Comment

Possible adverse effects of SGLT2 inhibitors on bone

Sodium-dependent glucose transporters 2 (SGLT2) inhibitors are a class of small-molecule drugs that have gained significant attention in recent years for their potential clinical applications in the treatment of type 2 diabetes mellitus (T2DM). These inhibitors function by obstructing the kidneys' ability to reabsorb glucose, resulting in a rise in the excretion of glucose in urine (UGE) and subsequently lowering blood glucose levels. Several SGLT2 inhibitors, such as Dapagliflozin, Canagliflozin, and Empagliflozin, have been approved by regulatory authorities and are currently available for clinical use. These inhibitors have shown notable enhancements in managing blood sugar levels, reducing body weight, and lowering blood pressure in individuals with T2DM. Additionally, they have exhibited potential advantages in decreasing the likelihood of cardiovascular incidents and renal complications among this group of patients. This review article focuses on the synthesis and clinical application of small-molecule SGLT2 inhibitors, which have provided a new therapeutic approach for the management of T2DM.

Magnesium disorders are common in clinical practice and when present can manifest clinically as cardiovascular, neuromuscular, or other organ dysfunction. Hypomagnesemia is far more common than hypermagnesemia, which is largely seen in patients with reduced glomerular filtration rates receiving magnesium-containing medications. In addition to inherited disorders of magnesium handling, hypomagnesemia is also seen with excessive gastrointestinal or renal losses and due to medications such as amphotericin B, aminoglycosides, and cisplatin. Laboratory assessment of body magnesium stores largely relies on the measurement of serum magnesium levels that are a poor proxy for total body stores but does correlate with the development of symptoms. Replacement of magnesium can be challenging, with oral replacement strategies being generally more effective at slowly replacing body stores but intravenous replacement being more effective at treating the more life-threatening and severe cases of hypomagnesemia. We conducted a thorough review of the literature using PubMed (1970-2022) and the search terms magnesium, hypomagnesemia, drugs, medications, treatment, and therapy. In the absence of clear data on optimal management of hypomagnesemia, we have made recommendations on magnesium replacement based on our clinical experience.

Diabetes is associated with increased risk of fracture. This study aims to evaluate the correlation between anti-diabetic agents and fracture risk in patients with type 2 diabetes.

Literature research was conducted using PubMed, Embase, and ClinicalTrials.gov. Search-term included “type 2 diabetes,” “fracture,” “randomized controlled trial,” and seven kinds of anti-diabetic agents. Random-effect models established fractures in the follow-up period as the primary outcome. A network meta-analysis was performed to compare available treatments within a single Bayesian analytical framework.

A total of 191,361 patients were included in 161 studies, with 2916 fractures. DPP-4i (risk ratio [RR] 1.76 [95 % confidence interval (CI) 1.21–2.55]), SGLT-2i (RR 1.5 [95 % CI 1.05–2.16]) and placebo (RR 1.44 [95 % CI 1.04–1.98]) increased fracture risk when compared to GLP1-RA. GLP1-RA (RR 0.5 [95 % CI 0.31–0.79]) and SU (RR 0.56 [95 % CI 0.41–0.77]) provided greater protection against fracture than TZD. DPP-4i increased fracture risk when compared to SU (RR 1.55 [95 % CI 1.08–2.22]), and was comparable in effect to TZD.

GLP1-RA offered better protection against fracture than placebo. Insulin and SU had effects comparable with GLP1-RA. SU offered greater protection against fractures than TZD and DPP-4i. SGLT-2i increased risk of fracture when compared to GLP1-RA.

Empagliflozin (Jardiance®) is an insulin independent antihyperglycemic agent used in treatment of T2D.The drug is a sodium glucose cotransporter-2 (SGLT2) inhibitor approved in USA and Europe and other countries of the world. As empagliflozin demonstrates cardioprotective and Reno protective properties its prime target are patients having CVD and CKD complicated by T2D.

This review sheds light on mechanism of action of the drug and with the help of clinical outcomes establishes the use of empagliflozin in T2D patients.

Although empagliflozin is a well-tolerated and easy to administer drug, it has some side effects and contraindications which are discussed in the article to help the reader weigh its beneficial effects against its adverse effect and understand its use in clinical medicine.

Sodium-glucose co-transporter-2 (SGLT-2) inhibitor-induced weight loss might play a role in the debated elevated fracture risk with these agents. The aim of the current study was to investigate the association between SGLT-2 inhibitor use, changes in body mass index (BMI) and fracture risk.

A retrospective cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) GOLD (2013–2018). The study population (N = 34,960) consisted of adults with diabetes initiating a sulphonylurea or SGLT-2 inhibitor. Cox proportional hazards models estimated hazard ratios (HRs) for major osteoporotic fracture with SGLT-2 inhibitor use versus sulphonylurea use, stratified by change in BMI, average daily dose and cumulative dose. Analyses were adjusted for age, sex, lifestyle variables, comorbidities, and concomitant drug use.

SGLT-2 inhibitor use was not associated with an increased fracture risk compared to sulphonylurea use (adjusted HR 1.19; 95% confidence interval (CI): 0.80–1.79). This finding remained consistent after stratification by BMI change. However, the highest cumulative dose category was associated with an increased fracture risk (adjusted HR: 2.10, 95 %CI: 1.11–3.99).

SGLT-2 inhibitor use was not associated with increased osteoporotic fracture risk, irrespective of change in BMI. However, a high cumulative dose could be an important risk factor.

Metabolic diseases, such as diabetes, gout and hyperlipidemia are global health challenges. Among them, diabetes has been extensively investigated. Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, is a complex metabolic disease that is associated with various metabolic disorders. The newly developed oral hypoglycemic agent, sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been associated with glucose-lowering effects and it affects metabolism in various ways. However, the potential mechanisms of SGLT2 inhibitors in metabolic diseases have not fully reviewed. Many of the effects beyond glycemic control must be considered off-target effects. Therefore, we reviewed the effects of SGLT2 inhibitors on metabolic diseases such as obesity, hypertension, hyperlipidemia, hyperuricemia, fatty liver disease, insulin resistance, osteoporosis and fractures. Moreover, we elucidated their molecular mechanisms to provide a theoretical basis for metabolic disease treatment.