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Association of Dulaglutide Initiation Timing With Treatment Patterns and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus in the United States

Open AccessPublished:May 24, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.04.005

      Abstract

      Purpose

      To describe clinical characteristics and treatment outcomes for early or late initiation of dulaglutide therapy in patients with type 2 diabetes.

      Methods

      This retrospective, claims-based analysis evaluated adults with type 2 diabetes, ≥1 claim for dulaglutide 0.75 mg or 1.5 mg once-weekly injection (between November 2014 and August 2019), and no prior use of glucagon-like peptide 1 receptor agonists or insulin. Cohorts were defined based on the number of oral antidiabetic drug (OAD) classes used within the 24-month baseline period before dulaglutide therapy initiation: 1 OAD, 2 OADs, or ≥3 OADs. The number of OAD classes used before dulaglutide therapy initiation served as a proxy for timing of initiation, with a higher number of OAD classes indicating a longer duration of T2D. Baseline demographic and clinical characteristics were compared across each cohort. Six-month follow-up outcomes, including change in glycosylated hemoglobin (HbA1c) and treatment patterns, were descriptively assessed within each cohort.

      Findings

      The study population consisted of 18,121 patients across the 1 OAD (n = 4822), 2 OADs (n = 6293), and ≥3 OADs (n = 7006) cohorts. Mean age at baseline was 54.7 years. Males were more prevalent in the ≥3 OADs cohort. Most patients (67%–70%) initiated treatment with dulaglutide 0.75 mg. Dose escalation to 1.5 mg was uncommon (15%–20%) but trended higher in the ≥3 OAD cohort. Adherence to dulaglutide at 6-month follow-up (61%–67%) increased with higher baseline OAD use. The HbA1c assessment (n = 3178) included 761 patients in the 1 OAD cohort, 1088 patients in the 2 OADs cohort, and 1329 patients in the ≥3 OADs cohort. Baseline mean [SD] HbA1c level increased with number of OAD classes (1 OAD: 8.18% [1.80]; 2 OADs: 8.56% [1.66]; and ≥3 OADs: 8.73% [1.51]). Patients in the early dulaglutide therapy initiator group experienced larger reductions in HbA1c levels (1 OAD: −1.39%; 95% CI, −1.50 to −1.27; 2 OADs: −1.30%; 95% CI, −1.39 to −1.20; and ≥3 OADs: −1.01%; 95% CI, −1.09 to −0.93) versus the patients in the delayed initiator group. Patients in the early dulaglutide therapy initiator group also achieved HbA1c <7% at 6-month follow-up more frequently than those in the later initiator group (1 OAD: 68%; 2 OADs: 51%; and ≥3 OADs: 33%).

      Implications

      Cohorts of dulaglutide therapy initiators, defined by prior OAD use as a proxy of timing of initiation, differed in their baseline characteristics and short-term follow-up outcomes. Earlier dulaglutide therapy initiation was associated with lower mean HbA1c levels and increased probability of achievement of HbA1c <7% during the 6-month follow-up period.

      Key words

      Introduction

      Diabetes is a chronic, multifactorial disease characterized by impaired insulin production and/or use. Most people with diabetes are affected by non–insulin-dependent type 2 diabetes (T2D).
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      A real-world study of the effect of timing of insulin initiation on outcomes in older medicare beneficiaries with type 2 diabetes mellitus.
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      Material and Methods

