Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes—A Systematic Review

Abstract

Diabetes poses a significant risk to bone health, with Type 1 diabetes (T1D) having a more detrimental impact than Type 2 diabetes (T2D). The group of hormones known as incretins, which includes gastric inhibitory peptide (GIP) and glucagon‐like peptide 1 (GLP‐1), play a role in regulating bowel function and insulin secretion during feeding. GLP‐1 receptor agonists (GLP‐1 RAs) are emerging as the primary treatment choice in T2D, particularly when atherosclerotic cardiovascular disease is present. Dipeptidyl peptidase 4 inhibitors (DPP‐4is), although less potent than GLP‐1 RAs, can also be used. Additionally, GLP‐1 RAs, either alone or in combination with GIP, may be employed to address overweight and obesity. Since feeding influences bone turnover, a relationship has been established between incretins and bone health. To explore this relationship, we conducted a systematic literature review following the PRISMA guidelines. While some studies on cells and animals have suggested positive effects of incretins on bone cells, turnover, and bone density, human studies have yielded either no or limited and conflicting results regarding their impact on bone mineral density (BMD) and fracture risk. The effect on fracture risk may vary depending on the choice of comparison drug and the duration of follow‐up, which was often limited in several studies. Nevertheless, GLP‐1 RAs may hold promise for people with T2D who have multiple fracture risk factors and poor metabolic control. Furthermore, a potential new area of interest is the use of GLP‐1 RAs in fracture prevention among overweight and obese people. Based on this systematic review, existing evidence remains insufficient to support a positive or a superior effect on bone health to reduce fracture risk in people with T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone metabolism in diabetes: a clinician’s guide to understanding the bone–glucose interplay

“…In type 2 diabetes, use of metformin [97,98], dipeptidyl peptidase-4 (DPP-4) inhibitors [99] and glucagon-like peptide-1 receptor agonists (GLP1-RAs) [100] appears to be neutral/beneficial with regard to BMD and fracture risk. Incretin therapies (DPP-4 inhibitors and GLP1-RAs) may directly promote bone formation and inhibit bone resorption [100].…”

“…In type 2 diabetes, use of metformin [97,98], dipeptidyl peptidase-4 (DPP-4) inhibitors [99] and glucagon-like peptide-1 receptor agonists (GLP1-RAs) [100] appears to be neutral/beneficial with regard to BMD and fracture risk. Incretin therapies (DPP-4 inhibitors and GLP1-RAs) may directly promote bone formation and inhibit bone resorption [100]. Treatment with liraglutide prevented bone loss and increased bone formation marker levels following low energy diet-induced weight loss in women with obesity and without diabetes [101].…”

From Flora to Pharmaceuticals: 100 new additions to angiosperms of Gafargaon subdistrict in Bangladesh and unraveling antidiabetic drug candidates targeting DPP4 through in silico approach

“…The promising target Dipeptidyl peptidase 4 (DPP4) was selected as the macromolecular receptor and fetched from the Protein Data Bank with PDB ID "2ONC" [31]. DPP4 has been chosen for its broad relevance in the field of in silico drug design research, due to its pivotal role in the degradation of incretin hormones, which are known to stimulate the secretion of insulin [15]. The protein was modified with MGL-Auto-DockTools v.1.5.6 and energy minimized using SWISS-PDB viewer v4.…”

“…The Dipeptidyl peptidase 4 (DPP4) enzyme is a key player involved in the regulation of glucose homeostasis [14] and plays a critical role in degrading incretin hormones that stimulate insulin secretion. Inhibiting DPP4 can enhance incretin activity, leading to improved glycemic control in individuals with diabetes [15]. Several SBDD studies have used this enzyme as the target protein to propose some bioactive phytochemicals as antidiabetic drug candidates from various angiosperms, such as Pueraria tuberosa, Moringa oleifera, Ocimum tenuiflorum and Amberboa ramosa [16][17][18][19].…”

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study

“…Studies conducted in vitro and on animals have shown that GLP-1RAs, and in particular liraglutide and exenatide, appear to have a positive effect on bone by stimulating new bone formation and reducing bone resorption. In fact, many of these studies have shown that treatment with GLP-1RAs reduces carboxy-terminal telopeptide (CTX) levels and tends to increase those of alkaline phosphatase (ALP) and amino-terminal propeptide of type I pro-collagen (PINP) [ 8 , 9 ]. Furthermore, some studies conducted on ovariectomized mice or rats have reported that the administration of GLP-1RAs increases BMD and appears to have a protective effect on bone microstructure [ 10 , 11 ].…”