Newer glucose-lowering agents versus thiazolidinediones on risk of incident cirrhosis and clinical decompensation events in patients with diabetes (Second-line GLDs and liver complications)

Study type

• Study topic:
  Human medicinal product

  Disease /health condition
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (A10BK) Sodium-glucose co-transporter 2 (SGLT2) inhibitors

  Sodium-glucose co-transporter 2 (SGLT2) inhibitors

  (A10BH) Dipeptidyl peptidase 4 (DPP-4) inhibitors

  Dipeptidyl peptidase 4 (DPP-4) inhibitors

  (A10BJ) Glucagon-like peptide-1 (GLP-1) analogues

  Glucagon-like peptide-1 (GLP-1) analogues

  (A10BG) Thiazolidinediones

  Thiazolidinediones
• Medical condition to be studied:
  Hepatic cirrhosis

Population studied

• Short description of the study population:
  The eligible population will consist of MarketScan enrollees aged 18-64, and Medicare enrollees aged ≥ 65 with a diagnosis of type 2 diabetes and without a diagnosis of cirrhosis in the 12 months prior to drug initiation date (index date). We will include patients with and without underlying chronic liver disease, such as known hepatitis B/C infection, alcoholism and/or nonalcoholic fatty liver disease.; We will exclude the following patients:; 1. Individuals without at least 12 months of continuous enrollment in MarketScan CCAE, or in Medicare Parts A, B and D prior to the first prescription dispensing claim.; 2. Patients who have received any of the study drugs part of the pairwise comparison in the 12 months preceding the first prescription dispensing claim; 3. Individuals with the following conditions in the 12-month period leading up to drug initiation:; - Previous diagnosis of cirrhosis; - Previous diagnosis of hepatocellular carcinoma or cholangiocarcinoma; - Prior hepatectomy or liver transplantation
• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Special population of interest:
  Other
• Special population of interest, other:
  Diabetes mellitus patients
• Estimated number of subjects:
  500000

Study design details

• Main study objective:
  To estimate the effects of newer glucose-lowering agents versus TZD on risk of incident cirrhosis and incident decompensation events in patients with diabetes. Newer glucose-lowering agents to be examined are SGLT2 inhibitors and the incretin therapies, dipeptyl peptidase-4 (DPP4) inhibitors and GLP-1 receptor agonists.
• Outcomes:
  For Aim 1, the primary outcome of interest is the first diagnosis of cirrhosis during follow-up. For Aim 2, the primary outcome of interest for this aim is any clinical decompensation event. Codes will be obtained from prior literature and clinical guidance.
• Data analysis plan:
  We will compare the risk of primary outcomes using pairwise comparisons with the 4 study drug classes of interest. Our primary aim is to identify active comparator drug initiators that will allow us to estimate what would have happened to the index drug initiators if they had instead initiated the comparator drug. To achieve this goal, we will estimate the average treatment effect in the treated (ATT) by reweighting the comparator drug initiators by the propensity score odds (PS/(1-PS)). We will estimate and compare the cumulative incidence of the primary outcome for each study cohort using weighted Kaplan-Meier methods. Crude and adjusted hazard ratios (HRs) for both primary and secondary outcomes will be estimated using weighted Cox proportional hazards models, controlling for age, sex, as well as any potential confounders that remain unbalanced after propensity score implementation.