JOURNAL CLUB

Lim J, Kwak S, Choi YJ, et al. Differing Efficacy of Dapagliflozin Versus Empagliflozin on the Risk of Incident Atrial
Fibrillation in Patients With Type 2 Diabetes: A Real-World Observation Using a Nationwide, Population-Based
Cohort. J Am Heart Assoc. 2024;13(3):e030552. doi:10.1161/JAHA.123.030552
Journal and Authors Journal:
-Journal of the American Heart Association
Author:
-Jaehyun Lim , MD; Internal Medicine physician at Seoul National University Hospital.
Also serves as a professor in the Internal Medicine department at Seoul National
University. He has 9 total publications focusing on diabetes, cardiology, and
cardiothoracic surgery.
Funding:
-This research was funded by a grant from Samjin Pharmaceutical (Manufacturer of
dapagliflozin in Seoul, South Korea). The funder had no role in study design, data
collection and analysis, preparation of the article, or decision to submit results.

Game:
- 2 teams - divided evenly
- Questions from the article, topic, medication class, etc.
- 1 person from each team will come up to their buzzer
- May consult their team, may use resources, may look up
- First one to buzz in will be allowed to answer
- 5 points for each correct answer
- Negative 2 points for each incorrect answer
- If missed, opposing team may steal the question
- Bonus Questions: If answered correctly, chance to make a basket with the ball for 2
additional points

Questions:
1. In what country was this study conducted?
a. South Korea
2. Who funded this study?
a. Samjin Pharmaceutical
3. What product does Samjin Pharmaceutical make?
a. dapagliflozin (potential source of bias??)
4. What was the purpose of the study?
a. to determine if the protective effects of SGLT2 inhibitors against AFIB were
more selective to dapagliflozin than empagliflozin
5. What are all of the FDA approved indications for SGLT-2 inhibitors?
a. T2DM, CHF, CKD
6. BONUS:Where do SGLT-2 inhibitors work in the kidney?
a. proximal tubule
7. List 3 of the mentioned mechanisms behind increased risk for AFIB in T2DM:
a. Glycemic fluctuations, inflammation, oxidative stress, cardiac autonomic
neuropathy → unregulated sympathetic activity → proarrhythmic electrical
remodeling, atrial structural remodeling
8. What is the proposed mechanism behind SGLT-2 inhibitor protection against AFIB?
a. Reduction of sympathetic activity, oxidative stress, and glycemic fluctuations,
9. What other antidiabetic agent was mentioned by the authors that decreases AFIB risk?
a. pioglitazone
10. BONUS:What is the mechanism of action of pioglitazone?
 a. TZD; not entirely clear, what we do know is it is a PPAR gamma agonist (potent
peroxisome proliferator-activated receptor-gamma)(AKA glitazone reverse
insulin resistance receptor): increases insulin-dependent glucose disposal,
decreases hepatic glucose output, decreases insulin resistance in the periphery
and liver.
11. How were the researchers able to obtain data from nearly the entire population?
a. NHIS is a single insurer covering almost the entire South Korean nation
b. database of all healthcare services (inpatient, outpatient, etc.)
12. What were the inclusion criteria?
a. Patients who had T2D who started SGLT2 inhibitors between May 2016 and
December 2018 in South Korea
b. underwent health screening within 2 years of index date (prescription date)
13. List all of the exclusion criteria:
a. They excluded any patients who:
i. were <20 years of age
ii. were exposed to both drugs during the study period
iii. were diagnosed with AF or end-stage renal disease before the index date
iv. who used SGLT2 inhibitors other than dapagliflozin or empagliflozin
v. who developed AF within 30 days of the initiation of dapagliflozin or
empagliflozin, because this was considered too short a duration for the
drug to have a discernible impact on the development of AF.
vi. Finally, we excluded patients with missing variables.
14. Describe the Study Design:
a. Nationwide population-based cohort (observational - not experimental)
b. new-user design - (all of the patients were new users of the medications)
c. Active-comparator (not placebo controlled), confounder controlled (PS)
15. BONUS:Who was included in the intention-to-treat group but not the sensitivity analysis?
a. The main group was an intention-to-treat group
b. The sensitivity analysis censored patients who skipped their medications for ≥30
days (more of a per protocol).
16. Which patients were included in the high cardiovascular risk group?
a. men greater than or equal to 55, women 60 with greater than or equal to 1 risk
factor for hypertension, dyslipidemia, current tobacco use,
b. All patients with hx of ischemic heart disease, ischemic stroke, PAD.
17. What was the propensity score matching? (and why was it used?)
a. That is a way to assign subjects to groups while accounting for covariates
b. Reducing bias and confounding
i. ensures nearly identical baseline characteristics between groups
1. 49 of the 64 total covariates had no significant difference
between groups PRIOR to propensity scoring
18. Which greek letter was for the coefficient of 0.05?
a. phi (φ) coefficient which means Absolute Standardized Differences between
groups were <0.10 (negligible).
b. kind of like the alpha of propensity scoring (measure of difference between
groups) - 0.05 correlation coefficient corresponds to <10% ASD - negligible
19. What was the primary outcome?
a. incident non-valvular AFIB (to date, research shows diabetes increases risk of
non-valvular AFIB but not valvular AFIB)
20. How did they record AFIB?
a. 1 or more hospitalization with AF as a primary diagnosis
b. 2 or more outpatient with AF as a primary diagnosis

21. Statistical analysis:

 a. What was used to estimate hazard ratios?
i. Cox proportional hazard regression
1. CPH model enables us to investigate the effects of several
continuous and categorical variables on survival, while
accounting for possible confounders.
2. Unlike the log-rank test (and other non-parametric models), CPH
facilitates quantification of differences in survival distribution
between two groups.
3. We do this by estimation of a hazard ratio. The hazard ratio is the
ratio of the event rate at any given time in one group (e.g.,
treatment group) relative to the other (e.g., control group)
22. Results:
a. BONUS:How many SGLT2 users were included in the final analysis (both
groups)?
i. 137,928
b. In the intention-to-treat analysis: compared with empagliflozin, how much less
likely (percent) were the dapagliflozin users to have incident AFIB?
i. 11.5% lower
c. What about sensitivity analysis?
i. 16.5% lower
d. How can you tell it was statistically significant?
i. CI does not cross 1.0
23. Patient Characteristics:
a. Which characteristics between the dapagliflozin and empagliflozin had an ASD
>0.10?
i. None (What is ASD)
1. Measure of distance between two group means in terms of one or
more variables
24. In which subgroup did the dapagliflozin have a higher AFIB incidence rate per1000
person-years and a higher Adjusted Hazard Ratio?
a. Congestive Heart Failure (Not significant - 13 patients dapa vs. 12 patients empa)
25. Discussion:
a. BONUS:Two proposed explanations for why dapagliflozin is better?
i. higher SGLT2 and SGLT1 affinity of dapagliflozin
ii. empagliflozin may increase aldosterone and norepinephrine levels (dapa
not)

Summary Talking points

26. Limitations:
a. Can we truly extrapolate these results to our patients? (South Korean only)
b. Not an RCT - not randomized
c. Variables: stratified by FBG only (not PPG, A1C?)
i. Glycemic fluctuations cause AFIB → including PPG could have a better
27. Clinical Implication (Overall):
a. Dapagliflozin more of cardiac SGLT-2
b. Empagliflozin more of CKD?
28. Clinical Implication (Lutheran):
a. formulary change to dapagliflozin (generic - cheaper)