Effect of anti-diabetic drugs on bone metabolism: Evidence from preclinical and clinical studies

Adil, Malik M; Khan, Rashid Ali; Kalam, Abul; Venkata, Shiva Kumar; Kandhare, Amit D.; Ghosh, Pranab; Sharma, Manju

doi:10.1016/j.pharep.2017.05.008

Cited by 55 publications

(39 citation statements)

References 152 publications

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“…Even in this context, only 1 participant, receiving ertugliflozin 5 mg, met bone rescue criteria. The effects of SGLT2 inhibitors on BMD and fractures have been studied in other members of the class; a 182‐patient study found comparable BMD percentage changes between dapagliflozin 10 mg/day and placebo at 52 weeks; at 102 weeks the difference in LS means (95% CI) at the total hip was −0.45 (−1.32, 0.43) . Canagliflozin treatment resulted in greater percentage reductions in BMD versus placebo at the total hip at all time points in a 104‐week 716‐patient study; at week 104 the difference was −0.9 (−1.5, −0.2) and −1.2 (−1.9, −0.6) for canagliflozin 100 mg and 300 mg versus placebo, respectively .…”

Section: Discussionmentioning

confidence: 99%

Long‐term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104‐week VERTIS MET trial

Gallo

Charbonnel

Goldman

et al. 2019

Diabetes Obesity Metabolism

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Aim To evaluate the long‐term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin. Materials and Methods A 104‐week Phase III, randomized double‐blind study with a 26‐week placebo‐controlled period (Phase A) and a 78‐week period (Phase B) where blinded glimepiride was added to non‐rescued placebo participants with fasting fingerstick glucose ≥6.1 mmol/L. Results through week 104 are reported. Results Mean (standard error) change in HbA1c from baseline was −0.7% (0.07) and −1.0% (0.07) at week 52; −0.6% (0.08) and −0.9% (0.08) at week 104 for ertugliflozin 5 and 15 mg. At week 52, 34.8% and 36.6% participants had HbA1c <7.0%, and 24.6% and 33.7% at week 104, for ertugliflozin 5 and 15 mg. Ertugliflozin reduced fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP) from baseline through week 104. The incidence of female genital mycotic infections (GMIs) was higher with ertugliflozin, and symptomatic hypoglycaemia was lower for ertugliflozin versus placebo/glimepiride. Minimal bone mineral density (BMD) changes were observed, similar to placebo/glimepiride, except at total hip where reduction in BMD was greater with ertugliflozin 15 mg versus placebo/glimepiride: difference in least squares means (95% CI) –0.50% (−0.95, −0.04) at week 52 and −0.84% (−1.44, −0.24) at week 104. Conclusions Ertugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non‐clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. http://ClinicalTrials.gov Identifier: NCT02033889.

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Section: Discussionmentioning

confidence: 99%

Long‐term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104‐week VERTIS MET trial

Gallo

Charbonnel

Goldman

et al. 2019

Diabetes Obesity Metabolism

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“…The AGEs accumulation in collagen triggers apoptosis of the osteoblast cells, whereas abnormal serum levels of markers of bone formation, such as alkaline phosphatase, osteocalcin, insulin‐like growth factor‐1 (IGF‐1), sclerostin, wingless/integrated (Wnt) signaling pathways, and Runt‐related transcription factor 2 (Runx2) levels, suggest abnormal osteoblastogenesis . Similarly, abnormal serum levels of markers of bone resorption, such as receptor activator of NF‐κB ligand, tartrate‐resistant acid phosphatase, and c‐terminal cross‐linked telopeptide, suggest that impaired bone reabsorption may also be involved in the pathogenesis of skeletal fragility in diabetes . Chronic hyperglycemia and AGEs accumulation also contribute to inflammation, a pathophysiological hallmark of diabetes.…”

Section: Sglt2i Effects On Bone Health and Mineral Metabolismmentioning

confidence: 99%

“…(36,38) The increased risk of fracture in these patients may be caused by poor bone quality, possibly because of greater cortical bone porosity and abnormal bone mineral strength. (39) Poor bone quality and abnormal bone microarchitecture in DBD is likely the consequence of many common variables, including chronic hyperglycemia, tissue-specific accumulation of advanced glycation end-products (AGEs), abnormal insulin levels, and chronic low-grade inflammation. (35,36) All these factors may be responsible for bone-remodeling abnormalities in diabetes.…”

Section: Diabetic Bone Diseasementioning

confidence: 99%

“…(36) Similarly, abnormal serum levels of markers of bone resorption, such as receptor activator of NF-κB ligand, tartrate-resistant acid phosphatase, and c-terminal cross-linked telopeptide, suggest that impaired bone reabsorption may also be involved in the pathogenesis of skeletal fragility in diabetes. (39) Chronic hyperglycemia and AGEs accumulation also contribute to inflammation, a pathophysiological hallmark of diabetes. Besides cardiovascular complications, any chronic inflammatory state can be expected to affect bone cell activity and bone health.…”

Section: Diabetic Bone Diseasementioning

confidence: 99%

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Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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The newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…11,173 Both rosiglitazone and pioglitazone were associated with increased risk of fluid retention and congestive heart failure, 176 leading to certain restrictions on prescribing by the FDA. 11,173 PPARγ has been implicated in bone metabolism, with specific effects on osteoblasts, osteocytes, and osteoclasts 177,178 ; therefore, it is not surprising that TZDs have also been associated with an increased risk of bone fractures based on a plethora of preclinical and clinical studies, 41, [179][180][181][182][183][184][185] although some have suggested that the fracture risk could be similar to the risk in patients with T2D receiving insulin treatment. 186…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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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.

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Effect of anti-diabetic drugs on bone metabolism: Evidence from preclinical and clinical studies

Cited by 55 publications

References 152 publications

Long‐term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104‐week VERTIS MET trial

Long‐term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104‐week VERTIS MET trial

Mineral and Electrolyte Disorders With SGLT2i Therapy

Diabetes pharmacotherapy and effects on the musculoskeletal system

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