      This retrospective, observational study was performed using health insurance claims data from the HealthCore Integrated Research Database (HIRD). The HIRD is a large, administrative health care database maintained by HealthCore for use in health outcomes and pharmacoepidemiologic research and is nationally representative of US commercially insured lives. The database tracks information such as member enrollment, medical care (professional and facility claims), outpatient prescription drug use, outpatient laboratory test result data, and health care utilization and costs. Researchers accessed data in the format of a limited data set for which data use agreements were in place with the covered entities in compliance with the Health Insurance Portability and Accountability Act Privacy Rule. An institutional review board did not review the study because only this limited data set was accessed.
      GLP-1 RA–naive patients with ≥1 outpatient pharmacy claim for dulaglutide 0.75 mg or 1.5 mg once-weekly injection from November 1, 2014, to August 31, 2019, were identified from the HIRD based on a review of their medical and pharmacy claims data (Supplemental Figure 1). Dulaglutide 3 mg and 4.5 mg, approved by the US Food and Drug Administration on September 3, 2020, were excluded from the analysis because of the timing of their approval. The index date was defined as the date of the first claim for a fill of dulaglutide. Data were analyzed from November 1, 2012, to February 29, 2020, to allow 24-month baseline and 6-month follow-up periods.
      Among the identified patients, those ≥18 years of age on the index date, with ≥2 medical claims with T2D codes during the 24-month baseline period were included in the study. Patients were required to have medical and pharmacy coverage via commercial or Medicare Advantage plans and continuous enrollment during the 24-month baseline and 6-month follow-up periods. In addition to the above inclusion criteria, a subgroup of patients with ≥1 HbA1c laboratory result at the 6-month baseline period (index date −183 days to index date +14 days) and ≥1 HbA1c laboratory result during the 6-month follow-up period (index date +91 days to index date +228 days) was included in the HbA1c analysis cohort.
      Key exclusion criteria were ≥1 pharmacy claim for any injectable antidiabetic (insulin and GLP-1 RA other than dulaglutide) or oral semaglutide and diagnosis of type 1 diabetes or other forms of diabetes on the index date or during the baseline period. Patients who were pregnant or had bariatric surgery during the baseline or follow-up periods were also excluded. The patients were classified into cohorts based on the number of OAD classes observed during the baseline period before dulaglutide therapy initiation. The number of OADs was used as a proxy for duration of T2D since first diagnosis, as established in prior published work, with a higher number of OAD classes indicating longer duration of T2D (ie, later initiation).
      • Boye KS
      • Mody R
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      • Malik RE.
      The relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist and glycosylated hemoglobin values among patients with type 2 diabetes.
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      • Zhou S
      • Wei W
      • Ajmera M
      • Sambamoorthi U.
      A real-world study of the effect of timing of insulin initiation on outcomes in older medicare beneficiaries with type 2 diabetes mellitus.
      The study cohorts included 1 OAD, 2 OADs, ≥3 OADs, and a combined cohort (all patients with ≥1 OAD). OADs of interest included metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, meglitinides, and α-glucosidase inhibitors. Oral semaglutide, approved by the US Food and Drug Administration on September 20, 2019, was excluded from the analysis because of the timing of its approval. Combination OAD products were assessed for each agent included in the formulation. Patients in each OAD cohort with complete HbA1c laboratory data were further classified into subgroups based on their baseline HbA1c level: <7%, 7% to <8%, 8% to <9%, 9% to <10%, and ≥10%.
      Demographic characteristics (age, sex, health plan type, and region of patient residence) and clinical characteristics were measured on index date or during the baseline period. Clinical characteristics included prescribing health care provider specialty, Quan-Charlson comorbidity index (QCI), adapted Diabetes Complications Severity Index (aDCSI), and select comorbidities of interest.
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      Six-month follow-up treatment patterns of patients using dulaglutide as the first injectable T2D treatment were assessed and included index dose, dose changes, adherence (proportion of days covered ≥0.80), persistence (no medication gap of ≥45 consecutive days between prior dulaglutide fill plus days’ supply and next dulaglutide fill), and use (any fills) of OADs, insulin, and GLP-1 RAs. The proportion of days covered was calculated as the number of days with drug on hand in the 6-month follow-up period divided by 183 (the number of days in the follow-up period), regardless of treatment discontinuation. In cases where patients had overlapping days' supply, the start of the new fill was adjusted to begin after the previous fill was considered to have run out. For the subgroup of patients with available HbA1c data, the change in HbA1c from baseline to follow-up, as well as the probability of achieving an HbA1c <7% during the follow-up period, were described for each cohort.
      All baseline and follow-up variables were summarized with descriptive statistics as mean (SD) for continuous variables and number (proportion) for categorical variables. Trend tests (Cochran-Armitage and Jonckheere-Terpstra) were used to assess whether there was a general tendency in the baseline variables to follow the ordering of the cohorts based on number of baseline OADs. For the within-cohort changes in HbA1c from baseline to follow-up, 95% CIs are reported. P < 0.05 was considered statistically significant, and no adjustment was made for multiple comparisons.

