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Liraglutide improves treatment satisfaction in people with type2 diabetes compared with sitagliptin, each as an add on to metformin

Liraglutide improves treatment satisfaction in peoplewith Type 2 diabetes compared with sitagliptin, eachas an add on to metformin M. Davies, R. Pratley*, M. Hammer†, A. B. Thomsen† and R. Cuddihy‡ University of Leicester, Leicester, UK, *University of Vermont, Burlington, VT, USA, †Novo Nordisk A ⁄ S, Bagsvaerd, Denmark and ‡International Diabetes Center,Minneapolis, MN, USA Patient-reported outcomes from clinical trials offer insight into the impact of disease on health-related quality of life, including treatment satisfaction. This patient-reported outcomes evaluation was a substudy of a 26-week randomized, open-label trial comparing the once-daily injectable human GLP-1 analogue liraglutide with once-daily oral sitagliptin, both added tometformin. The patient reported outcomes substudy aimed to evaluate treatment satisfaction using the Diabetes TreatmentSatisfaction Questionnaire (DTSQ) at baseline and 26 weeks.
In the main 26-week randomized, open-label study (n = 658), liraglutide, 1.2 or 1.8 mg, injected with a pen, led to greater HbA1c reduction than oral sitagliptin, 100 mg once daily, both added to metformin = 1500 mg daily: mean HbA1creduction was 1.5, 1.2 and 0.9% (7, 10 and 14 mmol ⁄ mol) for liraglutide 1.8 mg, 1.2 mg and sitagliptin, respectively(P < 0.0001 for both liraglutide doses vs. sitagliptin) and liraglutide patients lost more weight (3 vs.1 kg; P < 0.0001). In thispatient-reported outcomes substudy (liraglutide 1.8 mg, n = 171; 1.2 mg, n = 164; sitagliptin, n = 170) DTSQ scores wereanalyzed by ANCOVA with treatment and country as fixed effects and baseline value as covariate.
Overall treatment satisfaction, calculated by adding satisfaction scores for ‘current treatment’, ‘convenience’, ‘flexibility’, ‘understanding’, ‘recommend’, and ‘continue’, improved in all groups at 26 weeks; greater improvement withliraglutide (4.35 and 3.51 vs. 2.96; P = 0.03 for liraglutide 1.8 mg vs. sitagliptin) may reflect greater HbA1c reduction andweight loss. Patients perceived themselves to be hyperglycaemic significantly less frequently with liraglutide 1.8 mg(difference = )0.88; P < 0.0001) and 1.2 mg (difference = )0.49; P = 0.01). Perceived frequency of hypoglycaemia was similaracross all groups.
Injectable liraglutide may lead to greater treatment satisfaction than oral sitagliptin, potentially by facilitating greater improvement in glycaemic control, weight loss and ⁄ or perception of greater treatment efficacy.
GLP-1, glucagon-like peptide-1; HRQoL, health-related quality of life disease course [1,2] as well as influencing patients’ health-related quality of life (HRQoL), including treatment satisfaction [3,4].
In addition to the multiple physical sequelae of diabetes mellitus Patient-reported outcomes from clinical trials provide and its treatment, psychosocial factors significantly affect the information on the impact of a disease on HRQoL and mayidentify the extent to which treatment meets patients’ needs andexpectations. Patient-reported outcomes data typically reflect Correspondence to: Melanie Davies, Professor of Diabetes Medicine, perceptions of the efficacy and tolerability of treatment, as well as University Hospitals of Leicester, Leicester Royal Infirmary, Infirmary Square,Leicester LE1 5WW, UK. E-mail: [email protected] treatment preferences and, as such, complement physician ª 2011 The Authors.
