Non-alcoholic fatty liver disease (NAFLD) is a liver disease characterized by the build-up of fat in more than 5% of liver cells in the absence of excessive alcohol consumption or other chronic liver diseases. This condition is prevalent in up to an estimated 60% of patients with type 2 diabetes and left untreated, it can lead to long-term liver complications such as cirrhosis (scarring of the liver), hepatocellular carcinoma (liver cancer), and ultimately, liver-related death. As there are currently no approved therapies for the treatment of NAFLD, it is important to find new ways of preventing the long-term liver complications of this condition. There is strong biological evidence that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, drugs used in the management of type 2 diabetes, may prevent the long-term complications of NAFLD. Although many randomized controlled trials have investigated the effects of these drugs on fat build-up in the liver, none have specifically investigated the effects of these drugs on the prevention of the long-term complications of NAFLD. We will conduct a large, population-based cohort study using primary care, hospitalization, cancer registry, and death registry data from the United Kingdom. We will determine whether the use of GLP-1 RAs and SGLT-2 inhibitors, separately, when compared to the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors (anti-hyperglycemic drugs used in the same stage of type 2 diabetes), is associated with a decreased risk of long-term complications of NAFLD
GLP-1 RAs and SGLT-2 inhibitors may prevent long-term complications of NAFLD by reducing hepatic fat and inflammation. As such, the primary objective of this study is to determine whether the use of GLP-1 RAs and SGLT-2 inhibitors, separately, are associated with a reduced risk of cirrhosis (primary outcome), hepatocellular carcinoma (secondary outcome), and liver-related mortality (secondary outcome) among patients with type 2 diabetes. We will assemble two new-user, active comparator cohorts of patients, at least 18 years of age, who initiated the study drugs of interest from January 1, 2017 to December 31, 2020 in case of GLP-1 RA vs DPP-4 inhibitor cohort and January 1, 2013 to December 31, 2020 in case of SGLT-2 inhibitor vs DPP-4 inhibitor cohort. The first cohort will consist of initiators of GLP-1 RAs and initiators of DPP-4 inhibitors, the second cohort will consist of initiators of SGLT-2 inhibitors and initiators of DPP-4 inhibitors. Propensity scores will be computed to estimate the predicted probability of receiving a drug class of interest (GLP-1 RA or an SGLT-2 inhibitor) versus a DPP-4 inhibitor. The cohorts will be reweighed according to propensity score fine stratification weighting using the predicted probabilities generated from propensity scores. Weighted Cox proportional hazards models, stratified on calendar year, will be fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome of interest. Secondary analyses will be conducted to determine whether there is a duration-response relation, association with individual drug molecules, effect measure modification by age, sex, ethnicity, and to examine the association stratified by history of NAFLD. As there are no therapeutic agents approved for the treatment of NAFLD, a possible beneficial effect of GLP-1 RAs and SGLT-2 inhibitors would represent a significant clinical finding that has the potential of affecting the lives of millions of patients worldwide.
The primary outcome will be an incident event of cirrhosis. It will be identified using Read and SNOMED-CT codes in the CPRD and ICD-10 codes in HES (Appendix 1). There will be two secondary outcomes, hepatocellular carcinoma and liver-related mortality. We will use the ONS to identify all liver-related mortality events recorded as the primary cause of death.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Giada Sebastiani - Collaborator - McGill University
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Richeek Pradhan - Collaborator - Sir Mortimer B Davis Jewish General Hospital
HES Admitted Patient Care;ONS Death Registration Data