      Results

      Demographic and Clinical Characteristics

      A total of 18,121 patients met all inclusion criteria and were included in this study. Among the included patients, 4822 filled exactly 1 OAD prescription, 6293 filled exactly 2 OAD prescriptions, and 7006 filled ≥3 OAD prescriptions during the baseline period (Supplemental Figure 2). Mean (SD) age was 54.7 (9.78) years in the overall population, increasing with later initiation of dulaglutide therapy as proxied by number of OADs at baseline (Table I). Later initiators of dulaglutide therapy were also more likely to be male than female. Comorbidity burden, measured by mean QCI (1 OAD: 1.06, 2 OAD: 1.08, and ≥3 OAD: 1.13), and diabetes complications, measured by mean aDCSI (1 OAD: 0.83, 2 OAD: 0.99, and ≥3 OAD: 1.12), increased incrementally with later dulaglutide therapy initiation proxied by the number of baseline OADs. Chronic dyslipidemia and hypertension (>75%) were the most common comorbidities across all cohorts. The proportion of patients with dyslipidemia and hypertension increased with the number of baseline OADs used, whereas obesity and mental health conditions had an opposite trend.
      Table IBaseline demographic and clinical characteristics.
      CharacteristicOverall Cohort (N = 18,121)1 OAD Cohort (n = 4822)2 OADs Cohort (n = 6293)≥3 OADs Cohort (n = 7006)P for Trend Tests
      Female sex, No. (%)8498 (46.9)2596 (53.8)2953 (46.9)2949 (42.1)<0.001
      Age, mean (SD), y54.7 (9.78)53.0 (10.20)54.5 (9.79)56.0 (9.27)<0.001
      Geographic region, No. (%)
       Midwest3964 (21.9)1087 (22.5)1463 (23.2)1414 (20.2)<0.001
       Northeast1986 (11.0)519 (10.8)681 (10.8)786 (11.2)0.411
       South8695 (48.0)2333 (48.4)2962 (47.1)3400 (48.5)0.723
       West2605 (14.4)647 (13.4)895 (14.2)1063 (15.2)0.007
       Unknown871 (4.8)236 (4.9)292 (4.6)343 (4.9)0.930
      Health plan type, No. (%)
       HMO3661 (20.2)943 (19.6)1259 (20.0)1459 (20.8)0.083
       PPO10,967 (60.5)2948 (61.1)3821 (60.7)4198 (59.9)0.172
       CDHP3492 (19.3)930 (19.3)1213 (19.3)1,349 (19.3)0.944
      Medicare Advantage739 (4.1)147 (3.0)284 (4.5)308 (4.4)<0.001
      Index dulaglutide fill prescribing specialty, No. (%)
      Categories not listed include cardiologist and missing, which together account for the remainder of the total 100%.
       Primary care physician
      Primary care physician includes internal, geriatric, and pediatric medicine, family and general practice, and doctor of osteopathic medicine.
      9400 (51.9)2590 (53.7)3321 (52.8)3489 (49.8)<0.001
       Other
      Other includes physicians with other specialties (eg, neurology and oncology) and nonphysician health care providers who can prescribe medication (eg, nurse practitioner).
      5020 (27.7)1356 (28.1)1786 (28.4)1878 (26.8)0.085
       Endocrinologist3207 (17.7)738 (15.3)1023 (16.3)1446 (20.6)<0.001
      QCI score, mean (SD)1.09 (1.45)1.06 (1.48)1.08 (1.45)1.13 (1.42)<0.001
      aDCSI score, mean (SD)1.00 (1.38)0.83 (1.29)0.99 (1.37)1.12 (1.45)<0.001
      Chronic comorbidities, No. (%)
       Dyslipidemia15,058 (83.1)3654 (75.8)5218 (82.9)6186 (88.3)<0.001
       Hypertension14,925 (82.4)3781 (78.4)5145 (81.8)5999 (85.6)<0.001
       Obesity8502 (46.9)2545 (52.8)2871 (45.6)3086 (44.0)<0.001
       Mental health conditions
      Includes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 290.xx-311.xx and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes F01.%-F69.%.
      6801 (37.5)2024 (42.0)2396 (38.1)2381 (34.0)<0.001
      aDSCI = adapted Diabetes Complications Severity Index; CDHP = consumer-driven health plan; HMO = health maintenance organization; OAD = oral antidiabetic drug; PPO = preferred provider organization; QCI = Quan-Charlson Comorbidity Index.
      low asterisk Categories not listed include cardiologist and missing, which together account for the remainder of the total 100%.
      Primary care physician includes internal, geriatric, and pediatric medicine, family and general practice, and doctor of osteopathic medicine.
      Other includes physicians with other specialties (eg, neurology and oncology) and nonphysician health care providers who can prescribe medication (eg, nurse practitioner).
      § Includes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 290.xx-311.xx and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes F01.%-F69.%.

      Preindex Treatment Patterns

      In the overall population, dulaglutide was more commonly prescribed by primary care physicians (52%) and less frequently by endocrinologists (18%) based on the index claim (Table I). As the number of baseline OADs increased, indicating later dulaglutide initiation since the onset of T2D, diabetes complications and comorbidity burden increased, and patients were more likely to be prescribed dulaglutide by an endocrinologist. During the baseline period, the most commonly prescribed OAD among all patients taking ≥1 OADs was metformin (92%), followed by sulfonylureas (46%) (Table II). In the 1 OAD cohort, metformin was the most commonly used OAD (87%), followed by sulfonylurea (6%). In the 2 OAD cohort, the most commonly prescribed regimen before initiation of dulaglutide therapy was metformin in combination with sulfonylurea (39%) followed by metformin plus a dipeptidyl peptidase 4 inhibitor (28%). In the ≥3 OAD cohort, metformin in combination with a dipeptidyl peptidase 4 inhibitor and sulfonylurea (25%) was the most frequently prescribed regimen before dulaglutide treatment initiation.
      Table IIBaseline treatment patterns (top 5 regimens per cohort).
      TreatmentNo. (%) of Patients
      1 OAD class (n = 4822)
       Metformin4188 (86.9)
       Sulfonylureas272 (5.6)
       DPP-4i165 (3.4)
       SGLT-2i148 (3.1)
       Thiazolidinediones43 (0.9)
      2 OAD classes (n = 6293)
       Metformin and sulfonylureas2,447 (38.9)
       Metformin and DPP-4i1,788 (28.4)
       Metformin and SGLT-2i1,280 (20.3)
       Metformin and thiazolidinediones221 (3.5)
       DPP-4i and Sulfonylureas213 (3.4)
      ≥3 OAD classes (n = 7006)
       Metformin, DPP-4i, and sulfonylureas1781 (25.4)
       Metformin, DPP-4i, and SGLT-2i1209 (17.3)
       Metformin, DPP-4i, SGLT-2i, and sulfonylureas1104 (15.8)
       Metformin, SGLT-2i, and sulfonylureas988 (14.1)
       Metformin, thiazolidinediones, and sulfonylureas313 (4.5)
      All patients (N = 18,121)
       Metformin16,695 (92.1)
       Sulfonylureas8251 (45.5)
       DPP-4i7654 (42.2)
       SGLT-2i5932 (32.7)
       Thiazolidinediones1958 (10.8)
      DPP-4i = dipeptidyl peptidase 4 inhibitor; OAD = oral antidiabetic drug; SGLT-2i = sodium-glucose cotransporter 2 inhibitor.

