Plain Language Summary
Introduction
Methods
Results
Study Selection and Characteristics
Number of included studies
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A total of 34 publications that reported on the relationships between adherence to injectable antihyperglycemic medications and health outcomes in patients with T2DM were included All studies but two identified relied on unique study populations; otherwise, there was no overlap between these studies. Two studies used the same dataset (Linetsky et al. [10] and Linetsky et al. [22]), evaluating data from the same source and same study population but using different study designs |
Study design
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In total, there were 17 studies based on commercial administrative/claims data [5, 7, 8, 14, 15, 19, 25‐35], 1 based on US veterans’ data (linked claims and medical records) [11], 12 studies based on medical records [10, 12, 16, 17, 20‐24, 36‐38] (6 of these also used surveys [10, 12, 21‐24] and 1 used Geisinger electronic medical records [17]), 2 based on national surveys [9, 13], 1 based on a physician survey [6], and 1 based on a diabetic registry with survey [18] |
Study population
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Adherence measures
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Across the 34 included studies 1 used the Morisky Insulin Adherence Scale [12] Other types of surveys used for adherence: 1: identified continuers, interrupters, and discontinuers [9] 1: identified differences in insulin timing [23] 1: identified dosing irregularities [6] 1 used adequate refills for an entire quarter [15] 1 used the MPR in 5 categories [28] 1 used the adjusted MPR ≥ 80% [27] 1 reported on persistence at 2 years + assorted clinical outcomes [30] 1 reported on persistence at 132 weeks [38] 1 reported on persistence at 6 months [37] All identified methods to measure adherence were indirect, with no studies identified that measured adherence directly through observation of medication-taking or biological fluid samples |
Effects of adherence on disease outcomes
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References | Last name of first author | Year | Selection (maximum 4)**** | Comparability (maximum 2)** | Outcome (maximum 3)*** | Total score |
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[11] | Egede | 2014 | *** | ** | *** | 8 |
[16] | Donnelly | 2007 | *** | ** | *** | 8 |
[27] | Kleinman | 2008 | *** | ** | *** | 8 |
[5] | Wei | 2014 | *** | ** | ** | 7 |
[14] | Anderten | 2015 | ** | ** | *** | 7 |
[15] | Ayyagari | 2015 | *** | * | *** | 7 |
[26] | Cobden | 2007 | *** | ** | ** | 7 |
[29] | Perez-Nieves | 2016 | *** | ** | ** | 7 |
[30] | Kalirai | 2017 | *** | ** | ** | 7 |
[31] | Lin | 2017 | *** | ** | ** | 7 |
[33] | Durden | 2016 | *** | ** | ** | 7 |
[34] | Buysman | 2015 | *** | ** | ** | 7 |
[8] | Ascher-Svanum | 2014 | *** | ** | * | 6 |
[17] | Wu | 2012 | *** | * | ** | 6 |
[19] | Sambamoorthi | 2017 | *** | ** | * | 6 |
[35] | Carls | 2017 | ** | ** | ** | 6 |
[10] | Linetsky | 2017 | ** | ** | * | 5 |
[12] | Osborn | 2016 | ** | ** | * | 5 |
[22] | Linetzky | 2016 | ** | ** | * | 5 |
[24] | Aikens | 2013 | ** | * | ** | 5 |
[28] | Chandran | 2015 | *** | ** | 5 | |
[32] | Levin | 2014 | *** | ** | 5 | |
[36] | Buysschaert | 2010 | *** | ** | 5 | |
[7] | Wang | 2013 | *** | * | 4 | |
[18] | Mashitani | 2013 | ** | * | * | 4 |
[20] | Kindmalm | 2007 | ** | * | * | 4 |
[21] | Yavuz | 2015 | ** | * | * | 4 |
[25] | Hadjiyianni | 2017 | ** | * | * | 4 |
[38] | Ivanyi | 2012 | * | *** | 4 | |
[13] | DiBonaventura | 2014 | * | ** | 3 | |
[23] | Nishimura | 2017 | * | * | * | 3 |
[37] | Varanasi | 2011 | * | ** | 3 | |
[6] | Leiter | 2015 | * | * | 2 | |
[9] | Perez-Nieves | 2017 | ** | 2 |
Glycemic Control Results
Studies Regarding the Impact of Medication Adherence and Persistence on Glycemic Control
Improvements in Glycemic Control
