Comparative effectiveness of vildagliptin in

Current Medical Research & Opinion

Curr Med Res Opin Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 07/07/14 For personal use only.

0300-7995 doi:10.1185/03007995.2014.928274

2014, 1–8

Article RT-0124.R1/928274 All rights reserved: reproduction in whole or part not permitted

Original article Comparative effectiveness of vildagliptin in combination with other oral anti-diabetes agents in usual-care conditions: the EDGE–Latin America study Carlos O. Mendivil*

Abstract

Universidad de los Andes, School of Medicine, Bogota´, Colombia Fundacioń Santa Fe de Bogota´, Section of Endocrinology, Bogota´, Colombia

Objective: To assess the proportion of patients on vildagliptin add-on dual therapy who respond to treatment over a 12 month follow-up, relative to comparator oral anti-diabetes dual therapy, in a usual care setting.

Eduardo Ma´rquez-Rodrı´guez* Instituto Jalisciense de Metabolismo, Guadalajara, Me´xico Hospital Ańgeles del Carmen, Guadalajara, Me´xico

Ivań D. Ańgel Escuela de Nutricioń y Diete´tica, Universidad de Antioquia, Medellıń, Colombia

Gustavo Paz Hospital Carlos Andrade Marıń, Quito, Ecuador

Cruz Rodrı´guez InCardio, Maturıń (Mońagas), Venezuela

Jorge Almada Novartis Latin America, Mexico City, Mexico

Ofelia Szyskowsky Clıńica Santa Isabel, Buenos Aires, Argentina

Address for correspondence: Carlos O. Mendivil, Universidad de los Andes, School of Medicine, Cra 7a # 116-05, Of. 413, Bogota, Colombia. Tel.: +57 321.373.5051; [email protected] Keywords: Anti-diabetics – Diabetes – Dipeptidyl peptidase-IV inhibitors – Vildagliptin

Research design and methods: Participants were patients with type 2 diabetes (T2DM) aged 18 years and older from 311 centers in Argentina, Colombia, Ecuador, Mexico and Venezuela. Patients were taking monotherapy with an oral antidiabetes drug (OAD), and were prescribed a new add-on OAD based on the judgment of their personal physician. According to this choice, patients were assigned to one of the two cohorts: vildagliptin or comparator OADs. Main outcome measures: The primary endpoint was the proportion of patients achieving an A1c drop 40.3% without edema, hypoglycemia, weight gain or discontinuation due to gastrointestinal (GI) events. The secondary endpoint was the proportion of patients with baseline A1c 7% who reached the goal of an A1c 57% without hypoglycemia or weight gain. Results: The per-protocol population (a subset of the intention-to-treat population that excluded patients with prespecified protocol deviations) comprised 3773 patients, 3002 in the vildagliptin cohort and 771 in the comparator cohort. The proportion of patients reaching the primary endpoint was higher in the vildagliptin cohort (60.3%) than the comparator cohort (50.7%), OR 1.48 (95% CI: 1.25–1.73). The same was observed for the secondary endpoint (44.8 versus 33.1%) OR 1.64 (95% CI: 1.37–1.98). The incidence of adverse events was low and similar between treatment cohorts. Conclusion: In a usual care setting, patients treated with a vildagliptin combination succeeded in lowering A1c to57%, without weight gain, hypoglycemia or peripheral edema more often than patients treated with comparator combinations, without increased risk of adverse events. Key limitations are the observational nature of the study and its relatively limited 12 month timeframe.

Accepted: 21 May 2014; published online: 11 June 2014 Citation: Curr Med Res Opin 2014; 1–8

Introduction *These authors contributed equally to the development of this study.

! 2014 Informa UK Ltd www.cmrojournal.com

During the past three decades, the developing world has experienced a dramatic rise in the prevalence of type 2 diabetes mellitus (T2DM), and Latin America has not been the exception. The International Diabetes Federation (IDF) Vildagliptin combination effectiveness in Latin America Mendivil et al.