Diabetic Medicine ª 2011 Diabetes UK Satisfaction with liraglutide vs. sitagliptin • M. Davies et al.
appraisals of the clinical value of specific therapies. As greater plasma glucose, indices of B-cell function, body weight, fasting treatment satisfaction may be associated with improved lipids and treatment satisfaction. Safety assessments included adherence to treatment and self-management behaviour [5], adverse events and self-reported hypoglycaemia.
patient-reported measures of treatment satisfaction offer a Treatment satisfaction was assessed at baseline and 26 weeks, clinically valuable indication of the likelihood that patients will or on withdrawal if this occurred prior to study completion, using choose, and adhere to, a given treatment. In the case of incretin- the status version of the validated Diabetes Treatment based therapies, a relatively new class of anti-diabetic agents, Satisfaction Questionnaire (DTSQs) in a subgroup that healthcare practitioners require quantitative and qualitative included all exposed subjects from the 10 countries where patient feedback to guide prescribing decisions. This is patient-reported outcomes data were gathered (n = 505 ⁄ 658; particularly important given the advantages some of these 77% of exposed subjects). The remaining three countries were agents appear to offer over traditional oral anti-diabetic drugs excluded from the patient-reported outcomes substudy because and insulin, namely significantly lower risks of hypoglycaemia of lack of local, linguistically validated patient-reported and weight gain [6,7], both of which may affect treatment outcomes measures. As the DTSQ was completed either at satisfaction [8,9]. The present patient-reported outcomes 26 weeks or on withdrawal, no subjects were excluded from the evaluation was conducted in a predefined subpopulation of a patient-reported outcomes analysis. DTSQs consisted of eight randomized controlled trial that compared the efficacy and safety items, each analysed individually, while overall treatment of approved doses of two incretin-based therapies, liraglutide, an satisfaction was calculated by summing individual scores from injectable once-daily human glucagon-like peptide-1 (GLP-1) six items: satisfaction with ‘current treatment’, ‘convenience’, analogue and the orally administered dipeptidyl peptidase 4 ‘flexibility’, ‘understanding’, ‘recommend’ and ‘continue’, where (DPP-4) inhibitor sitagliptin, each added on to metformin in ‘recommend’ and ‘continue’ indicate the likelihood that a patients with Type 2 diabetes poorly controlled on metformin patient would recommend or continue treatment after study completion. Each item was scored on a scale from 0 (‘very In patients with Type 2 diabetes, adding liraglutide to failing dissatisfied ⁄ inconvenient’) to 6 (‘very satisfied ⁄ convenient’); a metformin monotherapy improves glycaemic control and lowers higher score indicates greater treatment satisfaction. Perceived weight with low hypoglycaemic risk, while reducing systolic frequency of hyperglycaemia and hypoglycaemia was measured blood pressure [11]. Synergism between sitagliptin and separately using one item each, also scored on a scale from 0 metformin also seems logical, as metformin stimulates GLP-1 (‘none of the time’) to 6 (‘most of the time’), where lower scores secretion [6], while sitagliptin increases the half-life of indicate lower frequency of perceived hypo- or hyperglycaemia endogenous GLP-1. In clinical trials, adding sitagliptin to and therefore better perceived glycaemic control. Subjects did not metformin therapy decreased key glycaemic control parameters receive guidance on how to determine whether their blood with minimal hypoglycaemia [12–14]. However, the magnitude glucose level was high or low; they simply answered the questions of HbA1c reduction appears significantly lower with DPP-4 ‘How often have you felt that your blood sugars have been inhibitors than with GLP-1 receptor agonists [10,15]. Other key unacceptably high ⁄ low recently?’ Patients were not specifically differentiators between these two therapy classes are their effects asked about their appetite or about symptoms of nausea.
on weight and mode of administration: GLP-1 receptor agonists Treatment satisfaction scores were analysed using an facilitate weight loss whereas DPP-4 inhibitor monotherapy is ANCOVA model, with treatment and country as fixed effects usually weight neutral [6] and, while GLP-1 receptor agonists are and baseline value as covariate, with no imputation for missing injected, DPP-4 inhibitors are taken orally. Although it is often stated that patients resist injectable therapies, published datasuggest this is not by any means a universal finding [4,5,16] and it is possible that this stance may at times be overvalued,representing a form of physician-driven clinical inertia rather Baseline characteristics of the full analysis set for the main study than an evidence-based concern [17].
population and patient-reported outcomes subpopulation werecomparable and treatment group demographics well balanced.
