidence of an increased risk of fractures with empagliflozin compared with placebo at any time point (Supplementary Fig. 1). Serious bone fracture AEs were reported in 30 patients (0.7%), 37 patients (0.9%), and 44 patients (1.0%) in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively. The proportion of patients with bone fracture AEs leading to treatment discontinuation was numerically greater in the placebo group than in the empagliflozin groups (Table 1). The most common sites for bone fractures in all of the treatment groups were the lower and upper limbs (Table 1). The rate of hip fractures was low in all treatment groups (Table 1). The proportion of patients with pathological fractures was similar between the empagliflozin and placebo groups (Table 1). The rate of falls was similar among the empagliflozin 10 mg (1.17/100 patient-years), empagliflozin 25 mg (1.07/100 patient-years), and placebo (1.07/100 patient-years) groups, respectively.

Figure 1

Incidence and rate ratios of bone fracture AEs in all patients and in subgroups from placebo-controlled trials and in all patients treated with empagliflozin or glimepiride in the EMPA-REG H2H-SU trial. Data from patients treated with one or more doses of study drug. Baseline eGFR was not available for four patients. Information on the time since the diagnosis of type 2 diabetes in categories ≤1, >1 to ≤5, >5 to ≤10, and >10 years was not available for 719 patients. Information on the presence of diabetic nephropathy, neuropathy, and retinopathy was not available for 108 patients. Rate ratio and 95% CI are not shown for patients with time since diagnosis of type 2 diabetes of ≤1 year because there were <14 events in that subgroup category. Pt-yr, patient-years.

Figure 1

Incidence and rate ratios of bone fracture AEs in all patients and in subgroups from placebo-controlled trials and in all patients treated with empagliflozin or glimepiride in the EMPA-REG H2H-SU trial. Data from patients treated with one or more doses of study drug. Baseline eGFR was not available for four patients. Information on the time since the diagnosis of type 2 diabetes in categories ≤1, >1 to ≤5, >5 to ≤10, and >10 years was not available for 719 patients. Information on the presence of diabetic nephropathy, neuropathy, and retinopathy was not available for 108 patients. Rate ratio and 95% CI are not shown for patients with time since diagnosis of type 2 diabetes of ≤1 year because there were <14 events in that subgroup category. Pt-yr, patient-years.

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Table 1

Patients with bone fracture AEs in placebo-controlled trials


Empagliflozin 10 mg group (n = 4,221)
Empagliflozin 25 mg group (n = 4,196)
Placebo group (n = 4,203)
n (%)Rate/100 patient-yearsn (%)Rate/100 patient-yearsn (%)Rate/100 patient-years
Any bone fracture AE 119 (2.8) 1.55 105 (2.5) 1.36 123 (2.9) 1.69 
Pathological fracturea 10 (0.2) 0.13 6 (0.1) 0.08 9 (0.2) 0.12 
Serious bone fracture AEb 30 (0.7) 0.38 37 (0.9) 0.47 44 (1.0) 0.59 
Bone fracture AE leading to treatment discontinuation 6 (0.1) 0.08 8 (0.2) 0.10 17 (0.4) 0.23 
Bone fracture site       
 Lower limb 30 (0.7) 0.38 41 (1.0) 0.53 45 (1.1) 0.61 
  Hip 3 (0.1) 0.04 9 (0.2) 0.12 5 (0.1) 0.07 
 Upper limb 41 (1.0) 0.53 25 (0.6) 0.32 23 (0.5) 0.31 
 Thoracic cage 22 (0.5) 0.28 16 (0.4) 0.20 17 (0.4) 0.23 
 Spinal 1 (<0.1) 0.01 9 (0.2) 0.12 12 (0.3) 0.16 
 Skull and facial 7 (0.2) 0.09 3 (0.1) 0.04 5 (0.1) 0.07 
 Pelvic 4 (0.1) 0.05 2 (<0.1) 0.03 3 (0.1) 0.04 
 Other 20 (0.5) 0.26 17 (0.4) 0.22 26 (0.6) 0.35 