1



2014

estimated for Latin America in the year 2011 a regional age-adjusted prevalence of diabetes of 9.2% in adults1, a huge figure for a region of 577 million people trying to escape from poverty and underdevelopment. Diabetes imposes a high economic burden in this subcontinent: at least 3.1 billion dollars a year in 2003 for Mexico, Central America, the Caribbean and South America, in direct medical costs alone, according to the Pan-American Health Organization (PAHO)2. Most of these costs are derived from the chronic complications of the disease, as they result in hospitalizations with expensive diagnostic and therapeutic procedures. Even though a tight control of glycemia and other risk factors has proven to prevent the appearance of the chronic complications of T2DM3, the rates of goal achievement are remarkably low in both industrialized4 and developing countries5. Achievement of treatment goals is the mainstay of T2DM care, but given the progressive nature of the condition this often requires the simultaneous use of lifestyle changes and a combination of drugs6–8. In addition to efficacy, recent guidelines suggest that effectiveness, tolerability, cost and patient preferences may influence the outcomes of therapy and should be considered when choosing anti-diabetes drugs9. Usual practice, usual care studies provide essential information about the results of an intervention when all factors potentially impacting treatment outcomes are taken into account. Despite the pivotal role of randomized controlled trials on the initial determination of efficacy, the generalizability of their results can be quite limited, and there is an increasing recognition of the importance of pragmatic trials10–12. EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) is a prospective, 1 year, usual care observational study conducted worldwide, that assesses the effectiveness and tolerability of vildagliptin, a dipeptidyl peptidase-IV (DPP-4) inhibitor, added to monotherapy with an oral anti-diabetes drug (OAD), compared to any two-OAD combination without vildagliptin (pooled). Physicians enrolled patients with T2DM inadequately controlled using one OAD, when a second glucose-lowering agent was considered. This study sought to assess the effectiveness and tolerability of vildagliptin combinations versus other OAD two-agent combinations, but also to illustrate the advantages and limitations of large usual care studies. Most multinational clinical trials or post-marketing studies include very few or no patients from Latin America, so there is a great paucity of reliable information on the pharmacological management of T2DM that is unmistakably applicable to our population. EDGE–Latin America aims to contribute in filling this gap. In this manuscript, we report on the effectiveness and tolerability of vildagliptin combinations versus other OAD two-agent combinations for patients enrolled in Latin 2

Vildagliptin combination effectiveness in Latin America Mendivil et al.

American countries (Argentina, Colombia, Ecuador, Mexico and Venezuela).

Methods Study design EDGE was a 12 month, observational, multicenter, postauthorization, prospective cohort study in which 45,868 patients from 2957 centers in 27 countries from Europe, Central and Latin America, Asia and Middle East were evaluated. Of these, 4145 patients were enrolled from 311 sites in Argentina, Colombia, Ecuador, Mexico and Venezuela. Adult patients (aged 418 years) with T2DM and inadequate glycemic control while receiving OAD monotherapy with a sulfonylurea (SU), metformin, thiazolidinedione (TZD), metiglinide, or alpha-glucosidase inhibitor (AGI), and for whom a second oral anti-diabetic agent (OAD) was considered, were eligible. Patients who were planned to initiate a DPP-4 inhibitor other than vildagliptin, or a glucagon-like peptide-1 (GLP-1) mimetic/analogue, or who required three or more OADs at study entry were excluded, as were patients changed from one OAD or OAD class to another at the time of study entry, prior to adding a new OAD. Patients who were using insulin at the time of study entry and patients with a history of hypersensitivity to any of the study drugs or drugs of similar chemical classes were excluded. Participants were required to provide written or oral informed consent (per country regulations) to have data collected and agree to follow all local medication labeling or prescribing requirements of their new OAD. Physicians chose glucose-lowering treatment for their patients at their discretion. To ensure non-interventional status, patient enrollment was agreed after the treatment decision was made. Suitable patients fell into one of two cohorts (vildagliptin or comparator). The term index therapy is used to represent the combination treatment initiated at enrollment. For any index therapy, a fixed dose combination, when available, was allowed13. The choice of the initial monotherapy and the decision to intensify was entirely determined by each treating physician individually.

Data collection Demography (age, gender, race, height, ethnicity), body weight, medical history, date of diagnosis of T2DM, antidiabetes medications taken prior to study entry, newly initiated add-on OAD (second component of index medication), other medications (by class), most recent A1c test date and result, and any other laboratory test dates and results were collected at baseline during a routine office visit. After 12 months, the final data collected included body weight, changes to newly initiated index OAD, most www.cmrojournal.com ! 2014 Informa UK Ltd



2014

recent A1c test data and result, other laboratory test dates and results, adverse events and study completion status. Interim assessments could occur at any time between baseline and final study data collection, or early termination. Laboratory testing was performed on patients in line with normal medical practice and/or as defined by local prescribing information and/or at a time period judged appropriate by the physician. Because of the ‘real-world’ nature of the study, central laboratories were not used. However, A1c measurements were performed in the participating centers using National Glycohemoglobin Standardization Program (NGSP)-approved methodologies from commercial manufacturers. In keeping with the non-interventional observational design employed, monitoring was conducted only at centers with high enrolment (about 5% of centers). However, physicians were requested to maintain source documents for each patient, including signed informed consent forms.