Baseline mean HbA 1c values were 8.4% (68 mmol ⁄ mol) in both liraglutide groups and 8.5% (69 mmol ⁄ mol) in the sitagliptin Liraglutide, 1.2 or 1.8 mg, injected once daily using a pen device, group and baseline weights were 93.7, 94.6 and 93.1 kg in was compared with oral sitagliptin, 100 mg once daily, both the 1.2 mg, 1.8 mg and sitagliptin groups, respectively.
added to a stable dose of metformin (‡ 1500 mg daily), in a Corresponding body mass indices were 32.6, 33.1 and 26-week randomized, open-label study carried out in 13 32.6 kg ⁄ m2. The main study randomized 665 individuals, of countries. Study design, methods, efficacy and safety results are which 658 were exposed to at least one dose of trial product, reported elsewhere [10]. The primary efficacy endpoint was and 554 (83%) completed the trial. A total of 505 subjects change in HbA1c from baseline to week 26, with secondary (liraglutide 1.2 mg n = 164; liraglutide 1.8 mg n = 171; endpoints including proportion of subjects reaching HbA1c sitagliptin n = 170) were included in the current patient- < 7% (53 mmol ⁄ mol) and £ 6.5% (48 mmol ⁄ mol), fasting In this trial, liraglutide led to significantly greater reduction in 1.8 mg than sitagliptin (difference = )0.88; P < 0.0001) and HbA1c than sitagliptin (mean HbA1c reduction: 1.50, 1.24 and the same was found when comparing the 1.2-mg dose of 0.90% (7, 10 and 14 mmol ⁄ mol) for liraglutide 1.8 mg, 1.2 mg liraglutide with sitagliptin (difference = )0.49; P = 0.01). The and sitagliptin, respectively; P < 0.0001 for both liraglutide doses perceived frequency of hypoglycaemia was similar across all vs. sitagliptin). The proportion of patients reaching HbA1c < 7% (53 mmol ⁄ mol) was 54.6, 43.4 and 22.4%, respectively, andliraglutide-treated subjects lost significantly more weight (3 vs.
1 kg). Treatment-emergent adverse events occurred in 66.1%(1.2 mg) and 72.9% (1.8 mg) of liraglutide-treated subjects vs.
While all groups reported an increase in treatment satisfaction, 58.0% of sitagliptin-treated patients. For liraglutide, the majority subjects receiving liraglutide 1.8 mg reported significantly of excess adverse events were early gastrointestinal side effects, greater improvement in overall treatment satisfaction than typically nausea that was mostly mild and transient [10]; those taking sitagliptin, despite the fact that liraglutide was although nausea occurred more frequently during the first few injected while sitagliptin was oral, and that treatment-emergent weeks with liraglutide (21–27%) than with sitagliptin (5%), adverse events occurred in more liraglutide patients. This could symptoms had decreased to levels observed with sitagliptin reflect patients’ recognition that the GLP-1 analogue offered (< 3%) by the end of the trial. The most common adverse events better control of hyperglycaemia and the potential for weight in sitagliptin-treated patients were nasopharyngitis and loss, although further data are needed to confirm this. Our data headache, reported in 11.9 and 10.0% of patients, respectively.
also highlight the positive impact of improved glycaemic control The proportion of subjects experiencing hypoglycaemia (mostly on treatment satisfaction. Of interest, there was no difference minor) was low and comparable in all groups [10].
between liraglutide and sitagliptin on DTSQ items relating to Table 1 presents the patient-reported outcomes results.
treatment convenience and flexibility, indicating that patients Overall, treatment satisfaction was comparable between were no less satisfied with the injectable than the oral agent.
groups at baseline and improved in all groups after 26 weeks.