Author | Medication and study population | Adherence/persistence | Glycemic control relationship to adherence or persistence |
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Ivanyi [38] | GLP-1 RA, naïve, initiators on metformin and/or SFU | Persistence: 132 weeks | Change in HbA1c from baseline (mean [SD]) (P < 0.0001 at all time points) Persisters: week 52: − 1.3% (0.10%) Persisters: week 100: − 1.0% (0.12%) Persisters: week 132: − 1.0% (0.13%) |
Varanasi [37] | GLP-1 RA, naïve, initiators on oral medication with or without insulin | Persistence: 6 weeks | Change in HbA1c from baseline (mean [SD]) Persisters: week 6: drop from 8.2% (0.5%) to 6.9% (0.4%), P < 0.001 Nonpersisters: at stop: drop from 7.7% (0.6%) to 7.2% (0.3%), P < 0.001 At 6 months after stop: rise to 7.4% (0.2%), P = 0.04 compared to value at stop |
Buysschaert [36] | GLP-1 RA, naïve, initiators on metformin and SFU | Persistence: 1 year | Change in HbA1c from baseline (mean) (P values not reported) Persisters: − 1.0% (8.1% to 7.2%) when baseline HbA1c was ≤ 9% Persisters: − 2.4% (10.2% to 7.8%) when baseline HbA1c was > 9% Nonpersisters: + 0.5% (8.4% to 8.9%) when baseline HbA1c was ≤ 9% Nonpersisters: − 0.6% (10.6% to 10.0%) when baseline HbA1c was > 9% |
Levin [32] | GLP-1 RA, naïve, initiators as third agent to two prior oral medications | Persistence: 2 years | Change in HbA1c from baseline (mean) (None is statistically significant) Persisters years 1 and 2: − 0.48% Persisters year 1 with switch year 2: − 0.27% Switched year 1: − 0.23% Discontinued (not filling any diabetes drug in last quarter of year 1 or year 2): − 0.38% |
Lin [31] | Initiators of combination of GLP-1 RA and insulin | Persistence: 1 year | Change in HbA1c from baseline (mean) Persisters vs nonpersisters: − 0.8% vs − 0.4%, P = 0.032 |
Buysman [34] | GLP-1 RA, naïve, initiators on oral medications and/or insulin | Adherence and persistence: 1 year | Odds ratio for adherent vs nonadherent at 1 year PDC ≥ 80% with HbA1c goal < 7.0%: OR 1.84, P < 0.001 (51% vs 39%) PDC ≥ 80% with HbA1c goal < 6.5%: OR 1.70, P < 0.001 (35% vs 26%) Reduction HbA1c ≥ 1.0%, with PDC ≥ 80%: OR 1.86, P < 0.001 (41% vs 30%) Odds ratio for persistent vs nonpersistent at 1 year With HbA1c goal < 7.0%: OR 2.34, P < 0.001 (34% vs 23%) With HbA1c goal < 6.5%: OR 2.01, P < 0.001 (49% vs 33%) Reduction in HbA1c ≥ 1.0% with persistence: OR 2.37 (P < 0.001) (39% vs 26%) |
Durden [33] | GLP-1 RA, naïve, initiators with or without prior oral medication | Adherence: 6 months | Odds ratio for adherent (PDC ≥ 80%) vs nonadherent to have HbA1c < 7% at 6 months OR 1.83, 95%CI 1.11–3.01, P < 0.05 |
Carls [35] | GLP-1 RA, naïve, initiators with prior oral medications | Adherence: 1 year | Change in HbA1c from baseline (mean) (P values not reported) PDC ≥ 80% vs PDC < 80%: − 0.86% vs − 0.39% For every 1-point increase in baseline HbA1c levels, final HbA1c decreased by an additional 0.275% Medication adherence accounted for ~ 75% of the estimated 0.41% HbA1c gap between real-world and randomized controlled trial results for patients receiving GLP-1 RA therapy |
Wu [17] | Insulin, non-naïve, upon discharge from hospital | Persistence: 1 year | Change in HbA1c from baseline (mean) Persisters vs nonpersisters: − 0.5% vs − 0.2%, P < 0.001 |
Wei [5] | Insulin, naïve, receiving > 1 oral medication or GLP-1 RA | Persistence: 1 year | Change in HbA1c from baseline (mean) Persisters vs nonpersisters: − 1.2% vs − 0.9%, P = 0.0078 |
Sambamoorthi [19] | Basal insulin, with addition of rapid-acting insulin | Persistence: 1 year | Change in HbA1c from baseline (mean [SD]) in elderly patients with low persistence rate (21%) Persisters vs nonpersisters: − 0.8% (1.55%) vs − 0.4% (1.41%) P < 0.01 |
Yavuz [21] | Insulin, naïve, initiated on pen therapy | Persistence: 6 months | HbA1c (mean [SD]) at end of study Total population baseline: 11.2% (1.5%) Persisters vs nonpersisters: 10.1% (1.8%) vs 10.4% (2.0%), P = 0.4 |