      Postindex Treatment Patterns

      During the 6-month follow-up period, in the overall population of initiators of dulaglutide therapy, metformin remained the most frequently prescribed OAD (77%) followed by sulfonylureas (34%) (Table III). Injectable antidiabetic agents, including GLP-1 RAs (other than dulaglutide) and insulin, were rarely used during the follow-up period (≤6% for all cohorts). Data presented in Table III include use of the specified antidiabetic medication at any point during the postindex period and are not limited to the first treatment received after initiation of dulaglutide therapy. Patients may have used >1 antidiabetic medication in the postindex period.
      Table IIISix-month follow-up antidiabetic treatment patterns.
      TreatmentNo. (%) of Patients
      Overall Cohort (N = 18,121)1 OAD Cohort (n = 4822)2 OADs Cohort (n = 6293)≥3 OADs Cohort (n = 7006)
      OADs
      Including combinations (patients counted once for each component of the combination).
       Metformin13,987 (77.2)3453 (71.6)4820 (76.6)5714 (81.6)
       Sulfonylureas6063 (33.5)335 (6.9)2057 (32.7)3671 (52.4)
       SGLT-2i4668 (25.8)387 (8.0)1340 (21.3)2941 (42.0)
       DPP-4i3464 (19.1)206 (4.3)1032 (16.4)2226 (31.8)
       Thiazolidinediones1491 (8.2)35 (0.7)244 (3.9)1212 (17.3)
       Meglitinides147 (0.8)NR27 (0.4)117 (1.7)
       α-Glucosidase inhibitors39 (0.2)NRNR35 (0.5)
      GLP-1 RAs
      Excluding dulaglutide.
       Liraglutide225 (1.2)63 (1.3)79 (1.3)83 (1.2)
       Low-dose semaglutide injectable135 (0.7)31 (0.6)59 (0.9)45 (0.6)
       High-dose semaglutide injectable51 (0.3)12 (0.2)24 (0.4)15 (0.2)
       Exenatide once-weekly pen81 (0.4)23 (0.5)28 (0.4)30 (0.4)
       Exenatide extended release37 (0.2)NR14 (0.2)15 (0.2)
      Insulin
       Long-acting insulin671 (3.7)109 (2.3)194 (3.1)368 (5.3)
       Rapid and ultra-rapid-acting insulin160 (0.9)39 (0.8)49 (0.8)72 (1.0)
       Short-acting insulin29 (0.2)NR11 (0.2)12 (0.2)
       Premixed insulin23 (0.1)NRNR13 (0.2)
      DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1 RA = glucagon-like peptide 1 receptor agonist; NR = not reported (masked count for N ≤ 10 to protect patient privacy); OAD = oral antidiabetic drug; SGLT-2i = sodium-glucose cotransporter 2 inhibitor.
      low asterisk Including combinations (patients counted once for each component of the combination).
      Excluding dulaglutide.
      Within the total study population, across all cohorts, 68% of patients initiated use of dulaglutide 0.75 mg compared with 32% of patients taking 1.5 mg (Table IV). Most patients (82%) continued with their index dose for the 6-month follow-up period. Among those who escalated from 0.75 to 1.5 mg (17%), the first dose change occurred a mean of 69 days after the index date. Patients with greater OAD use during the baseline period had a higher rate of dose escalation: 15% in the 1 OAD cohort, 16% for 2 OADs, and 20% in the ≥3 OAD cohort. Dulaglutide adherence at 6-month follow-up (65% overall) was slightly greater with higher baseline OAD use, as was persistence (74% overall).
      Table IVSix-month follow-up dulaglutide treatment patterns.
      Treatment characteristicOverall Cohort (N = 18,121)1 OAD Cohort (n = 4822)2 OADs Cohort (n = 6293)≥3 OADs Cohort (n = 7006)
      Index dose, No. (%)
      A total of 117 of the 18,121 patients had fills for both low- and high-dose dulaglutide on the same day. A total of 90% of these events occurred on the index date, and their distribution was similar across the individual OAD cohorts. These patients were classified as high-dose initiators.
       0.75 mg12,377 (68.3)3328 (69.0)4380 (69.6)4669 (66.6)
       1.5 mg5744 (31.7)1494 (31.0)1913 (30.4)2337 (33.4)
      Dose on last fill before end of follow-up period,
      Among patients with ≥2 dulaglutide fills (1 OAD, n = 4185; 2 OADs, n = 5542; and ≥3 OADs, n = 6243).
      No. (%)
       0.75 mg7719 (48.3)2220 (53.0)2788 (50.3)2711 (43.4)
       1.5 mg8251 (51.7)1965 (47.0)2754 (49.7)3532 (56.6)
      Dose change during follow-up,
      Among patients with ≥2 dulaglutide fills (1 OAD, n = 4185; 2 OADs, n = 5542; and ≥3 OADs, n = 6243).
      No. (%)
       0.75 to 1.5 mg2763 (17.3)630 (15.1)897 (16.2)1236 (19.8)
       1.5 to 0.75 mg143 (0.9)45 (1.1)40 (0.7)58 (0.9)
       No dose change13,064 (81.8)3510 (83.9)4605 (83.1)4949 (79.3)
      Time to first dose change,
      Among patients with ≥2 dulaglutide fills (1 OAD, n = 4185; 2 OADs, n = 5542; and ≥3 OADs, n = 6243).
      mean (SD), d
       0.75 to 1.5 mg69.3 (44.23)67.4 (44.46)66.3 (42.27)72.5 (45.32)
       1.5 to 0.75 mg45.6 (41.19)42.0 (35.33)57.6 (49.97)40.1 (37.60)
      Adherence (PDC ≥80%), No. (%)11,698 (64.6)2942 (61.0)4062 (64.5)4694 (67.0)
      Persistence,
      Persistence defined as not having a gap of ≥45 days between dulaglutide fills.
      No. (%)
      13,399 (73.9)3427 (71.1)4658 (74.0)5314 (75.8)
      OAD = oral antidiabetic drug; PDC = proportion of days covered.
      low asterisk A total of 117 of the 18,121 patients had fills for both low- and high-dose dulaglutide on the same day. A total of 90% of these events occurred on the index date, and their distribution was similar across the individual OAD cohorts. These patients were classified as high-dose initiators.
      Among patients with ≥2 dulaglutide fills (1 OAD, n = 4185; 2 OADs, n = 5542; and ≥3 OADs, n = 6243).
      Persistence defined as not having a gap of ≥45 days between dulaglutide fills.

