Summary

• Results from retrospective analyses from claims data revealed that adherence and persistence were significantly better with INVOKANA compared to other newer antihyperglycemic agents (AHAs) including dapagliflozin (DAPA), dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin (SITA), and glucagon-like peptide-1 (GLP-1) receptor agonists.¹
• Similar retrospective cohort analyses showed that patients on INVOKANA had high adherence rates.^2-4
• Patients receiving INVOKANA remained on their therapy longer (e.g., longer persistence) than patients receiving DPP-4 inhibitors, including SITA, or GLP-1 agonists.^5-7

BACKGROUND

Measuring medication compliance is challenging because it is based on individual behavior of actually taking the medication as directed.^8,9 Medication compliance can be divided into two concepts: adherence, persistence.¹⁰

Medication adherence is defined as the extent to which patients’ acts in accordance with the prescribed interval and dose of a dosage regimen.¹¹ Furthermore, there is no gold standard in terms of measuring adherence; however, pharmacy refill data and patient self-report are the mostly commonly used adherence assessment methods.^6,10

Common methods to estimate a patient’s adherence using administrative claims database are medication possession ratio (MPR) and proportion of days covered (PDC).^6,12,13 Adherence measured by the MPR looks at a single medication over a period of time. The calculation of MPR is the summation of the total days’ supply divided by the total number of days in the observation period.⁹

The preferred method to calculate adherence is using PDC as it is a more conservative estimate and does not tend to overestimate the true rate of adherence. MPR can be greater than 100% due to a final fill of a medication occurring immediately before the end of the observation period or due to early refills; however, the maximum level of adherence when calculated with PDC is capped at 1.0. An acceptable level of medication adherence (measured as PDC or MPR) that is generally considered to be high adherence is at 80% or above.⁹

Medication persistence is the duration of time from initiation to discontinuation of therapy.¹¹ Discontinuation is identified as a gap in therapy. There is also a prespecified limit on the number of days allowed between refills in persistence analyses.¹¹

Adherence and persistence to AHAs can have significant impact on a patient’s health outcomes. In terms of glycemic control, the mean glycosylated hemoglobin (A1C) difference between patients with optimal adherence and patients with worst adherence was 1.4%.^2,14

Furthermore, a 10% increase in MPR for an oral diabetes medication is associated with a 0.1% decrease in A1C.¹⁵ Hence, adherence and persistence to antihyperglycemic agents are associated with higher likelihood of achieving A1C goals and lower likelihood of poor glycemic control (A1C>9%)^16-18 and, lower total and diabetes-related healthcare^16,19 and lower cause mortality.²⁰

ADHERENCE AND PERSISTENCE MEASURES

Truven Databases

Cai et al (2016)^1,21 conducted a retrospective cohort study utilizing data from Truven Health Analytics MarketScan Commercial (Population A, n=38,083)¹ and Commercial and Medicare Supplemental Claims (Population B, n=11,961)²¹ databases to assess treatment persistence and adherence in patients with type 2 diabetes mellitus (T2DM) who initiated treatment with one of the newer (AHAs) including, SGLT2 inhibitors: INVOKANA 100 or 300 mg or dapagliflozin (DAPA) 5 or 10 mg; DPP-4 inhibitors: SITA, saxagliptin (SAXA), or linagliptin (LINA); GLP-1 receptor agonists: liraglutide (LIRA), exenatide (EXEN), or exenatide long-acting (EXEN LA).

Study Design/Methods

• Patient selection for Population A (Commercially Insured)¹ was from February 2014 through October 2014 and consisted of only commercially insured patients who were continuously enrolled for ≥6 months pre-index and ≥9 months post-index.
• Patient selection for Population B^1,21(Commercial or Medicare Supplement) was from February 2014 through July 2014 and consisted of commercially insured and Medicare Supplemental patients that were continuously enrolled for ≥12 months pre-index and ≥12 months post-index.

Results

Population A (Commercial)

• A total of 38,083 patients met all study criteria; the mean (±SD) age was 52(±8) years.
• Persistence was assessed 9 months post-index, and approximately two-thirds of patients (64%-67%) who initiated INVOKANA remained on treatment after 9 months vs approximately half or less for DAPA (46%), DPP-4 inhibitors (47%-53%), and GLP-1 receptor agonists (26%-50%).
• Patients who initiated INVOKANA were more likely to maintain treatment during the 9-month follow up compared to patients who initiated another AHA.