Analysis of primary and secondary effectiveness and tolerability endpoints

Effectiveness and tolerability endpoints

Ethics

Primary endpoint The primary endpoint was defined as the proportion of patients having a treatment response (A1c reduction 40.3% from baseline to month 12) while presenting no tolerability findings (peripheral edema, proven hypoglycemic event, discontinuation due to a gastrointestinal (GI) event, or weight gain 5%). Patients who could not be categorized as a success or failure (e.g. due to missing A1c or body weight data at 12 month endpoint) were considered non-evaluable. Non-evaluable patient data were considered failures in calculation of the odds ratio (OR) for success. The main analysis of the primary endpoint utilized the per-protocol (PP) population; data were censored if patient changed index therapy. Patients were defined as having proven hypoglycemia if they experienced any hypoglycemic event as defined below, confirmed by the opinion of the physician, at any time during the 12 month observation period: i. symptoms suggestive of hypoglycemia that resolved promptly on the administration of oral carbohydrate, ii. symptoms suggestive of hypoglycemia accompanied by a plasma glucose below 3.1 mmol/L (56 mg/dL), or iii. symptoms suggestive of hypoglycemia and patient unable to initiate selftreatment therefore requiring assistance of a third party or hospitalization.

The protocol for EDGE was approved by the following Independent Review Boards (IRBs) in each country: Argentina: Comite´ Independiente de E´tica para Ensayos en Farmacologıá Clıńica de la Fundacioń de Estudios Farmacolo´gicos y de Medicamentos ‘Profesor Luis M. Zieher’, Colombia: Comite´ Independiente de E´tica e Investigacioń Biome´dica AVANZAR, Ecuador: Comite´ de Bioe´tica de la Universidad San Francisco de Quito, Me´xico: Instituto Mexicano de Educacioń Me´dica e Investigacioń Clıńica S.C., Venezuela: Comite´ de E´tica del CENREV – Centro Nacional De Retina Y Vı´treo. We obtained written informed consent from participants in all countries except Mexico, where local regulations allow IRBs to authorize a verbal informed consent in studies with minimal risk like this one. The consent was recorded at the medical record and at the case report form. All Ethics Committees/IRBs involved in the study approved the consent procedure.

Secondary endpoint The secondary endpoint was defined as the proportion of patients with a baseline A1c 7% who achieved an A1c 57% without experiencing proven hypoglycemia or weight gain 3%. ! 2014 Informa UK Ltd www.cmrojournal.com

Data were collected at baseline and at any time point in the next 12 months, with a required reporting at 12 months. This manuscript constitutes a post-hoc analysis of the global EDGE study and, as such, it provides mainly descriptive statistics. For the primary and secondary endpoints, the probability of success was analyzed using a binary logistic regression model to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). The OR expresses the odds in favor of success in the vildagliptin group relative to odds in favor of success in the comparator OADs group. Given the post-hoc nature of this analysis, only the unadjusted OR and a single multivariate model (as an exploratory analysis) are provided. The betweengroups difference in A1c drop was analyzed using ANCOVA, with treatment group as a fixed factor and baseline A1c as the model covariate.

Results Patient populations and baseline characteristics The enrolled population comprised 4145 patients with documented informed consent, but 296 patients (229 in the vildagliptin and 67 in the comparator cohort) were excluded due to inadequate source documentation or problems with the quality or accuracy of data entry (Figure 1). The intention-to-treat (ITT) population, used for baseline demographics and safety analyses, comprised 3065 and 781 patients receiving dual therapy with newly prescribed vildagliptin or a non-vildagliptin OAD added to prior Vildagliptin combination effectiveness in Latin America Mendivil et al.

