AbstractPurpose

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.

IntroductionDiabetes 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).1WHO Global report on diabetes: a summary.,2Centers for Disease Control and Prevention The prevalence of diabetes was estimated to be 34 million people in the United States in 2018 and is expected to increase to 55 million by 2030.2Centers for Disease Control and Prevention ,3Rowley WR Bezold C Arikan Y Byrne E Diabetes Krohe S. 2030: insights from yesterday, today, and future trends. Diabetes is a serious public health issue and requires effective clinical management.2Centers for Disease Control and Prevention Optimal glycemic control, predominantly defined as a glycosylated hemoglobin A1c (HbA1c) level 4Association American Diabetes Glycemic targets: standards of medical care in diabetes—2021. Glycemic control reduces the risk of stroke, kidney failure, vision loss, premature death, and other long-term complications of diabetes, thus lowering the associated clinical and economic burden.2Centers for Disease Control and Prevention ,5Ali 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.,6Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Accomplishing glycemic control early in the course of T2D has a greater impact in reducing the risk of myocardial infarction and overall mortality compared with those who achieve glycemic targets 10 years after diagnosis.7Lind M Imberg H Coleman RL Nerman O Holman RR. Historical HbA(1c) values may explain the type 2 diabetes legacy effect: UKPDS 88. In addition, pancreatic B-cell function preservation is affected by glycemic control and has the potential to delay diabetes progression.8Tabák AG Jokela M Akbaraly TN Brunner EJ Kivimäki M Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Although substantial research has been devoted to discovering a means of preserving B-cell function, various treatment regimens have produced mixed results.9Retnakaran R Emery A Ye C et al.Short-term intensive insulin as induction and maintenance therapy for the preservation of beta-cell function in early type 2 diabetes (RESET-IT Main): a 2-year randomized controlled trial., 10Impact of insulin and metformin versus metformin alone on β-cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes., 11Xiang AH Trigo E Martinez M et al.Impact of gastric banding versus metformin on β-cell function in adults with impaired glucose tolerance or mild type 2 diabetes. However, treatment with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has a greater impact on visceral adipose tissue reductions and B-cell function than lifestyle modification and other antidiabetic agents that produce similar glycemic control, indicating that mechanisms beyond simple glycemic reduction are at play.12Santilli F Simeone PG Guagnano MT et al.Effects of liraglutide on weight loss, fat distribution, and β-cell function in obese subjects with prediabetes or early type 2 diabetes., 13Degn KB Juhl CB Sturis J et al.One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes., 14Li YM Zhang LH Li XJ Zhang B Hou JN Tong NW. Efficacy and safety of dulaglutide monotherapy compared to glimepiride in oral antihyperglycemic medication-naïve Chinese patients with type 2 diabetes: a post hoc analysis of AWARD-CHN1., 15Mari A Del Prato S Ludvik B et al.Differential effects of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide and metformin on pancreatic β-cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes.Early initial combination therapy with oral antidiabetic drugs (OADs) and an injectable GLP-1 RA is more effective in T2D than sequential addition of therapies (OADs followed by insulin) to achieve glycemic control and weight loss and avoid hypoglycemia.16Abdul-Ghani M Puckett C Triplitt C et al.Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes: results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. In addition, initiating use of an injectable GLP-1 RA earlier in disease progression, proxied by the use of fewer OADs before treatment initiation, was associated with lower HbA1c value and an increased likelihood of having a posttreatment HbA1c value 17Boye 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. Despite this evidence, studies have found reluctance among patients and health care professionals to intensify treatment within the recommended 3 months in patients unable to achieve glycemic targets.18Khunti K Gomes MB Pocock S et al.Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: a systematic review., 19Khunti K Wolden ML Thorsted BL Andersen M Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people., 20Boye KS Stein D Matza LS et al.Timing of GLP-1 receptor agonist initiation for treatment of type 2 diabetes in the UK. Clinical inertia resulting in long durations of poor glycemic control is associated with serious diabetes-related complications.18Khunti K Gomes MB Pocock S et al.Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: a systematic review.,21Reach G Pechtner V Gentilella R Corcos A Ceriello A. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus.Treatment intensification with the addition of a GLP-1 RA improves patient outcomes.22Robinson S Boye KS Mody R et al.Real-world effectiveness of dulaglutide in patients with type 2 diabetes mellitus: a literature review. However, few studies have explored the benefits of early initiation of a specific GLP-1 RA, such as dulaglutide, in managing T2D. This study focused on dulaglutide because previous studies have found better adherence and patient preference for dulaglutide compared with other GLP-1 RAs.23Mody 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., 24Matza LS Boye KS Currie BM et al.Patient perceptions of injection devices used with dulaglutide and liraglutide for treatment of type 2 diabetes., 25Matza LS Boye KS Stewart KD et al.Assessing patient PREFERence between the dulaglutide pen and the semaglutide pen: A crossover study (PREFER). Although the exact duration of T2D cannot be directly determined from claims data, the number of prescribed OADs has been used as a proxy for disease duration in other studies, with a lower number of OADs representing earlier initiation.17Boye 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.,26Bhattacharya 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. The purpose of this study was to describe patient characteristics as well as glycemic and treatment pattern outcomes in patients initiating use of dulaglutide after 1, 2, or ≥3 OADs, using the number of baseline OADs as a proxy for diabetes duration.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).17Boye 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.,26Bhattacharya 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. 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: 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.27Chang HY Weiner JP Richards TM Bleich SN Segal JB. Validating the adapted Diabetes Complications Severity Index in claims data.,28Quan H Li B Couris CM et al.Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. 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

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.

DiscussionThis 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 HbA1c17Boye 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.,26Bhattacharya 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.29Association American Diabetes Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.,30Davies 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.5Ali 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 HbA1c1c levels and reduce clinical and economic burden, as opposed to later initiation.29Association American Diabetes Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.,22Robinson 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.17Boye 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.,31Mata-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., 32DeFronzo 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., 33Bloomgarden 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.,34Ruiz-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.17Boye 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.23Mody 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.,35Mody R Grabner M Yu M et al.Real-world effectiveness, adherence and persistence among patients with type 2 diabetes mellitus initiating dulaglutide treatment., 36Mody 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., 37Alatorre 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., 38Uzoigwe 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.29Association American Diabetes Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021.