Population B (Commercial and Medicare Supplement)

• A total of 11,961 patients, of which 10,237 (86%) were commercially insured and 1724 (14%) were covered by Medicare Supplemental
• Median adherence (MRP and PDC) rates over the 12-month follow-up were higher for INVOKANA100 mg and 300 mg (0.79-0.92) compared with other AHAs (0.33-0.75).
• The proportions of patients persistent on treatment at 12 months (P values compared with INVOKANA 100 mg) were the following: INVOKANA 100 mg, 61%; INVOKANA 300 mg, 64% (P=0.037); DAPA 5 mg, 40% (P=0.001); DAPA 10 mg, 41% (P<0.001); SITA, 48% (P<0.001); SAXA, 42% (P<0.001); LINA, 52% (P<0.001); LIRA, 47% (P<0.001); EXEN, 23% (P<0.001); and EXEN LA, 39% (P<0.001). See Figure: Time to Discontinuation in Population B.

IMS PharMetrics Plus

Cai et al (2016)¹³ conducted another retrospective cohort study using IMS’ PharMetrics Plus Database to evaluate treatment patterns (adherence and persistence) in patients with T2DM that are newly initiating AHAs from February 2014 through June 2014. Patients were required to have ≥12 months pre-index and post-index eligibility. Study medications included INVOKANA, dapagliflozin (DAPA), GLP-1 agonists (GLP-1s), and DPP-4 inhibitors (DPP-4is).

Patient Characteristics

• The study consisted of 23,702 T2DM patients who met the study criteria, with 6546 in INVOKANA group, 3087 in DAPA group, 7796 in DPP-4i group, and 6273 in GLP-1 group.
• The mean age ranged from 53.2 years for GLP-1 group to 55.9 years for DPP-4i group. GLP-1 group had the highest proportion of female (50.4%), whereas DPP-4 group had the lowest proportion of female (40.9%).
• More than half of the population in all four groups were commercially insured.

Results

• Patients on INVOKANA 300 mg had the highest persistence (70%), followed by INVOKANA 100 mg (66%), DAPA 5 mg (58%), DAPA 10 mg (57%), DPP-4 (54%), and GLP-1 (52%).
• INVOKANA was associated with significantly lower risk of discontinuation compared with other study drugs (all P<0.05). INVOKANA was associated with significantly lower likelihood of non-adherence compared with other study drugs (all P<0.05).
• Patients on INVOKANA 300 mg had the highest mean PDC and MPR (0.72 and 0.73, respectively), followed by INVOKANA 100 mg (0.70 and 0.71, respectively), DAPA 5 mg and 10 mg (0.64 and 0.65, respectively), DPP-4 (0.62 and 0.62, respectively), and GLP-1 (0.56 and 0.57, respectively).
• INVOKANA was associated with significantly lower likelihood of nonadherence compared with other study drugs (all P<0.05).

ADHERENCE MEASURE

Clinical Trial Data

Cai et al (2018)²² evaluated patient-reported outcomes (PRO) data from four^23-26 randomized controlled clinical trials of INVOKANA vs. placebo or sitagliptin (N=2536), to determine patient interest in study drug continuation at the end of each study (26 or 52-week durations).

• Interest in study drug continuation was gathered via patient-reported outcome instruments: Current Health Satisfaction Questionnaire (CHES-Q); Impact of Weight on Quality of Life-Lite (IWQoL-Lite); and Short Form-36 (SF-36).
• At the end of each study (26 or 52-weeks), participants treated with INVOKANA were more likely to show interest in continuing treatment compared with those treated with placebo/sitagliptin (odds ratio [OR] 1.54; 95% CI 1.19-1.99; P=0.001), with 85.6% and 79.8% of participants, respectively, expressing interest in treatment continuation.
• Participants treated with INVOKANA were also more likely to be satisfied with their weight and outcomes related to physical and emotional health.

HealthCore

Singhal et al (2018)⁴ conducted a retrospective analysis using laboratory data from HealthCore Integrated Research Database (HIRD) to assess medication adherence of commercially or Medicare insured patients with T2DM in the United States initiating INVOKANA or a GLP-1 receptor agonist between April 1, 2013 through February 28, 2016 with up to 12 months of follow-up.

Study Design/Methods

• A total of 750 patients in the INVOKANA cohort and 2417 patients in the GLP-1 cohort were included in the study after applying stabilized inverse probability of treatment weighting.