3


2014

4,145 enrolled* 3,294 Vildagliptin cohort 229 Insufficient data quality

848 Comparator cohort 67 Insufficient data quality


3,065 ITT**

781 ITT**

63 Protocol deviations

10 Protocol deviations

3,002 Per protocol*** 540 Discontinued

2,525 Patients completed

771 Per protocol*** 118 Discontinued

663 Patients completed

Figure 1. Patient population and flow. *The enrolled population includes all patients who gave documented informed consent. **The intention-to-treat (ITT) population is a subset of the enrolled population and includes all patients who were assigned to new treatment at study start. Sites and/or patients identified with quality and compliance findings, irregular data were excluded from the ITT analysis population. ***The per-protocol (PP) population is a subset of the ITT population. The PP population was used for the analyses of effectiveness endpoints. Patients with the following deviations at baseline assessment were excluded from the per protocol population: patients receiving DPP-4 inhibitors at baseline or within 1 month prior to baseline; patients receiving GLP-1 mimetics/analogues at baseline or within 1 month prior to baseline; patients receiving insulin at baseline; patients receiving only newly initiated monotherapy or more than two oral anti-diabetes medications at baseline; drug-naive patients at baseline (patients not taking any diabetic medication prior to baseline); patients who swapped from one oral anti-diabetes medication or class to another at baseline; patients receiving vildagliptin at baseline or 30 days prior to baseline or five half-lives prior to baseline; patients receiving more than one oral anti-diabetes medication prior to baseline.

monotherapy, respectively. The per-protocol population was a subset of the ITT population that excluded participants with pre-defined protocol deviations (Figure 1). The per-protocol population was used for the analyses of effectiveness endpoints and comprised 3002 patients in the vildagliptin, and 771 in the comparator cohort. The number of patients with a baseline A1c57% whose treatment was intensified during the study were 288 (9.4%) in the vildagliptin cohort, and 66 (8.4%) in the comparator cohort. The baseline characteristics of the ITT population are summarized in Table 1. Study participants were on average 55.9 years old, had been diagnosed with diabetes 5.6 years ago, had a BMI of 29.5 kg/m2, and an A1c level of 8.5%. The sex distribution was almost even. Hypertension was present in 46.1% of participants, lipid disorders in 32.9%, established macrovascular complications in 5.3% and 4

Vildagliptin combination effectiveness in Latin America Mendivil et al.

established microvascular complications in 4.8%. The vildagliptin and comparator groups were similar in important clinical variables like sex distribution, body-mass index and baseline A1c, and had small but statistically significant differences in other variables: participants in the comparator group were on average 2 years older (p50.001), their T2DM had lasted 0.9 years longer (p50.001), had a higher prevalence of hypertension (49.4 vs 45.2%, p ¼ 0.034), lipid disorders (36.2 vs 32.0%, p ¼ 0.025) and a slightly higher prevalence of microvascular complications (6.7 vs 4.4%, p ¼ 0.008). The different OAD combination schemes received by the ITT population in each group are displayed in Table 2. In the vildagliptin cohort, the most frequent combination was with metformin (80%). After metformin, the most frequent coexisting therapy was SUs, followed by TZDs, AGIs and in the last place metiglinides. Conversely, in the comparator group the most frequent combination therapy was metformin þ SUs (62%), followed by metformin þ TZDs, SU þ TZDs, metiglinides þ metformin, AGIs þ metformin, AGIs þ sulfonylureas, metiglinides þ TZDs, AGIs þ TZDs and in the last place metiglinides þ SUs.

Primary and secondary endpoints Table 3 shows the success rates and ORs for the primary and secondary endpoints. The percentage of patients in the vildagliptin group who successfully reached the primary endpoint of a decrease in A1c 40.3%, without peripheral edema, hypoglycemia, discontinuation due to GI side-effects or hypoglycemia was 60.3%. In the comparator group this percentage was 50.7%. This difference resulted in an OR of 1.48 (95% CI: 1.26–1.73). As indicated in Table 3, a similar advantage for vildagliptin-based therapies was seen for the secondary endpoint, with 44.8% of vildagliptin-treated patients compared to 33.1% of comparator-treated patients reaching the secondary endpoint, resulting in an OR of 1.64 (95% CI: 1.37–1.98). The mean change in A1c at 12 months by treatment group is illustrated in Figure 2: 1.70% (95% CI: 1.74– 1.67) in vildagliptin-treated patients and 1.50% (95% CI: 1.58–1.43) in comparator-treated patients (analysis not pre-specified in protocol).

Safety analyses The number of patients with any reported adverse event in any primary system organ class was 202 in the vildagliptin cohort (6.6%) and 124 in the comparator cohort (25.9%). Table 4 summarizes adverse events that occurred during the study, listed by system organ class. There were four deaths reported among the 3065 patients in the vildagliptin cohort ITT population, and one death among the 781 www.cmrojournal.com ! 2014 Informa UK Ltd


2014

Table 1. Demographic and patient baseline characteristics (ITT population).