Levin [32] | Insulin, naïve, initiated as third agent | Persistence: 2 years | Change in HbA1c from baseline (mean) (P values not reported) Persisters years 1 and 2: − 0.99% Persisters year 1 with switch year 2: − 0.93% Switched year 1: − 0.59% (P < 0.05, when compared with persisters years 1 and 2) Discontinued (not filling any diabetes drug in last quarter of year 1 or year 2): − 0.97% |
Ayyagari [15] | Insulin, naïve, previously on oral medication or GLP-1 RA | Adherence: 1 year | Adjusted change in HbA1c from baseline (mean) Adherers vs nonadherers: greater mean decrease in HbA1c from baseline when using same type of device, but differences within device type not statistically significant Vial: − 0.2% (P = 0.138) Pen: − 0.2% (P = 0.138) |
Egede [11] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: 12 years, measured at 3-month intervals over time | Adjusted change in HbA1c from baseline for insulin-only patients (P value not reported) 0.05% for each percentage increase in MPR |
Donnelly [16] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: 6 years | Change in HbA1c from baseline PDC ≥ 80% were more likely to demonstrate improved HbA1c Significant inverse association between log adherence and HbA1c (P < 0.0001) HbA1c increased over time, demonstrating a significant quadratic trend (P = 0.0023), accompanied by a significant linear trend (P < 0.0001) In addition there was a significant interaction between adherence and time, suggesting longitudinal changes in HbA1c varied according to adherence (P < 0.0001) |
Kindmalm [20] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: 1 year | HbA1c at end of study period Refill adherence ≥ 80% had a lower mean HbA1c (6.6% vs 7.3%) (P = 0.025) |
Linetsky [10] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: baseline data | Cross-sectional measurement of HbA1c at baseline Patients with “missed shots” had a 0.43% higher HbA1c in path analysis |
Linetsky [22] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: baseline data | Change in HbA1c from baseline (mean, 95%CI) Patients with “no missed shots” had a lower HbA1c in multivariate linear regression − 0.19% (− 0.34 to − 0.05), P = 0.0104 |
Aikens [24] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: 6 months | Cross-sectional measurement of adherence at baseline and HbA1c at end of study period 1-unit increase in 4-unit Morisky score (nonadherence) associated with a 0.16% increase in HbA1c (P value not reported) |
Osborn [12] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: at time of HbA1c measurement | Cross-sectional measurement of HbA1c at baseline Increase in 4-unit modified Morisky score (adherence) (modified for insulin use—MIAS) associated with a decrease in HbA1c (−0.26%, P = 0.001) |
Mashitani [18] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: at time of HbA1c measurement | Cross-sectional measurement of HbA1c at baseline Compared to participants with higher adherence, the crude RRj for good glycemic control (HbA1c < 7.0%) for those with middle adherence was 0.82 (0.67–1.00), and for lower adherence 0.64 (0.31–1.31) (P = 0.029 for trend) |
Nishimura [23] | Insulin glargine, non-naïve, switching to insulin degludec | Adherence: 12 weeks | Cross-sectional measurement of HbA1c at baseline (mean [SE]) Timing of shots: higher HbA1c with longer delays (P > 0.05) 0-120 min delayed dosing: 8.2% (1.2%) to 8.1% (1.0%), P = NS 121-240 min delayed dosing: switch caused HbA1c change from 8.0% (1.2%) to 7.7% (1.3%), P = 0.039 |
Perez-Nieves [9] | Insulin, naïve, initiators of basal insulin | Continuers vs interrupters vs discontinuers (identified retrospectively) | Cross-sectional survey Continuers were more likely to report a positive impact of insulin on glycemic control compared to interrupters and discontinuers (73.0% vs 63.0% vs 61.8%, P < 0.01 vs continuers) |