Empagliflozin 10 mg group (n = 4,221)
Empagliflozin 25 mg group (n = 4,196)
Placebo group (n = 4,203)
n (%)Rate/100 patient-yearsn (%)Rate/100 patient-yearsn (%)Rate/100 patient-years
Any bone fracture AE 119 (2.8) 1.55 105 (2.5) 1.36 123 (2.9) 1.69 
Pathological fracturea 10 (0.2) 0.13 6 (0.1) 0.08 9 (0.2) 0.12 
Serious bone fracture AEb 30 (0.7) 0.38 37 (0.9) 0.47 44 (1.0) 0.59 
Bone fracture AE leading to treatment discontinuation 6 (0.1) 0.08 8 (0.2) 0.10 17 (0.4) 0.23 
Bone fracture site       
 Lower limb 30 (0.7) 0.38 41 (1.0) 0.53 45 (1.1) 0.61 
  Hip 3 (0.1) 0.04 9 (0.2) 0.12 5 (0.1) 0.07 
 Upper limb 41 (1.0) 0.53 25 (0.6) 0.32 23 (0.5) 0.31 
 Thoracic cage 22 (0.5) 0.28 16 (0.4) 0.20 17 (0.4) 0.23 
 Spinal 1 (<0.1) 0.01 9 (0.2) 0.12 12 (0.3) 0.16 
 Skull and facial 7 (0.2) 0.09 3 (0.1) 0.04 5 (0.1) 0.07 
 Pelvic 4 (0.1) 0.05 2 (<0.1) 0.03 3 (0.1) 0.04 
 Other 20 (0.5) 0.26 17 (0.4) 0.22 26 (0.6) 0.35 

Patients treated with one or more doses of study drug.

aMedDRA preferred terms “pathological fracture” and “osteoporotic fracture.”

bAE reported as serious AE by investigator.

A numerically greater proportion of female than male patients experienced bone fracture AEs with empagliflozin 10 mg or placebo, but not with empagliflozin 25 mg (Fig. 1). The proportion of patients with bone fracture AEs increased with age, regardless of treatment (Fig. 1). In the subgroup of patients who were ≥75 years of age, there were numerically more fractures in the empagliflozin groups (13 of 277 patients [4.7%] receiving empagliflozin 10 mg and 13 of 285 patients [4.6%] receiving empagliflozin 25 mg) than in the placebo group (11 of 282 patients [3.9%]), but the number of patients ≥75 years of age at baseline was small. The proportion of patients with bone fractures was numerically greater in those with moderate renal impairment at baseline than in those with no/mild renal impairment in all treatment groups (Fig. 1). The proportion of patients with bone fractures increased with increasing time since the diagnosis of type 2 diabetes in all treatment groups but was similar between the empagliflozin and placebo groups (Fig. 1). Fracture rates were higher in patients who were receiving insulin at baseline but remained similar between the empagliflozin and placebo groups (Fig. 1). Fracture rates were slightly higher in patients with diabetic nephropathy, neuropathy, or retinopathy at baseline but remained similar between the empagliflozin and placebo groups (Fig. 1).

Bone Fracture AEs in EMPA-REG H2H-SU Trial

In the 4-year head-to-head study of empagliflozin 25 mg versus glimepiride 1–4 mg in patients with type 2 diabetes, bone fracture AEs were reported in 31 patients (4.1%) treated with empagliflozin and 33 patients (4.2%) treated with glimepiride (Fig. 1 and Table 2). Kaplan-Meier estimates of time to first fracture were similar between the empagliflozin and glimepiride groups, and there was no evidence of an increased risk of fractures with empagliflozin compared with glimepiride at any time point (Supplementary Fig. 2). Serious bone fracture AEs were reported in a numerically greater proportion of patients receiving empagliflozin (1.4%) than receiving glimepiride (0.5%). No bone fracture AEs led to treatment discontinuation in either group. The upper limb was the most common site for fractures in both groups (Table 2).

Table 2

Patients with bone fracture AEs in the EMPA-REG H2H-SU trial

Empagliflozin 25 mg (n = 765)
Glimepiride 1–4 mg (n = 780)
n (%)Rate/100 patient-yearsn (%)Rate/100 patient-years
Total with bone fracture AEs 31 (4.1) 1.28 33 (4.2) 1.40 
Serious bone fracture AEsa 11 (1.4) 0.45 4 (0.5) 0.17 
Bone fracture AEs leading to treatment discontinuation 
Bone fracture site     
 Upper limb 11 (1.4) 0.45 15 (1.9) 0.63 
 Lower limb 9 (1.2) 0.37 5 (0.6) 0.21 
 Thoracic cage 1 (0.1) 0.04 6 (0.8) 0.25 
 Spinal 2 (0.3) 0.08 
 Skull and facial 1 (0.1) 0.04 1 (0.1) 0.04 
 Pelvic 1 (0.1) 0.04 
 Other 10 (1.3) 0.41 3 (0.4) 0.12 
Empagliflozin 25 mg (n = 765)
Glimepiride 1–4 mg (n = 780)
n (%)Rate/100 patient-yearsn (%)Rate/100 patient-years
Total with bone fracture AEs 31 (4.1) 1.28 33 (4.2) 1.40 
Serious bone fracture AEsa 11 (1.4) 0.45 4 (0.5) 0.17 
Bone fracture AEs leading to treatment discontinuation 
Bone fracture site     
 Upper limb 11 (1.4) 0.45 15 (1.9) 0.63 
 Lower limb 9 (1.2) 0.37 5 (0.6) 0.21 
 Thoracic cage 1 (0.1) 0.04 6 (0.8) 0.25 
 Spinal 2 (0.3) 0.08 
 Skull and facial 1 (0.1) 0.04 1 (0.1) 0.04 
 Pelvic 1 (0.1) 0.04 
 Other 10 (1.3) 0.41 3 (0.4) 0.12 

Patients treated with one or more doses of study drug.

aAEs reported as serious AEs by investigator.