Characteristic

Age (years) Female sex (%) BMI (kg/m2) Baseline A1c (%) Duration of T2DM (years) Hypertension (%) Lipid disorders (%) Macrovascular disease (%) Microvascular disease (%)

Vildagliptin n ¼ 3065

Comparator n ¼ 781

Total n ¼ 3846

p Value

55.5 12.5 1597 (52.1) 29.5 5.33 8.5 1.7 5.5 6.1 1385 (45.2) 981 (32.0) 154 (5.0) 134 (4.4)

57.5 11.7 426 (54.6) 29.3 5.2 8.5 1.66 6.4 6.2 386 (49.4) 283 (36.2) 51 (6.5) 52 (6.7)

55.9 12.4 2023 (52.6) 29.5 5.3 8.5 1.69 5.66 6.1 1771 (46.1) 1264 (32.9) 205 (5.3) 186 (4.8)

50.001 0.22 0.24 0.42 50.001 0.034 0.025 0.094 0.008

Data are means SD or n (%).

Table 2. Index medications by study group (ITT population). Vildagliptin cohort* (n ¼ 3065) Vildagliptin þ Metformin Sulfonylureas Thiazolidinediones Alpha glucosidase inhibitors Metiglinides

Comparator cohort* (n ¼ 781) n (%)

Combination

n (%)

2451 (80.0) 439 (14.3) 132 (4.31) 25 (0.82) 15 (0.49)

Metformin þ Sulfonylureas Metformin þ Thiazolidinediones Sulfonylureas þ Thiazolidinediones Metiglinides þ Metformin Alpha glucosidase inhibitors þ Metformin Alpha glucosidase inhibitors þ Sulfonylureas Metiglinides þ Thiazolidinediones Alpha glucosidase inhibitors þ Thiazolidinediones Metiglinides þ Sulfonylureas

483 (62.0) 148 (19.0) 89 (11.4) 29 (3.72) 13 (1.67) 8 (1.03) 4 (0.51) 3 (0.39) 2 (0.26)

*For three patients in the vildagliptin cohort and two in the comparator cohort, it was not possible to identify the index medication.

Table 3. Primary and secondary efficacy and tolerability endpoints. Vildagliptin n ¼ 3002 n ¼ 2422

Comparator n ¼ 771 n ¼ 626

OR (95% CI)

p Value

Primary Endpoint Decrease in A1c 40.3%, no hypoglycemia, no weight gain, no discontinuation for gastrointestinal events, no peripheral edema

1810 (60.3)

391 (50.7)

1.48 (1.25–1.73)

50.001

Secondary Endpoint Among participants with baseline A1c 7%: achievement of A1c 57% at end of study without proven hypoglycemic events or weight gain 3%

1085 (44.8)

207 (33.1)

1.64 (1.37–1.98)

50.001

Sample size for primary endpoint Sample size for secondary endpoint

Analyses were performed on the per-protocol population. The per-protocol (PP) population is a subset of the ITT population from which patients with any of the following deviations from the protocol were excluded: use of DPP-4 inhibitors at baseline or within 1 month prior to baseline, use of GLP-1 mimetics/analogues at baseline or within 1 month prior to baseline, use of insulin at baseline, use of more than two oral anti-diabetes medications at baseline, use of no anti-diabetes drug (drug-naive patients) at baseline, change from one oral anti-diabetes medication or class to another at baseline, use of vildagliptin at baseline or 30 days prior to baseline and use of more than one oral anti-diabetes medication prior to baseline. Only unadjusted ORs are shown.

patients in the comparator cohort ITT population. Hypoglycemia was reported by 7 patients (0.23%) in the vildagliptin cohort, and by 10 patients (1.28%) in the comparator cohort. After adjusting for baseline weight by ANCOVA, the change in body weight for patients in the vildagliptin-therapies cohort was 3.05 kg (95% CI: 3.27–2.85), while in the comparator cohort this weight change was 2.50 kg (95% CI: 2.94–2.08). ! 2014 Informa UK Ltd www.cmrojournal.com

Given the presence of small but significant differences between groups in some baseline variables, we ran a multivariable logistic regression model that included as predictors (besides treatment group), the following covariates: age, diabetes duration, hypertension (yes/no), lipid disorders (yes/no), and microvascular complications (yes/no). After multivariable adjustment, the odds of achieving the primary endpoint were still significantly Vildagliptin combination effectiveness in Latin America Mendivil et al.

5


2014

p