      HbA1c Analysis

      Among patients who had HbA1c laboratory results available (n = 3178), 761 patients filled 1 OAD prescription, 1088 patients filled 2 OAD prescriptions, and 1329 patients filled ≥3 OAD prescriptions. Trends in baseline demographic and clinical characteristics for the HbA1c cohort were similar to the overall cohort (Table V). Notable demographic differences were observed in the geographic region of residence (a higher proportion of the HbA1c cohort resided in the South) and health plan type (lower preferred provider organization and higher health maintenance organization selection). Clinical characteristics were fairly similar between the full population and the HbA1c cohort, with similar QCI scores (full population: 1.09; HbA1c cohort: 1.09) and aDCSI scores (full population: 1.00; HbA1c cohort: 0.97).
      Table VBaseline demographic and clinical characteristics among the HbA1c cohort.
      CharacteristicOverall Cohort (N = 3178)1 OAD Cohort (n = 761)2 OADs Cohort (n = 1088)≥3 OADs Cohort (n = 1328)P for Trend Tests
      Female sex, No. (%)1,494 (47.0)426 (56.0)509 (46.8)559 (42.1)<0.001
      Age, mean (SD), y55.0 (9.0)53.5 (9.6)54.8 (9.1)56.1 (8.5)<0.001
      Geographic region, No. (%)
       Midwest341 (10.7)85 (11.2)136 (12.5)120 (9.0)0.060
       Northeast404 (12.7)92 (12.1)134 (12.3)178 (13.4)0.353
       South1,758 (55.3)426 (56.0)596 (54.8)736 (55.4)0.850
       West582 (18.3)131 (17.2)193 (17.7)258 (19.4)0.183
       Unknown93 (2.9)27 (3.5)29 (2.7)37 (2.8)0.378
      Health plan type, No. (%)
       HMO969 (30.5)236 (31.0)321 (29.5)412 (31.0)0.891
       PPO1,634 (51.4)380 (49.9)573 (52.7)681 (51.2)0.688
       CDHP575 (18.1)145 (19.1)194 (17.8)236 (17.8)0.493
      Medicare Advantage67 (2.1)18 (2.4)26 (2.4)23 (1.7)0.276
      Index dulaglutide fill prescribing specialty, No. (%)
      Categories not listed include cardiologist and missing, which together account for the remainder of the total 100%.
       Primary care physician
      Primary care physician includes internal, geriatric, or pediatric medicine, family or general practice, and doctor of osteopathic medicine.
      1,624 (51.1)386 (50.7)579 (53.2)659 (49.6)0.439
       Other
      Other includes physicians with other specialties (eg, neurology or oncology) and nonphysician health care providers who can prescribe medication (eg, nurse practitioner)
      854 (26.9)213 (28.0)291 (26.7)350 (26.3)0.429
       Endocrinologist611 (19.2)140 (18.4)194 (17.8)277 (20.8)0.114
      QCI score, mean (SD)1.09 (1.42)1.06 (1.38)1.05 (1.39)1.14 (1.47)0.148
      aDCSI score, mean (SD)0.97 (1.35)0.81 (1.29)0.96 (1.29)1.08 (1.43)<0.001
      Chronic comorbidities, No. (%)
       Dyslipidemia2,757 (86.8)605 (79.5)940 (86.4)1,212 (91.2)<0.001
       Hypertension2,637 (83.0)598 (78.6)903 (83.0)1,136 (85.5)<0.001
       Obesity1,529 (48.1)421 (55.3)502 (46.1)606 (45.6)<0.001
       Mental health conditions
      Includes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 290.xx-311.xx and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes F01.%-F69.%
      1,120 (35.2)315 (41.4)387 (35.6)418 (31.5)<0.001
      aDSCI = adapted Diabetes Complications Severity Index; CDHP = consumer-driven health plan; HMO = health maintenance organization; OAD = oral antidiabetic drug; PPO = preferred provider organization; QCI = Quan-Charlson Comorbidity Index.
      low asterisk Categories not listed include cardiologist and missing, which together account for the remainder of the total 100%.
      Primary care physician includes internal, geriatric, or pediatric medicine, family or general practice, and doctor of osteopathic medicine.
      Other includes physicians with other specialties (eg, neurology or oncology) and nonphysician health care providers who can prescribe medication (eg, nurse practitioner)
      § Includes International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 290.xx-311.xx and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes F01.%-F69.%
      The mean HbA1c level at baseline was higher for patients who had more OADs. Mean (SD) HbA1c levels were as follows: 8.18% (1.80) for the 1 OAD cohort, 8.56% (1.66) for 2 OADs, and 8.73% (1.51) for ≥3 OADs (Figure 1). Overall reductions in HbA1c levels after initiation of dulaglutide therapy were inversely related to the number of OADs at baseline, indicating a greater response in the earlier initiators (1 OAD: −1.39%; 95% CI, −1.50% to −1.27%; 2 OAD, −1.30%; 95% CI, −1.39% to −1.20%; ≥3 OAD: −1.01%; 95% CI, −1.09% to −0.93%). Within each OAD cohort, the magnitude of HbA1c change increased with higher baseline HbA1c values.
      Figure 1
      Figure 1Mean change in glycosylated hemoglobin (HbA1c) from baseline to follow-up, classified by baseline HbA1c levels. OAD = oral antidiabetic.
      The proportion of patients with an HbA1c level <7% increased from baseline to follow-up period in all OAD cohorts; the largest increase (41%) was observed among the 1 OAD cohort (early initiators) (Figure 2).
      Figure 2
      Figure 2Proportion of patients by glycosylated hemoglobin (HbA1c) category during the baseline and follow-up periods. Sample sizes were 761 for the 1 oral antidiabetic (OAD) cohort, 1088 for the 2 OADs cohort, and 1329 for the ≥3 OADs cohort.