These findings concur with much of the published literature in However, improvement in overall treatment satisfaction was suggesting that patients may prefer an injected to an oral therapy significantly greater with liraglutide 1.8 mg (4.35) than if it leads to greater improvement in glycaemic control, sitagliptin (2.96) [between-group difference = 1.39 (95% CI perception of greater treatment efficacy and ⁄ or facilitates 0.13; 2.64); P = 0.03]; differences in overall treatment weight loss [4,5,16]. As obese subjects with Type 2 diabetes satisfaction between liraglutide 1.2 mg and sitagliptin, and report poorer health status and greater symptom impact than between the two liraglutide doses, were not significant. Patients non-obese patients [18,19], the improvement in HRQoL reported significantly greater improvement in treatment afforded by weight-lowering therapies may be particularly satisfaction with liraglutide 1.8 mg than sitagliptin on three welcome. Our finding of reduced perceived frequency of hyperglycaemia with liraglutide is also in accordance with data ‘recommend’ (difference = 0.41; P = 0.003) and ‘continue’ showing that the association between HbA1c and HRQoL may (difference = 0.44; P = 0.01). Patients perceived themselves to be mediated by the perceived frequency of hyper- and be hyperglycaemic significantly less frequently with liraglutide Table 1 Patient-reported outcomes summary )0.49 ()0.86; )0.12) P = 0.01  )0.88 ()1.25; )0.51) P < 0.0001  Data are differences in Diabetes Treatment Satisfaction Questionnaire score least square means between weeks 0 and 26.
*Columns on the right show estimated treatment difference with 95% confidence intervals.
 P-values indicate statistical significance at the 5% level.
ª 2011 The Authors.
Diabetic Medicine ª 2011 Diabetes UK Satisfaction with liraglutide vs. sitagliptin • M. Davies et al.
Despite the potential for greater glucose-lowering efficacy and weight loss with GLP-1 receptor agonists compared withDPP-4 inhibitors, and the reported effects on patient The authors accept direct responsibility for this paper and are satisfaction and adherence, some clinicians remain hesitant grateful for the contribution made by Watermeadow Medical to use GLP-1 receptor agonists, perhaps perceiving injectable (supported by Novo Nordisk A ⁄ S, Bagsvaerd, Denmark) in therapies to be more complex and less desirable than a once- developing the draft manuscript from an agreed outline and for daily oral medication. However, this reluctance to prescribe GLP-1 receptor agonists fails to take into account the fact thatmany commonly used anti-diabetic therapies are associated with weight gain and hypoglycaemia, both of whichnegatively affect patient quality of life, and that weight gain 1 Davis WK, Hess GE, Hiss RG. Psychosocial correlates of survival in itself may exacerbate other components of the metabolic diabetes. Diabetes Care 1988; 11: 538–545.
2 Lustman PJ, Anderson RJ, Freedland KE, De Groot M, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic Patient-reported outcomes and treatment satisfaction are review of the literature. Diabetes Care 2000; 23: 934–942.
important factors to consider when choosing a glucose- 3 Bradley C, Speight J. Patient perceptions of diabetes and diabetes lowering therapy for patients with Type 2 diabetes. This study therapy: assessing quality of life. Diabetes Metab Res Rev 2002; 18: provides evidence of greater improvement in treatment 4 Nicolucci A, Cucinotta D, Squatrito S, Lapolla A, Musacchio N, satisfaction with an injectable GLP-1 agent, liraglutide 1.8 mg, Leotta S et al.; QuoLITy Study Group. Clinical and socio-eco- than an oral DPP-4 inhibitor, sitagliptin, potentially by nomic correlates of quality of life and treatment satisfaction in facilitating greater improvement in glycaemic control and patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 2009; weight loss. These results challenge the perception that patients ‘prefer’ oral to injected glucose-lowering therapies.
5 Peyrot M, Rubin RR. How does treatment satisfaction work?: modeling determinants of treatment satisfaction and preference.
Diabetes Care 2009; 32: 1411–1417.
6 Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin Emerg Drugs 2008; 13: 593– MD has acted as consultant, advisory board member and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, 7 Lovshin J, Drucker D. Incretin-based therapies for type 2 diabetes mellitus. J Nat Rev Endocrinol 2009; 5: 262–269.
Merck Sharp & Dohme, Roche, BMS and speaker for Servier.
8 Marrett E, Stargardt T, Mavros P, Alexander C. Patient-reported She has received grants in support of investigator and outcomes in a survey of patients treated with oral antihypergly- investigator-initiated trials from Novartis, Novo Nordisk, caemic medications: associations with hypoglycaemia and weight Sanofi-Aventis, Lilly, Pfizer, Merck Sharp & Dohme, gain. Diabetes Obes Metab 2009; 11: 1138–1144.
