Sodium-glucose co-transporter (SGLT-2) inhibitors are a new class of drugs used to treat type 2 diabetes. They have been shown to reduce blood sugar levels, heart failure, heart attacks, strokes, and the chances of dying from reasons related to the heart. These benefits have led to an increase in their use. However, several safety concerns have emerged related to their use, including the risk of genital and urinary tract infections, diabetic ketoacidosis (increased acidity of the blood), and lower limb amputations.
These drugs work in the kidney to eliminate sugar through the urine and simultaneously cause extra water loss, which can cause dehydration. Dehydration can lead to an increased risk of blood clots in the lungs or legs (a condition known as venous thromboembolism). For this reason, the US Food and Drug Administration (FDA) has released a warning of a potential increased risk for blood clots with this class of drugs. A recent study did not find an increased risk; however, it may have been too small to conclusively assess this potential drug side effect. Given the potential severe consequences of blood clots, we believe it is important to further assess this potential side effect.
To do this, we will use data from the United Kingdoms (UK) Clinical Practice Research Datalink (CPRD) to compare the number of patients with type 2 diabetes who develop a blood clot while taking an SGLT-2 inhibitor to that in patients taking a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is another class of drugs used to treat diabetes.
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of anti-diabetic drugs that entered the market in 2013. Their main mechanism of action is the inhibition of the SGLT-2 in the kidney’s proximal convoluted tubule, resulting in increased urine glucose excretion. This induced osmotic diuresis can cause dehydration and subsequent hemoconcentration, which has been associated with an increased risk of venous thromboembolism (VTE).
A recent meta-analysis of RCTs did not find a significant association between SGLT2 inhibitor use and VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). The meta-analysis was, however, limited by the fact that VTE was not the primary endpoint of the included trials. Publication bias could also not be ruled out. The rates of VTE were comparable between SGLT-2 users and control groups. Nonetheless, the FDA has released a warning of a potential risk for stroke and thromboembolic events with SGLT-2 inhibitors. A recent cohort study evaluated the risk of seven adverse events with SGLT-2 inhibitor use and did not find an increased risk of VTE. However, the analyses may have been underpowered since the number of events was low.
This retrospective cohort study will examine the risk of VTE with the use of SGLT-2 inhibitors using the United Kingdom’s (UK) Clinical Practice Research Datalink (CPRD) linked to hospitalization and vital statistics data. The primary endpoint will be VTE, defined by either hospitalization for VTE, an outpatient diagnosis of VTE accompanied by a prescription for an anticoagulant, treatment at an anticoagulation clinic, or international normalized ratio (INR) testing (suggesting anticoagulation with warfarin), or death with a recorded diagnosis of VTE as a contributing cause of death. We will use time-dependent Cox proportional hazards models to compare event rates with the use of SGLT-2 inhibitors to those with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors.
Venous thromboembolism, including deep venous thrombosis and/or pulmonary embolism
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Christopher Filliter - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Samuel Igweokpala - Collaborator - McGill University
Shahrzad Salmasi - Collaborator - McGill University
Stephanie Aloe - Collaborator - McGill University
Vicky Tagalakis - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation