SUMMARY

• Several real-world analyses in type 2 diabetes mellitus (T2DM) patients found that cardiovascular (CV) and mortality outcomes occurred at a reduced rate in patients treated with INVOKANA or the sodium glucose co-transporter 2 inhibitor (SGLT2i) class, compared to other antihyperglycemic agents (AHAs).^1-3
• A large database observational analysis found no difference in risk of hospitalization for heart failure (HHF) between new users of INVOKANA and new users of other SGLT2i in overall and established cardiovascular disease (CVD) populations.⁴
  • A statistically significant decrease in risk of HHF between new users of INVOKANA and all non-SGLT2i was reported in both overall and established CVD populations.
• In a retrospective, real-world CV safety analysis of INVOKANA compared to non-SGLT2i, HHF was significantly reduced compared to other AHAs and a composite CV endpoint was numerically reduced compared to non-SGLT2is in most cases.⁵
• A Japanese retrospective cohort study compared the subsequent CV risk, including heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2i, including INVOKANA. Results from this study are not summarized in this response.⁶

CLINICAL DATA

CVD-REAL2

Kosiborod M et al (2018)² conducted another real-world analysis utilizing health records from claims databases and registries (CVD-REAL2) in geographical areas not studied in CVD-REAL¹, including South Korea, Japan, Singapore, Israel, Australia, and Canada.

Outcomes included all-cause death (ACD), HHF, the composite of ACD or HHF, MI, and stroke (all countries except Australia).

• Inclusion criteria were adults, new users receiving SGLT2i or other AHAs with established T2DM and >1-year data history.
• Outcomes were defined as primary discharge diagnosis codes. In Japan and Singapore, for the outcome of ACD, only information on deaths occurring in-hospital was available. However, in-hospital deaths represent the majority of fatal events in those countries.
• Baseline characteristics for propensity match cohorts were similar including a mean age of 57 years, ~45% female, 74% without known CVD, 26% with established CVD, and 62% receiving antihypertensive therapy.

Results

• A total of 470,128 new episodes of users receiving an SGLT2i (N=235,064) or other AHA (N=235,064) were identified after a 1:1 propensity match ratio was utilized to randomize patients.
• Baseline characteristics for propensity match cohorts were similar, including 74% who did not have known CVD and 26% who had established CVD.
• Compared to treatment with other AHAs, SGLT2i resulted in significantly lower risk of:
  • ACD (hazard ratio [HR] 0.51; 95% CI: 0.37-0.70; P<0.001).
  • HHF (HR 0.64; 95% CI: 0.50-0.82; P=0.001).
  • Composite of HHF or ACD (HR 0.60; 95% CI: 0.47-0.76; P<0.001).
  • MI (HR 0.81; 95% CI: 0.74-0.88; P<0.001).
  • Stroke (HR 0.68; 95% CI: 0.55-0.84; P<0.001).

OBSERVE-4D

OBSERVE-4D⁴, a large database observational analysis, utilized clinical characterization and population-level effect estimation to evaluate risks of HHF associated with INVOKANA compared to other SGLT2i and non-SGLT2i in clinical practice via a retrospective comparative cohort design. These risks were evaluated across all new users and in the subpopulation of patients with established CVD.

Study Design

Four U.S. claims databases included patients with a confirmed diagnosis of T2DM and first exposure to cohort-defining drug between 4/1/2013 and 5/15/2017.

HHF was defined as all hospital admissions with a primary diagnosis of HF as identified by ICD-9-CM and ICD-10-CM codes.

The six exposure cohorts consisted of new users of:

• INVOKANA
• Empagliflozin or dapagliflozin
• Empagliflozin
• Dapagliflozin
• Select non-SGLT2i (any dipeptidyl peptidase-4 inhibitor [DPP-4i], glucagon-like peptide-1 [GLP-1] receptor agonist, select other AHAs)
• All non-SGLT2i (any DPP-4i, GLP-1 receptor agonist, thiazolidinediones [TZD], sulfonylureas [SU], insulin, select other AHAs)

Time at Risk Periods

• The on-treatment period evaluated risk of HHF during drug exposure, defined as 1 day after drug start date to the exposure end date (end of the first persistent period of exposure with 30-day gap between exposures).
• The intent-to-treat (ITT) period evaluated overall risk after starting drug therapy; defined as 1 day after start date to the end of the patient’s observation period.

