Use of Sodium-glucose co-transporter-2 inhibitors, changes in body mass index and risk of major osteoporotic fracture

Date of ISAC Approval: 
Lay Summary: 
Diabetes type 2 is associated with an increased risk of fractures. Since 2013 there is a new class of anti-diabetic drugs known as sodium-glucose inhibitors co-transporter-2 inhibitors (SGLT2-Is) on the market. Use of these drugs reduces body weight. Unfortunately, those SGLT2-Is have also been linked to a potential increase in fracture risk. One of the potential mechanisms could be that the decrease in body weight due to use of SGLT2-Is may increase fracture risk. As low body weight and loss of body weight have been associated with an increased risk of fracture. However, up to date, studies investigating the association between use of SGLT2I-s and fracture risk have not investigated the effect of loss of body weight. Therefore, the aim of this study is to investigate the relation between SGLT2-Is, changes in body weight and risk of fracture.
Technical Summary: 
The objective of this study is to evaluate the association between current use of SGLT-2 inhibitors and fracture risk as compared to current sulphonylurea (SU) use. In addition, we will investigate what the effect of change in BMI is on this association. We will first create a base study population including all patients who start with metformin only during 1-1-98 and 30-6-2018. From this base population we will select all patients with a first ever prescription of a sulphonylurea (SU), SGLT-2-inhibitor or dipeptidyl peptidase 4 inhibitor (DPP4-I) prescription during 1-1-2013 and 30-6-2018. SU use will be the reference group. In addition, we will compare fracture risk between SGLT-2-I use and DPP4-I use. Exposure will be assessed time-dependently, with groups distinguishing between current, and past use. Cox proportional hazard models will be used to derive hazard ratios for the association between use of SGLT-2-Is and fracture risk. These models will be adjusted for potential confounders.
Health Outcomes to be Measured: 
Primary: Major osteoporotic fracture Secondary: Hip, radius/ulna, clinical symptomatic vertebral fracture

Frank de Vries - Chief Investigator - Utrecht University
Ms Bernardette Rossi - Collaborator - Maastricht University Medical Centre
Frank de Vries - Corresponding Applicant - Utrecht University
Johanna Annemariek Driessen - Collaborator - Utrecht University
Joop van den Bergh - Collaborator - Maastricht University
Dr Nicklas Rasmussen - Collaborator - Aalborg University Hospital
Dr Olaf Klungel - Collaborator - Utrecht University
Peter Vestergaard - Collaborator - Aalborg University Hospital
Richard Eastell - Collaborator - University Of Sheffield