Bone Mineral Density, Bone Mineral Content, and Bone Markers

No clinically relevant changes from baseline in bone markers were observed with empagliflozin or placebo in placebo-controlled trials (Supplementary Table 4) or with empagliflozin compared with glimepiride in the EMPA-REG H2H-SU trial (Supplementary Table 5).

In the EMPA-REG H2H-SU trial, there were no significant differences between empagliflozin and glimepiride in changes from baseline in femoral neck or lumbar spine T-scores at weeks 52, 104, 156, or 208 (Supplementary Fig. 3). In both groups, the mean femoral neck and lumbar spine T-scores remained in the normal range (above −1) at weeks 52, 104, 156, and 208 (Supplementary Fig. 3). There were no significant differences between empagliflozin and glimepiride groups in change from baseline in bone mineral content at weeks 52, 104, 156, or 208 (Supplementary Fig. 4).

In a large pooled analysis of placebo-controlled clinical trial data from >12,000 patients with type 2 diabetes, the incidence of nonadjudicated bone fracture AEs was low and similar between the empagliflozin and placebo groups. In the EMPA-REG H2H-SU study, the incidence of bone fracture AEs was similar between the empagliflozin 25 mg and glimepiride groups over 4 years; the incidence of serious bone fracture AEs was low but was numerically higher in patients treated with empagliflozin than with glimepiride. The incidence of upper limb fractures and lower limb fractures, including hip fractures, appeared to be similar between patients treated with empagliflozin and patients treated with placebo or glimepiride.

In all subgroups by age, sex, renal function, time since diagnosis of type 2 diabetes, and presence of diabetes complications, the proportions of patients with bone fracture AEs were similar across treatment groups except for a numerically higher proportion of patients receiving empagliflozin than placebo in patients aged ≥75 years; however, the total exposure in the subgroup of patients aged ≥75 years was limited. The proportion of patients with fractures increased with age and was numerically greater in female than in male patients, which is consistent with published data (28); however, female patients comprised only 35% of the total study population. An eGFR of <60 mL/min/1.73 m2 is a known risk factor for bone fracture (28), and in our analyses the proportion of patients with bone fracture AEs was numerically greater in those with moderate renal impairment compared with those with no/mild renal impairment in both the empagliflozin and placebo groups. A duration of diabetes of ≥10 years is a risk factor for fractures (29,30), and in our analyses the proportion of patients with bone fracture AEs was numerically greater in those with >10 years since receiving a diagnosis of type 2 diabetes in both the empagliflozin and placebo groups. Patients with diabetes receiving insulin are at increased risk of fractures, which may relate to the fact that these patients are more likely to have long-term disease and complications (2,4). In our analyses, the proportion of patients with bone fracture AEs was greater in patients receiving than not receiving insulin at baseline, but fracture rates were similar between the empagliflozin and placebo groups. There is some evidence that diabetic retinopathy (30,31), nephropathy (32), and neuropathy (33) are risk factors for fractures, and in our analyses the proportion of patients with bone fracture AEs was numerically greater in those with retinopathy in both the empagliflozin and placebo groups. Complications associated with diabetes, such as retinopathy, neuropathy, and hypoglycemia, may increase the risk of falls. In our analyses, the rate of falls was similar between the empagliflozin and placebo groups, suggesting that the risk of fractures related to falls was not increased in patients treated with empagliflozin. The proportion of patients with bone fracture AEs was numerically greater in those with retinopathy or neuropathy in both the empagliflozin and placebo groups.

Although patients with type 2 diabetes have an increased risk of bone fractures compared with individuals without diabetes (13), patients with type 2 diabetes have higher bone mineral density than patients without type 2 diabetes, independent of skeletal site, sex, age, BMI, and medication use; the reasons for this association remain to be established (34,35). In the EMPA-REG H2H-SU study, the mean femoral neck and lumbar spine T-scores remained in the normal range in the empagliflozin 25 mg group up to week 104, and no clinically relevant differences were observed between the empagliflozin and glimepiride groups. Although the number of patients who underwent DXA scans was limited, there were no clinically relevant changes in bone mineral content at weeks 52, 104, 156, or 208 with empagliflozin or glimepiride treatment.