Statistical Analysis

• Population-level effect estimation analyses were applied for 7 pairwise comparisons. Baseline characteristics of populations varied greatly among databases. A propensity score-adjusted new user cohort design was used to examined relative hazards of outcomes across all new users and the subpopulation with established CVD.
• A set of negative control outcomes was used to control for any potential systematic errors after propensity score adjustment.
• Propensity score adjustment was performed to reduce potential confounding due to imbalances between target and comparator cohorts with respect to baseline covariates.

Results

A total of 142,800 new INVOKANA users (43,043 in CVD subpopulation), 110,897 new users of other SGLT2i (31,011 in CVD subpopulation), and 460,885 new users of all non-SGLT2i AHAs (141,579 in CVD subpopulation) were evaluated.

The complete study results are available publicly through an interactive web-based application at: http://data.ohdsi.org/AhasHfBkleAmputation.

• Of HHF events that occurred, 75% were reported from the 30% of the overall population with established CVD.
• Meta-analytic results found no difference in risk of HHF in the overall and established CVD populations between new users of INVOKANA and new users of other SGLT2i, both during the on-treatment and ITT periods.
• Meta-analytic results found a statistically significant decrease in risk of HHF between new users of INVOKANA and all non-SGLT2i in the overall and established CVD populations. See Table: Meta-analytic estimate of the risk of HHF in the on-treatment population.

• Sensitivity analyses did not find differences in HHF risk among SGLT2i. In the INVOKANA vs non-SGLT2i comparison, INVOKANA showed consistent decreased HHF risk in on-treatment and ITT populations; a larger decrease was seen with the on-treatment population.
• The confirmatory findings of a reduction in risk of HHF with SGLT2i from this study were consistent with those from other real-world analyses of the SGLT2i class.

EASEL Study

Udell et al (2017)³ conducted a retrospective, population-based, event-driven, cohort study within the US Department of Defense (DoD) Military Health System to evaluate CV benefits in T2DM patients with established CVD newly exposed to SGLT2i, compared to new users of non-SGLT2i AHAs from April 1, 2013 to December 31, 2016.

• The primary outcome was the composite of all-cause mortality (ACM) and HHF. Other endpoints included a composite of major adverse cardiovascular events (MACE), MACE plus HHF, as well as individual components of the composite endpoints.
• A total of 25,258 patients were matched 1:1 (12,629 new users of SGLT2i with 12,629 new users of non-SGLT-2i AHAs).
  • Of patients initiated on SGLT2i, 7,333 (58.1%) started INVOKANA, 3,341 (26.4%) empagliflozin, and 1,955 (15.5%) dapagliflozin. Baseline characteristics were well-balanced. See Table: EASEL Study Results for results.

CVD-REAL

CVD-REAL¹ was another real-world analysis conducted by Kosiborod M et al (2017)¹ that utilized health records from claims databases and registries across 6 countries: U.S., Norway, Denmark, Sweden, U.K., and Germany to compare the primary endpoint of risk of HHF in T2DM patients (n=309,056) newly initiated on SGLT2i vs. other AHAs.

Secondary endpoints compared risk of ACD between 2 treatment groups and the composite risk of HHF or ACD across 5 of the 6 countries (excluding Germany [n=215,622]).

• Inclusion criteria were adults, new users receiving SGLT2i or other AHAs with T2DM.
• In the U.S., U.K., and Germany, HHF was defined as hospital admissions for HF. In Nordic countries (Sweden, Norway, and Denmark), HHF was defined by any in-or outpatient hospital visit with a primary diagnosis of HF.
• Baseline characteristics for propensity match cohorts were similar including a mean age of 57 years, ~44% female, 87% without known CVD, 13% with established CVD, and 80% receiving antihypertensive therapy.