      Discussion

      This observational study described glycemic control, treatment patterns, and patient demographic and clinical characteristics within an injectable antidiabetic–naive population that initiated dulaglutide therapy for the management of T2D. Earlier initiation of dulaglutide therapy, proxied by use of fewer OADs before initiation, was associated with lower mean HbA1c levels and increased likelihood of achieving an HbA1c <7% during follow-up. Because claims data typically do not contain the entirety of a person's medical history, the duration of chronic diseases, such as T2D, cannot always be determined from the claims data. Previous published research has established that using the number of prescribed OAD medications is a reasonable indicator of T2D duration and disease progression.
      • Boye KS
      • Mody R
      • Lage MJ
      • Malik RE.
      The relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist and glycosylated hemoglobin values among patients with type 2 diabetes.
      ,
      • Bhattacharya R
      • Zhou S
      • Wei W
      • Ajmera M
      • Sambamoorthi U.
      A real-world study of the effect of timing of insulin initiation on outcomes in older medicare beneficiaries with type 2 diabetes mellitus.
      This method is based on the long-standing recommendations of hyperglycemia management guidelines, which recommend treatment initiation with metformin followed by augmentation with OADs in a stepwise fashion for those who do not achieve glycemic goals.
      • Association American Diabetes
      Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.
      ,
      • Davies MJ
      • D'Alessio DA
      • Fradkin J
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      For the purpose of mitigating this limitation of claims-based research in our study, the duration of T2D was similarly proxied by classifying cohorts based on number of OAD medications at baseline. The demographic and clinical characteristics of patients observed in this study were consistent with this approach because those with a greater number of prior OADs also tended to be older, had a greater number of diabetic complications, and had higher baseline HbA1c levels.
      Disease progression, coupled with clinical inertia, is associated with considerable clinical and economic burden. A delay of 1 year in diabetes treatment intensification was associated with an additional economic burden of US $7.3 billion, whereas a 7-year delay was associated with a reduction in life expectancy of approximately 0.22 years per patient during a 30-year time horizon.
      • Ali SN
      • Dang-Tan T
      • Valentine WJ
      • Hansen BB.
      Evaluation of the clinical and economic burden of poor glycemic control associated with therapeutic inertia in patients with type 2 diabetes in the United States.
      In this study, early initiation of dulaglutide therapy was associated with a higher proportion of patients achieving an HbA1c <7% during the 6-month follow-up period compared with patients with later initiation of dulaglutide therapy. Following recommended guidelines and using a GLP-1 RA, such as dulaglutide, as the first injectable early in treatment can potentially facilitate achievement of target HbA1c levels and reduce clinical and economic burden, as opposed to later initiation.
      • Association American Diabetes
      Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.
      ,
      • Robinson S
      • Boye KS
      • Mody R
      • et al.
      Real-world effectiveness of dulaglutide in patients with type 2 diabetes mellitus: a literature review.
      This observation may provide an incentive for payers and providers to focus on addressing factors associated with clinical inertia.
      All patients initiating use of dulaglutide, regardless of the number of OADs used, experienced HbA1c reduction compared with baseline. In line with previous research, baseline HbA1c levels were a strong predictor for reduced follow-up HbA1c levels.
      • Boye KS
      • Mody R
      • Lage MJ
      • Malik RE.
      The relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist and glycosylated hemoglobin values among patients with type 2 diabetes.
      ,
      • Mata-Cases M
      • Franch-Nadal J
      • Ortega E
      • et al.
      Glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes:real-world evidence from a Mediterranean area.
      • DeFronzo RA
      • Stonehouse AH
      • Han J
      • Wintle ME.
      Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials.
      • Bloomgarden ZT
      • Dodis R
      • Viscoli CM
      • Holmboe ES
      • Inzucchi SE.
      Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis.
      Thus, within each dulaglutide OAD cohort, the magnitude of follow-up HbA1c reduction was greater for patients with higher baseline HbA1c levels. Across dulaglutide OAD cohorts, the magnitude of HbA1c reduction was greater for the early initiators compared with later initiators, despite the early initiators having lower baseline HbA1c levels. This finding concurs with the work of Ruiz-Negron et al.,
      • Ruiz-Negron N
      • Wander C
      • McAdam-Marx C
      • Pesa J
      • Bailey RA
      • Bellows BK.
      Factors associated with diabetes-related clinical inertia in a managed care population and its effect on hemoglobin A1c goal attainment: a claims-based analysis.
      which found that longer duration of insufficient glycemic control (clinical inertia) was associated with a reduced magnitude of change in HbA1c levels after treatment intensification with any antidiabetic agent. Previous research by Boye et al.
      • Boye KS
      • Mody R
      • Lage MJ
      • Malik RE.
      The relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist and glycosylated hemoglobin values among patients with type 2 diabetes.
      also found that early initiators of dulaglutide therapy (the 1 OAD cohort) experienced larger reductions in HbA1c levels compared with later initiators. Although the present research was not specifically designed to evaluate how varying HbA1c levels at baseline impact future changes, the descriptive results observed are an important indicator of the relationship.