Dibonaventura [13] | Insulin, non-naïve, in a cohort based on calendar year of study period | Adherence: at time of HbA1c report | Cross-sectional survey Each point increase in 4-unit Morisky score (nonadherence) was associated with a 0.21% increase in HbA1c (P < 0.05) |
Leiter [6] | Insulin, perspectives of healthcare providers | Adherence | Cross-sectional survey regarding healthcare providers’ assessment of the number of occasions of dosing irregularities in 30-day period that would impact glycemic control 3.6 for missed doses 5.7 for mistimed doses 4.1 for reduced doses 39% of healthcare providers reported not discussing dosing irregularities with patients |
GLP-1 RA Studies
Insulin Studies
Healthcare Resource Use Results
Studies Regarding the Impact of Adherence and Persistence on Medical Resource Use
Improvements in Healthcare Resource Use
GLP-1 RA Studies
Insulin Studies
Healthcare Costs Results
Studies Regarding the Impact of Adherence and Persistence on Healthcare Costs
Improvements in Costs
Author | Medication and study population | Adherence/persistence | Costs for adherent/persistent vs nonadherent/nonpersistent groups |
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Buysman [34] | GLP-1 RA, naïve, initiators on oral medications and/or insulin | Adherence and persistence: 1 year | Diabetes-related, unadjusted (mean [SD]; median) Total: $9,081 ($8685); $6797 vs $7717 ($13,679); $4647, P = 0.028 Pharmacy total: $6338 ($2,639); $5606 vs $3568 ($2439); $3074, P < 0.001 Total medical: $2743 ($8,065); $683 vs $4149 ($13,383); $687, P = 0.018 |
Adherence: 1 year | Diabetes-related, adjusted Total (95%CI): $9419 ($8574-10,308) vs $7667 ($6903-8573), P = 0.005 Pharmacy total (estimated from figure): $6000 vs $4000, P < 0.001 Total medical (estimated from figure): $3000 vs $4000, P = 0.080 | ||
Persistence: 1 year | Diabetes-related, unadjusted (mean [SD]; median) Total: $8675 ($10,611); $6180 vs $7447 ($14,270); $3864, P = 0.092 Pharmacy total: $5571 ($2658); $5039 vs $2931 ($2298); $2341, P < 0.001 Total medical: $3103 ($10,124); $682 vs $4516 ($14,017); $699, P = 0.047 | ||
Persistence: 1 year | Diabetes-related, adjusted (mean) Total (estimated from figure): $8700 vs $7500, P = 0.010 Pharmacy total (estimated from figure): $5000 vs $3500, P = 0.010 Total medical (stated in text): $3298 vs $4805, P = 0.017 | ||
Lin [31] | aInitiators of combination of GLP-1 RA and insulin | Persistence: 1 year | All-cause, unadjusted Total: $43,096 vs $51,084, P = 0.028 Pharmacy total: $14,691 vs $10,791, P < 0.001 Total medical: $28,405 vs $40,292, P = 0.001 |
Persistence: 1 year | Diabetes-related, unadjusted Total: $19,255 vs $20,327, P = 0.441 Pharmacy total: $8142 vs $5124, P < 0.001 Total medical: $11,114 vs $15,203, P = 0.003 | ||
Kalirai [30] | Insulin, naïve, initiators | Persistence: 1 and 2 years | Year 1: Adjusted estimates from regression models All-cause total medical, inpatient and ED costs were significantly lower, but not outpatient costs Diabetes related total medical, inpatient and ED costs were significantly lower, but not outpatient costs Diabetes-related pharmacy basal and other insulins and total pharmacy costs were significantly higher, but this was not true for other injectables and oral antidiabetic medications All-cause healthcare (medical + pharmacy) costs were nonsignificantly lower for continuers Year 2: Results were similar with the exception that diabetes-related pharmacy costs for injectables were also significantly higher for continuers |
Ascher-Svanum [8] | Insulin, naïve, initiators | Early discontinuation (gap ≥ 30 days after first prescription): 1 year | Adjusted estimates from regression models, all P values < 0.05 Acute care costs (inpatient + ED): 9.6% higher Outpatient costs: 6.4% lower Diabetes-related pharmacy costs: 42.9% lower All-cause pharmacy costs: 34.0% lower Total medical costs: 10.9% lower |