Results

A total of 309,056 new users receiving an SGLT2i or other AHA were identified after a 1:1 propensity match ratio was utilized to randomize patients.

• Among the 154,528 patients initiated on SGLT2i in the HHF cohort comprised of 6 countries, the proportion of exposure time was greatest with INVOKANA (52.7%) vs. dapagliflozin (41.8%) vs. empagliflozin (5.5%).
  • Among US patients in the SGLT2i group of the HHF cohort, the proportion of exposure time was greatest with INVOKANA (75.9%) vs dapagliflozin (19%) vs empagliflozin (5.1%).
• Among the 107,811 patients initiated on SGLT2i in the ACD or composite of HHF or ACD cohort across 5 countries, the proportion of exposure time with INVOKANA was 42.3%, 51% with dapagliflozin, and 6.7% with empagliflozin in the ACD cohort and 45%, 49%, and 6%, respectively, in the composite cohort.
  • Among U.S. patients initiated on SGLT2i in the ACD cohort and composite cohort, the proportion of exposure time was greatest with INVOKANA (75.4%) vs dapagliflozin (19.3%) vs empagliflozin (5.3%).
• Compared to treatment with other AHAs, SGLT2i resulted in a significantly lower risk of HHF (HR 0.61; 95% CI, 0.51 to 0.73; P<0.001).
• For the secondary endpoints, SGLT2i treatment resulted in significantly lower risk of ACD (HR, 0.49; 95% CI, 0.41 to 0.57; P<0.001) and a lower risk for the composite endpoint of HHF or ACD (HR, 0.54, 95% CI, 0.48 to 0.60; P<0.001) compared with other AHAs.
• See Table: Results for CVD-REAL Study Outcomes (HHF, All-cause Death, Composite).
• For additional information on CVD-REAL including limitations, please visit: https://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=7f5d0c3c0a2343a3a04b16fc60a883fb or https://clinicaltrials.gov/ct2/show/NCT02993614.

Other Real-World Analyses

Patorno et al (2017)⁵ conducted a retrospective real-world analysis of CV safety of INVOKANA compared with non-SGLT2i using data from a large US commercial healthcare dataset from April 2013-September 2015. The study used three pairwise 1:1 propensity score-matched cohorts of patients.

• Investigators examined HHF associated with initiation of INVOKANA vs. non-SGLT-2i (DDP-4i, GLP-1 RA, and SU) in adult T2DM patients
• Primary outcome was HHF and a composite CV endpoint (being admitted to hospital for acute MI, ischemic stroke, or hemorrhagic stroke)
• The investigators identified three pairwise 1:1 propensity score-matched cohorts of patients: (17,667 pairs initiated on INVOKANA or a DDP-4i), (20,539 pairs initiated on INVOKANA or a GLP-1 RA), (17,354 pairs initiated on INVOKANA or a SU)
• Risk of HHF was lower in patients treated with INVOKANA vs other AHAs:
  • INVOKANA vs. DPP-4i (8.9 vs 12.8 per 1000 PY, HR: 0.70, 95% CI 0.54-0.92)
  • INVOKANA vs. GLP-1 RA (7.5 vs. 12.4 per 1000 PY, HR: 0.61, 95% CI 0.47-0.78)
  • INVOKANA vs. SUs (7.3 vs. 14.4 per 1000 PY, HR:0.51, 95% CI 0.38-0.67)
• Risk of the composite CV endpoint was lower in patients treated with INVOKANA vs other AHAs:
  • INVOKANA vs. DPP-4i (9.9 vs 11.1 per 1000 PY, HR: 0.89, 95% CI 0.68-1.17)
  • INVOKANA vs. GLP-1 RA (8.8 vs. 8.5 per 1000 PY, HR: 1.03, 95% CI 0.79-1.35)
  • INVOKANA vs. SUs (8.8 vs. 10.3 per 1000 PY, HR:0.51, 95% 0.65-1.13)

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 22 January 2025.