Results

• A higher proportion of patients in the INVOKANA cohort remained adherent to the index medication (PDC≥80%) compared to the GLP-1 cohort (47.5% vs. 37.5%; P<0.0001); the mean PDC was higher in the INVOKANA cohort (0.67 vs. 0.59; P<0.0001).
• A lower proportion of patients in the INVOKANA cohort discontinued (49.6% vs. 57.4%; P<0.0001) or switched medications (33.8% vs. 38.4%; P=0.023) compared to patients in the GLP-1 cohort.

Jain et al (2016)² conducted a retrospective cohort analysis utilizing HIRD to assess medication adherence among commercially insured patients (N=881) with T2DM who initiated on INVOKANA from April 01, 2013 through April 30, 2014. In addition, these patients had continuous medical and pharmacy eligibility during the 12-month baseline and 12-month follow-up periods.

Study Design/Methods

• A total of 881 patients met the study criteria; mean age (SD): 55.2 (9.1) years; mean baseline A1C (SD): 8.4% (1.6%).
• PDC and MPR were calculated for all patients (N=881), and for patients in the sensitivity analysis who had ≥ 2 claims of INVOKANA (N=807) and for patients with baseline A1C ≥7% (N=741).

Results

• For all patients, the median PDC and MPR were 83% and 88%, respectively.
• For patients in the sensitivity analysis, the median PDC and MPR were 85% and 94%, respectively.
• PDC and MPR for INVOKANA patients with baseline A1C ≥7% were similar to those for the overall cohort.

Optum Database

Buysman et al (2017)³ in a retrospective study evaluated medication adherence to INVOKANA therapy among patients with T2DM who initiated on INVOKANA by utilizing data from a large US insurance claims database that included commercial and Medicare Advantage members from April 2013 through August 2014.

Patient Characteristics

• A total of 2261 patients had continuous health plan enrollment for ≥12 months pre-index and ≥12 months post-index date.
• The mean (±SD) age was 55.6 (±9.4) years.

Results

• The mean PDC was 0.68 and the median MPR was 0.70. Approximately 50% of the patients had PDC or MPR ≥80%.
• In the subset of patients with ≥2 INVOKANA fills in the follow-up period (n=2084), mean (±SD) PDC was 0.73 (±0.25) and MPR was 0.75 (±0.26).

PERSISTENCE MEASURE

QuintilesIMS Electronic Medical Records - US Database

Pfeifer et al (2017)⁷ conducted a retrospective cohort study to compare A1C control in the context of persistence, treatment progression, and durability in patients with T2DM initiated on oral INVOKANA 300 mg vs an injectable GLP-1 receptor agonist.

Study Design/Methods

• Electronic medical records between March 29, 2012, and April 30, 2016, were collected.
• Patients were required to have: ≥1 diagnosis for T2DM at any time; been initiated on INVOKANA or a GLP-1 receptor agonist on or after March 29, 2013, with no prescription for INVOKANA or a GLP-1 receptor agonist in the 12 months prior; ≥12 months of clinical activity before the index date; ≥18 years of age on index date; and ≥1 available A1C measurement at baseline. Those initiated on both INVOKANA and a GLP-1 receptor agonist on the same day were excluded.
• Patients were grouped into 2 cohorts, INVOKANA or GLP-1 receptor agonist, based on the first of the 2 agents prescribed.
• Primary study outcomes included: time to reach the HEDIS A1C threshold of <8% among those patients with baseline A1C ≥8%; and persistence, defined as having no gap of >90 days from the last day of supply until the next prescription.

Results

Patient Characteristics

• Baseline demographics and clinical characteristics, including A1C, were generally balanced between the weighted cohorts during the 12-month baseline period.
• The majority of patients in both cohorts used other antihyperglycemic agents (INVOKANA, 95.3%; GLP-1, 92.9), antihyperlipidemic agents (INVOKANA, 71.8%; GLP-1, 71.5%), and antihypertensive agents (INVOKANA, 79.2%; GLP-1, 80.0%) prior to the index date.
• A total of 5540 patients were initiated on INVOKANA and 17,477 patients were initiated on a GLP-1 receptor agonist.

A1C Control

• A1C decreased during the first 3 months following initiation of therapy and remained lower through the 12 months post-index date. Mean A1C levels were generally similar between the INVOKANA and GLP-1 cohorts at each time point.
• INVOKANA-treated patients were as likely as GLP-1 agonist-treated patients to reach A1C <8% (P=0.642; median time to reach threshold: 12.4 vs 13.1 months, respectively).
  • INVOKANA-treated patients were as likely as GLP-1 agonist-treated patients to maintain A1C <8% (P=0.988).