Wu [17] | Insulin, non-naïve, upon discharge from hospital | Persistence: 6 months | Regression models with adjustment for pre-discharge costs and other baseline covariates Lower total medical service costs (difference of $2569, P = 0.007) Results driven by lower facility and other services costs (difference of $2265; P = 0.010), and physician service costs (difference of $524; P = 0.001) (pharmacy costs not reported) |
Perez-Nieves [29] | Insulin, naive, initiators of non-mixed basal insulin during study period | Continuers vs interrupters vs discontinuers | Year 1 Continuers had lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers $13,021 Continuers had higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers $4857 P < 0.05 for all comparisons of continuers vs interrupters and continuers vs discontinuers Total healthcare costs similar across the 3 cohorts Year 2: findings were similar |
Anderten [14] | Insulin, naive, initiators of basal insulin | Persistence: 1 year | No differences in treatment or prescription costs or medical services by persistence to insulin glargine vs NPH |
Kleinman [27] | Insulin, naive, initiators | Adherence (MPR): 1 year | Regression models stratified by high vs low prior costs Higher MPR was associated with significantly lower total healthcare costs for patients with high (upper quartile) prior costs: $450 in savings per 10% increase in MPR Higher MPR was associated with significantly higher total healthcare costs for patients with low (lower quartile) prior costs (amount not stated) Both groups of patients experienced significantly lower medical costs (removing prescription costs) when MPR was high Higher prior cost group: 100% MPR group had $6,653 in medical costs vs 10% MPR group had $11,763 in medical costs Lower prior cost group: 100% MPR group had $3329 in medical costs vs 10% MPR group had $4,590 in medical costs |
Ayyagari [15] | Insulin, naïve, previously on oral medication or GLP-1 RA | Adherence: 1 year | Adjusted costs using marginal structural models Pharmacy costs higher for adherent insulin users, averaging an additional $2,074 more annually for pen users and $2923 more for vial users (P < 0.001 for both patterns) Annual health care costs for both pen and vial users demonstrated lower costs for nonadherent patients, but these differences were not statistically significant |
Cobden [26] | Insulin, continuing, who converted from an insulin analog or human insulin administered using a vial/syringe to a biphasic insulin analog administered with a pen device | Adherence (MPR ≥ 80%): 2 years | Adjusted costs Adherence was associated with significant reductions in all-cause healthcare costs (exponentiated coefficient estimate 0.55, 95% CI 0.31–0.80, P < 0.05). This implies an average 45% decrease in all-cause total healthcare costs for adherent compared to nonadherent patients |
Wei [5] | Insulin, naïve, receiving > 1 oral medication or GLP-1 RA | Persistence: 1 year | Unadjusted costs Pharmacy costs: $5761 vs $4319, P < 0.0001 Total medical costs: $17,007 vs $18,367, P = 0.1419 |
Hadjiyianni [25] | Insulin, naive, initiators of basal insulin | Continuers vs interrupters vs discontinuers:1 year | Adjusted costs (in yen) Those who interrupted or discontinued had higher costs of hospitalization than continuers Total costs did not differ among the 3 groups Total medical costs did not differ among the 3 groups Total pharmacy costs were higher for the continuers |
Chandran [28] | Insulin, naive, pen prescription within study period | Adherence (MPR): 1 year | Unadjusted costs Average annual per-patient healthcare expenditures (P = 0.007) Least adherent group (MPR < 0.20, 11.0% of patients): $26,310 Most adherent group (MPR > 0.80; 34.6% of patients): $23,839 Average annual per-patient pharmacy expenditures (P < 0.001) Least adherent group: $5395 Most adherent group: $10,174 |
Perez-Nieves [9] | Insulin, naïve, initiating basal insulin | Continuers vs interrupters vs discontinuers (identified retrospectively) | Cross-sectional survey The three groups did not differ in reporting the impact of insulin use on budget management |