      Adherence and persistence with dulaglutide during the 6-month follow-up period were similar to those reported in prior studies.
      • Mody R
      • Yu M
      • Nepal B
      • Konig M
      • Grabner M.
      Adherence and persistence among patients with type 2 diabetes initiating dulaglutide compared with semaglutide and exenatide BCise: 6-month follow-up from US real-world data.
      ,
      • Mody R
      • Grabner M
      • Yu M
      • et al.
      Real-world effectiveness, adherence and persistence among patients with type 2 diabetes mellitus initiating dulaglutide treatment.
      • Mody R
      • Huang Q
      • Yu M
      • et al.
      Adherence, persistence, glycaemic control and costs among patients with type 2 diabetes initiating dulaglutide compared with liraglutide or exenatide once weekly at 12-month follow-up in a real-world setting in the United States.
      • Alatorre C
      • Fernandez Lando L
      • Yu M
      • et al.
      Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.
      • Uzoigwe C
      • Liang Y
      • Whitmire S
      • Paprocki Y.
      Semaglutide once-weekly persistence and adherence versus other GLP-1 RAs in patients with type 2 diabetes in a US real-world setting.
      A possible trend of higher adherence and persistence with higher baseline use of OADs was observed; however, the study was not designed to test this relationship or evaluate reasons for it. Further research into drivers of adherence and persistence would be of benefit. Metformin (alone or in combination) was the most commonly prescribed OAD in all 3 cohorts at both baseline and follow-up. As expected, adherence to the current American Diabetes Association guideline within the prescribing community dictates that patients with T2D are generally initially given metformin, and as T2D progresses, antidiabetic agents are added to the regimen rather than replacing the original agent.
      • Association American Diabetes
      Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.
      The tendency to adjust the dulaglutide dosage within 2 to 3 months after therapy initiation indicates some level of prescriber adherence to the guideline recommendation to assess and modify treatment within 3 to 6 months.
      • Association American Diabetes
      Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.
      Similar to a previous study that examined prior OAD use for insulin initiators,
      • Bhattacharya R
      • Zhou S
      • Wei W
      • Ajmera M
      • Sambamoorthi U.
      A real-world study of the effect of timing of insulin initiation on outcomes in older medicare beneficiaries with type 2 diabetes mellitus.
      patients who used more OADs before dulaglutide therapy initiation were older and had higher diabetic complication rates as well as comorbidity burden, which supports the use of OAD count as a proxy for T2D duration and progression. Within the full study population as well as the HbA1c subgroup, the late initiators cohort (≥3 OADs) was the largest cohort. Published research indicates that incomplete guideline awareness among providers as well as concerns about cost and hesitancy among patients and providers to initiate injectable antidiabetic therapy, may be significant factors in delaying dulaglutide therapy initiation.
      • Boye KS
      • Matza LS
      • Stewart KD
      • et al.
      Patient preferences and health state utilities associated with dulaglutide and semaglutide injection devices among patients with type 2 diabetes in Italy.
      • Chen T
      • Zhou L
      • Wang K
      • et al.
      The unmet medical needs of current injectable antidiabetic therapies in china: patient and health care professional perspectives.
      • Ciemins EL
      • McKinnon M
      • Hamersky CM
      • Iyer NN
      • Powelson J.
      Cardiovascular disease in patients with type 2 diabetes: a qualitative analysis of knowledge, attitudes, and beliefs of health care professionals.
      This topic would benefit from further evaluation.
      Clinical and demographic characteristics were similar between the full population and the subgroup of patients with available HbA1c results. The differences seen between the full population and the HbA1c cohort were likely related to region of residence, which dictates health care insurance product availability and access to the laboratory data within the database. Because the full population was similar to the HbA1c cohort on important clinical characteristics, the results of the HbA1c cohort are reasonably generalizable to the full population.
      The study has limitations that are typical to claims-based research. Claims data are subject to data coding limitations, data entry error, and misclassification. Duration of diabetes could not be confirmed using the data source; however, the number of OADs as a proxy for disease progression (as indicated by duration of the disease) has been used in prior studies and was considered to be a reasonable surrogate.
      • Boye KS
      • Mody R
      • Lage MJ
      • Malik RE.
      The relationship between timing of initiation on a glucagon-like peptide-1 receptor agonist and glycosylated hemoglobin values among patients with type 2 diabetes.
      ,
      • Bhattacharya R
      • Zhou S
      • Wei W
      • Ajmera M
      • Sambamoorthi U.
      A real-world study of the effect of timing of insulin initiation on outcomes in older medicare beneficiaries with type 2 diabetes mellitus.
      In addition, this study did not examine other patient-centered variables, such as duration of treatment with antidiabetic agents, treatment augmentation, cost, tolerability, and patient awareness, or provider-centered variables, which could affect the decision to initiate dulaglutide therapy and/or glycemic control at follow-up. The study results were limited to commercially insured patients with T2D in the United States and may not be generalizable to all adults with T2D. Finally, the study assessed associations and should be considered hypothesis-generating; it was not designed to make causal comparisons of the glycemic impact of dulaglutide therapy initiation across HbA1c cohorts. Further study on this topic would be beneficial.