Treatment Discontinuation

• Discontinuation of treatment was 30% less likely in the INVOKANA cohort vs the GLP-1 agonist cohort (P<0.001; median time to discontinuation: 12.4 vs 8.6 months, respectively).
• Fewer INVOKANA-treated patients vs GLP-1 agonist-treated patients had a prescription for a new AHA (36.4% vs 44.8%, respectively; P<0.001; median time to new AHA prescription: 21.3 vs 15.1 months, respectively).

Persistence

• Medication persistence at 24 months after the index date was as follows: INVOKANA, 29.4%; GLP-1 agonist, 17.1%; P<0.001.  

Truven Database

Thayer et al (2016)⁵ conducted a retrospective study utilizing data from a large US insurance claims database that included enrollees in commercial and Medicare Advantage plans to compare the persistence to treatment among matched patients with T2DM receiving INVOKANA (100 or 300 mg) vs SITA (25 mg, 50 mg, or 100 mg).

Study Design/Methods

• The identification period for the prescription fills for SITA or INVOKANA was from April 2013 through December 2013.
• The study population consisted of patients with continuous health plan enrollment 6 months before and 9 months after the index date.
• Patients in each stratum were matched 1:1 using propensity score matching (PSM) to control demographic and clinical differences between cohorts.
• Samples studied included the (1) overall matched samples for INVOKANA and SITA, and (2) matched subgroup of patients with baseline A1C ≥7.0%.

Results

• After PSM, each cohort had 1472 patients that were balanced on baseline characteristics.
• The mean (±SD) age was 55.5 (±10.1) years for INVOKANA cohort and 56.1 (±11.2) years for SITA cohort.
• The mean number of days persistent with index therapy was significantly longer for INVOKANA patients than SITA patients (152 days vs 139 days, P<0.001).
• Similar results were found among the subgroup of patients with baseline A1C ≥7.0%. See Figure: Kaplan-Meier survival curves of time to discontinuation by index drug in (A) the overall cohorts and (B) baseline A1C≥7.0% cohorts.
• Significantly less INVOKANA patients were estimated to discontinue the index medication during the follow-up period than SITA patients (37.4% vs 52.0%, P<0.001).

Truven and Optum Database

Diels et al (2015)⁶ conducted a retrospective cohort analysis using data from two US claims databases of Commercially Insured patients (Truven and Optum) from January 2013 through September 2014 to compare persistence amongst AHAs, including SGLT2 inhibitors.

Study Design/Methods

• The analysis included all patients who were observed to have a first claim in 2013 for the following AHAs: INVOKANA 100 or 300 mg; DPP-4 inhibitors: sitagliptin (SITA), saxagliptin (SAXA), or linagliptin (LINA); GLP-1 receptor agonists: liraglutide (LIRA), exenatide (EXEN), or exenatide long-acting (EXEN LA).
• The analytical sample included only patients with ≥6 months of retrospective data prior to their first paid claim. The date of this claim was defined as the index date.
• Discontinuation was defined as an observed refill gap of ≥90 days between 2 subsequent prescriptions. Sensitivity analyses for alternative discontinuation definitions using 30- and 60-day refill gaps were conducted.
• A dose change in any drug was not considered as treatment discontinuation.

Patient Characteristics

• The study consisted of 66,206 and 19,536 patients in the Truven and Optum databases, respectively; mean age was 52.6/52.9 years across both data sources (Truven/Optum respectively).

Results

• Among patients in the Truven database, 64.0% and 65.0% of patients with INVOKANA 100 and 300 mg at the index date remained on treatment after 12 months, which were significantly higher compared to DPP-4 inhibitors (30.2% LINA to 51.1% SITA) and GLP-1 agonists (24.3% EXEN to 43.0% LIRA, P<0.0001 for all comparisons). See Figure: Kaplan-Meier Curves Showing Time to Discontinuation for Truven and Optum.
• In a Cox Proportional Hazards Model, adjusted hazard ratios for discontinuation in the Truven and Optum databases for INVOKANA 100 mg (reference) and 300 mg were significantly lower (HR = 0.92 and 0.99, respectively) compared with DPP-4 inhibitors (SITA [HR = 1.28 and 2.70]; SAXA [HR = 2.01 and 2.05]; LINA [HR = 2.08 and 2.38]) and GLP-1 agonists (EXEN [HR = 2.59 and 3.12]; EXEN LA [HR = 1.87 and 2.47]; LIRA [HR = 1.58 and 1.79]).

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 25 November 2024.