GlaxoSmithKline and Servier. RP has received research 9 Pollack MF, Purayidathil FW, Bolge SC, Williams SA. Patient- grants, funds for speaking, honoraria and consulting fees associations with adherence; treatment satisfaction and health- from Novartis and has ownership interests in Novartis; related quality of life. Diabetes Res Clin Pract 2010; 87: 204– research grants, speakers fees, honoraria and consulting fees from Takeda; research grants speakers fees, honoraria and 10 Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy E, Filetti S consulting fees from Novartis fees from Merck; research et al., for the 1860-LIRA-DPP-4 Study Group. Liraglutide versussitagliptin for patients with type 2 diabetes who did not have grants, honoraria and consulting fees from Roche; research adequate glycaemic control with metformin: a 26-week, rando- grants, honoraria and consulting fees from GlaxoSmithKline; mised, parallel-group, open-label trial. Lancet 2010; 375: 1447– research grants from Eli Lilly; research grants, speakers fees, honoraria and consulting fees from Novo Nordisk; research 11 Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH grants from Mannkind, Sanofi-Aventis and Pfizer, and et al.; LEAD-2 Study Group Efficacy and safety comparisonof liraglutide, glimepiride, and placebo, all in combination honoraria and consulting fees from Eisai, Glenmark and with metformin, in type 2 diabetes: the LEAD (liraglutide effect and AstraZeneca ⁄ BMS. MH is an employee and stakeholder of action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90.
Novo Nordisk A ⁄ S. ABT is an employee of Novo Nordisk 12 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and and has shares in the company. RC serves as PI or co- safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to investigator for sponsored clinical trials research for Amylin, ongoing metformin therapy in patients with type 2 diabetes inade-quately controlled with metformin alone. Diabetes Care 2006; 29: 13 Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM et al.
Johnson ⁄ Lifescan, Mannkind, Medtronic, Novo Nordisk, Efficacy and safety of sitagliptin added to ongoing metformin Quotient Diagnostics, ResMed, Roche, Sanofi-Aventis and therapy in patients with type 2 diabetes. Curr Med Res Opin 2008; Takeda; is an advisory board member for Abbott, Bayer, 14 Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of CeQur, Eli Lilly, Novo Nordisk and Roche; receives support sitagliptin when added to ongoing metformin therapy in patients for educational activities from Lifescan, Eli Lilly, Merck, with type 2 diabetes. Diabetes Obes Metab 2008; 10: 959– 15 Gilbert MP, Pratley RE. Efficacy and safety of incretin-based ther- 18 Matza L, Yurgin N, Boye KS, Malley K, Shorr JM. Obese versus apies in patients with type 2 diabetes mellitus. Eur J Intern Med non-obese patients with type 2 diabetes: patient-reported outcomes and utility of weight change. Curr Med Res Opin 2007; 23: 2051– 16 Houlden R, Ross S, Harris S, Yale JF, Sauriol L, Gerstein HC.
Treatment satisfaction and quality of life using an early insuliniza- 19 Sundaram M, Kavookjian J, Patrick J, Miller LA, Madhavan SS, tion strategy with insulin glargine compared to an adjusted oral Scott VG. Quality of life, health status and clinical outcomes in therapy in the management of Type 2 diabetes: The Canadian type 2 diabetes patients. Qual Life Res 2007; 16: 165–167.
INSIGHT Study. Diabetes Res Clin Pract 2007; 78: 254–258.
20 Kleefstra N, Ubink-Veltmaat L, Houweling S, Groenier KH, 17 Kruger D, Spollett G. Addressing barriers to timely intensification Meyboom-de Jong B, Bilo HJ. Cross-sectional relationship of diabetes care: the relationship between clinical inertia and patient between glycaemic control, hyperglycaemic symptoms and quality of behavior. Consultant 2009; 49: S20–25.
life in type 2 diabetes (ZODIAC-2). Neth J Med 2005; 63: 215–221.
ª 2011 The Authors.
Diabetic Medicine ª 2011 Diabetes UK

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