It has been suggested that SGLT2 inhibitors may be associated with an increased risk of bone fractures due to the modulation of renal calcium and phosphate reabsorption as a result of changes in renal sodium and glucose reabsorption (7,36,37). There were no changes in calcium or phosphate levels with empagliflozin, placebo, or glimepiride in our analyses and no notable differences in changes in other bone markers with empagliflozin treatment compared with placebo or glimepiride treatment. It has also been suggested that changes in hydration status as a result of osmotic diuresis may increase the risk of bone fractures in patients treated with SGLT2 inhibitors (38). In a pooled analysis of data from 16 phase I–III trials of empagliflozin plus six extension studies and an interim analysis from the EMPA-REG OUTCOME trial, the incidence of events consistent with volume depletion was similar between the empagliflozin and placebo groups, except for a higher incidence with empagliflozin 25 mg treatment in patients aged ≥75 years (39). In 104-week data from the EMPA-REG H2H-SU study (14), events consistent with volume depletion were reported in 1% of patients in both the empagliflozin 25 mg and glimepiride 1–4 mg groups.

SGLT2 inhibitors differ with regard to their pharmacologic features, such as selectivity over SGLT1 (40). In phase III trials, an increased risk of bone fractures was observed with the SGLT2 inhibitor canagliflozin compared with placebo, primarily in the upper and lower extremities (41,42), and significant reductions in hip bone mineral density were noted with canagliflozin treatment compared with placebo over 104 weeks (41). In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program in patients with high cardiovascular risk, the rate of all fractures was higher with canagliflozin treatment than with placebo (hazard ratio 1.26 [95% CI 1.04, 1.52]) (43). In phase II/III studies, the SGLT2 inhibitor dapagliflozin had no apparent effect on bone fractures in patients with type 2 diabetes and normal renal function or mild renal impairment (44), but bone fracture AEs were more common in patients with moderate renal impairment (eGFR >30 to <60 mL/min/1.73 m2) treated with dapagliflozin compared with placebo (6.0% and 9.4% for dapagliflozin 5 mg and 10 mg, respectively, vs. 0% for placebo) (45). A recent meta-analysis of 20 SGLT2 inhibitor trials with a duration of ≥24 weeks found no increased risk of bone fractures with empagliflozin, dapagliflozin, or canagliflozin compared with placebo (46).

The strengths of our analyses are the large number of patients included in the pooled analysis of placebo-controlled clinical trial data, including 7,020 patients with high cardiovascular risk from the EMPA-REG OUTCOME trial (13), and the 4-year treatment duration of the EMPA-REG H2H-SU trial. A limitation of our analyses is that fractures were not adjudicated in the studies. The analyses are based on the events reported by investigators, but investigators were not provided with dedicated case report forms on which to report fractures or guidance on how to detect fractures. Limitations of the pooled analysis include the differences in the designs of the studies included in the pooled analysis and the lack of data on AEs that occurred >7 days after the study drug was discontinued. Analyses of data from the EMPA-REG H2H-SU trial are limited by the relatively small number of patients who participated in the body composition substudy and had DXA scans. An even smaller number of patients provided measurements at week 208, which may affect the precision of the estimated treatment differences and the risk of bias. It should also be noted that bone fragility may develop over a longer period than the treatment periods of the trials in these analyses.

In conclusion, in a pooled analysis of >12,000 patients with type 2 diabetes in placebo-controlled empagliflozin trials, there was no increase in bone fracture AEs between empagliflozin and placebo. In addition, empagliflozin 25 mg did not increase the risk of bone fracture AEs compared with glimepiride 1–4 mg in a 4-year head-to-head study.

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Funding. The studies that provided data for these analyses were funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Tove Anderson and Elizabeth Ng of FleishmanHillard Fishburn, London, U.K., during the preparation of this manuscript.

Duality of Interest. S.Ko., S.Ka., A.S., and C.Z. are employees of Boehringer Ingelheim. H.J.W. was an employee of Boehringer Ingelheim at the time these analyses were performed. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.Ko., S.Ka., A.S., and H.J.W. contributed to the interpretation of the data, had full access to the study data, reviewed/edited the manuscript, approved the final version of the manuscript, and were responsible for the final decision to submit the manuscript. C.Z. contributed to the analysis of the data, had full access to the study data, reviewed/edited the manuscript, approved the final version of the manuscript, and was responsible for the final decision to submit the manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. S.Ko. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented in abstract form at the 76th Scientific Sessions of the American Diabetes Association, New Orleans, LA, 10–14 June 2016, and at the 52nd Annual Meeting of the European Association for the Study of Diabetes, Munich, Germany, 12–16 September 2016.

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