      Conclusion

      The study findings indicate that early initiation of dulaglutide therapy is associated with better glycemic control compared with later initiation. Earlier initiation of dulaglutide therapy, proxied by use of fewer OADs before dulaglutide treatment, was correlated with lower mean HbA1c levels at follow-up and increased likelihood of achieving follow-up HbA1c <7%. The demographic and clinical characteristics of the study population (eg, age, diabetes-related complications, and HbA1c level) reported in the claims supported the use of baseline OAD as a proxy for T2D duration and progression. The large number of dulaglutide therapy initiators with ≥3 OADs (late initiators with the highest mean HbA1c level and complication burden) coupled with the greater HbA1c reductions seen in early initiators suggest that earlier initiation of therapy is underused and could be advantageous.

      Funding Sources

      The study was funded by Eli Lilly and Company.

      Declaration of Interest

      The sponsor was involved in the study design, in the interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication.

      Acknowledgments

      We acknowledge Swati Krishnan (Eli Lilly) and Elizabeth Marks (HealthCore) for assisting in the preparation of the manuscript. Meredith Hoog, Maria Yu, Jennifer Peleshok, and Reema Mody are employees and shareholders of Eli Lilly and Company. Michael Grabner and Joseph Smith are employees of HealthCore Inc, a wholly owned subsidiary of Anthem Inc. HealthCore was under contract with Eli Lilly and Company for the conduct of the study. Michael Grabner and Joseph Smith are shareholders of Anthem Inc. Meredith Hoog, Maria Yu, Jennifer Peleshok, and Reema Mody contributed to the conception and design of the study; interpreted the data; and provided critical revisions of the manuscript for important intellectual content. Joseph L. Smith and Michael Grabner contributed to the conception and design of the study; collected, analyzed and interpreted the data; and drafted the manuscript.

      Supplementary materials

      Figure S1
      Figure S1Study design
      The baseline window for HbA1c assessment was (index date -183 days to index date +14 days). The follow-up window for HbA1c assessment was (index date +91 days to index date +228 days). Abbreviations: OAD oral antidiabetic drug.
      Figure S2
      Figure S2Patient selection
      Abbreviations: HbA1c, glycosylated hemoglobin; OAD, oral antidiabetic drug; T2D, type 2 diabetes.

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