Analysis of Fractures in Patients With Type 2 Diabetes Treated With Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride

Köhler, Sven; Kaspers, Stefan; Salsali, Afshin; Zeller, Cordula; Woerle, Hans J.

doi:10.2337/dc17-1525

Cited by 51 publications

(48 citation statements)

References 47 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A 4‐year head‐to‐head study (EMPA‐REG H2H‐SU), conducted in T2D patients inadequately controlled on metformin alone (baseline HbA1c 7%‐10%), looked specifically at the relationship between hypoglycemia and fracture risk, comparing the SGLT2 inhibitor empagliflozin (25 mg) vs glimepiride (1‐4 mg), as add‐on to metformin. Hypoglycemic events occurred in 28% of patients on glimepiride vs only 3% on empagliflozin; however, bone fracture occurrence was similar across the groups (4.1% in empagliflozin group; 4.2% in glimepiride group) . In the ACCORD BONE study, intensive glycemic control with any SU was not associated with a higher risk of falls or fracture, in spite of more hypoglycemic episodes .…”

Section: Drugs and Bonementioning

confidence: 88%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

View full text Add to dashboard Cite

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.

show abstract

Section: Drugs and Bonementioning

confidence: 88%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

View full text Add to dashboard Cite

show abstract

“…Thirty‐eight eligible RCTs with 30 384 patients were involved from inception to January 2016, but the study lacked evidence of the harmful effect of SGLT2 inhibitors on fracture. In 2018, Kohler et al analysed the fracture risk in empagliflozin‐treated diabetics with pooled data, and bone fractures were reported in 2.8%, 2.5%, and 2.9% patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively . However, all of the reviews lacked details on bone health outcomes, and most trials were short‐term studies.…”

Section: Discussionmentioning

confidence: 99%

Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta‐analysis

Cheng

et al. 2019

Diabetes Metabolism Res

View full text Add to dashboard Cite

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.

show abstract

“…Data for dapagliflozin came from the main report of the DECLARE TIMI‐58 trial . For the safety outcome fracture, empagliflozin data were obtained from a pooling study of phase 1, 2 and 3 studies, where the majority of data came from the EMPA‐REG OUTCOME trial …”

Section: Methodsmentioning

confidence: 99%

Effects of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes in women versus men

Rådholm

Zhou

Clemens

et al. 2019

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA‐REG OUTCOME, CANVAS Program, DECLARE TIMI‐58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men.

show abstract

Analysis of Fractures in Patients With Type 2 Diabetes Treated With Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride

Abstract: 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.

Cited by 51 publications

References 47 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta‐analysis

Effects of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes in women versus men

Contact Info

Product

Resources

About