"Glucose-lowering star" increases the risk of fracture?

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The new hypoglycemic drug SGLT-2i inhibits the reabsorption of glucose by the proximal convoluted tubules of the kidneys, and at the same time may affect the reabsorption of calcium and phosphorus by the kidneys, leading to an increased risk of fractures.
In addition, the risk of fractures in patients with type 2 diabetes is higher than that of the general population.
The recommended status of these drugs in the 2020 version of the CDS guidelines has been improved (it is reported that the full version of the guidelines is expected to be published in the "Chinese Journal of Diabetes" and "Chinese Journal of Endocrinology and Metabolism" at the end of this month.
For updated points, see the 2020 version of "China Type 2 Diabetes Prevention and Treatment" The "Guide" was released!), the fracture risk of this "star drug" has naturally become one of the topics of clinical concern.

 Will SGLT-2i increase the risk of fractures? The first pharmacovigilance study gave a conclusion that was inconsistent with the instructions.
.
.
Beginning-SGLT-2i's fracture risk controversy In September 2015, the US FDA issued a warning, emphasizing that the use of canagliflozin may be related to patients Increased fracture risk (4.
0% vs.
2.
6%) is related.

This concern stems from a two-year CANVAS study: In this study, compared with the control group, canagliflozin increased the bone turnover rate and lowered the bone density of the total hip joint.
Related content is also described.

Source: Canagliflozin Instructions for Concerns-Originating from the results of the CANVAS study on the unique mechanism of action of SGLT-2i, some scholars speculate that SGLT-2i may change the balance of calcium and phosphorus in the body, leading to a decrease in bone density and an increased risk of fractures.
The underlying mechanism may be that SGLT-2i inhibits sodium and glucose transporters and increases serum phosphorus levels, leading to increased levels of fibroblast growth factor-23 and parathyroid hormone (PTH), and ultimately leading to osteomalacia.

 However, in other similar studies that evaluated the effect of treatment on the basis of canagliflozin, no changes in serum PTH, vitamin D, and serum/urinary calcium levels were found.

However, a random crossover study conducted by Blau et al.
found that canagliflozin can induce an increase in serum phosphorus, thereby causing changes in PTH and 1,25-dihydroxyvitamin D, which may have an adverse effect on bone health.

Another study found that dapagliflozin increased serum phosphate and plasma PTH, and this effect had nothing to do with eGFR levels.

In short, there are also some controversies in the mechanism.

 SGLT-2i and fracture risk: previous studies have divergent opinions.
In recent years, more and more studies about SGLT-2i and fracture risk have been published.
For example, a meta-analysis based on 9 clinical trials published in JCEM in 2015 It shows that the incidence of fractures is higher in the canagliflozin group.

However, some studies have put forward the opposite view: ➤The case-control study published in Diabetes Obes Metab in 2019 shows that SGLT-2i does not increase the risk of fractures in patients compared with DPP-4i; ➤The case-control study published in Diabetes Care in 2018 A study showed that: compared with placebo or glimepiride, empagliflozin does not increase the risk of fractures.

 The results of the first pharmacovigilance study were announced: the use of SGLT-2i did not increase the risk of fractures.
Due to the relatively short time to market for such drugs, no relevant pharmacovigilance studies have been conducted.

To this end, Zhao Bin et al.
used the relevant data in the US FDA's Adverse Event Reporting System (FAERS) to evaluate the "relevance of the use of SGLT-2i and fracture events".

This real world study (RWS) was published in the Journal of diabetes investigation (IF: 3.
761).

  The researchers included relevant data from the first quarter of 2004 to the fourth quarter of 2019 in the FAERS database, and a total of 44,558 SGLT-2i-related adverse events and 169,132 fracture-related reports were recorded.

In the end, 317 cases of fracture reports suspected to be related to SGLT-2i were screened out.

 The patients in the reported cases are mostly in North America (61.
83%) and Europe (17.
04%).

The patients were older than 45 years old (68.
76%), and there were more men than women.

Among these reports, canagliflozin accounts for the largest proportion (51.
10%), followed by dapagliflozin (24.
60%) and empagliflozin (23.
66%).
Fracture events are more common in type 2 diabetes patients (57.
19%).
.

The results of the study showed that there was no correlation between the use of SGLT-2i and the risk of fracture.

 In the same year, the research team of Guo Lixin and Professor Pan Qi published a meta-analysis study in Diabetes Obes Metab, which comprehensively evaluated the safety of SGLT-2i in the treatment of type 1 diabetes (T1DM).

A similar conclusion was reached: Compared with the control group, SGLT-2i was not associated with increased fracture risk when used in T1DM treatment (OR 0.
86, 95% CI 0.
58-1.
28, P=0.
46, I^2=0%).

 Views have not yet been unified.
When receiving high-risk patients, it is recommended to prescribe cautiously.
In summary, in general, the academic community has not yet reached a unified view on the relevance of "SGLT-2i and fracture risk", and more high-quality products are needed in the future.
Evidence is used for evaluation.

At present, when facing people with a high risk of fracture (such as menopausal women or patients with osteoporosis), it is recommended to consider the risks comprehensively and prescribe carefully.

References: [1] Zhao B, Shen J, Zhao J, et al.
Do sodium-glucose cotransporter 2 inhibitors lead to fracture risk? A pharmacovigilance real-world study[J].
J Diabetes Investig,2020.
[2]Wang W, Zhang L, Pei X, Pan Q, Guo L.
Evaluation of the safety of SGLT-2 inhibitors for treating patients with type 1 diabetes[J].
Diabetes Obes Metab.
2020.
DOI: 10.
1111/dom.
14092.