Effectiveness and tolerability of second-line therapy with vildagliptin versus other oral agents in type 2 diabetes (EDGE): post-hoc subanalysis of the Belgian data J. Hoste1, E. Daci2, C. Mathieu1 1
Department of Endocrinology, UZ Leuven, Belgium, 2N.V. Novartis Pharma S.A., Vilvoorde, Belgium
Aim: To assess the efficacy and safety of vildagliptin versus other oral glucose-lowering drugs added to antidiabetic monotherapy in Belgian patients with type 2 diabetes mellitus, in comparison to the global EDGE study results. Methods: This is a pre-specified post-hoc subanalysis of the Belgian patient cohort from a worldwide 1-year observational study that compared the effectiveness and tolerability of vildagliptin to other oral antidiabetic agents in type 2 diabetes patients failing monotherapy with oral glucose-lowering agents (EDGE). A total of 1793 Belgian patients were enrolled. Physicians could add any oral antidiabetic drug and patients entered either into the vildagliptin or the comparator cohort. The primary effectiveness and tolerability endpoint was defined as the proportion of patients having a treatment response (HbA1c reduction from baseline to month 12 endpoint .0.3%) without hypoglycemia, weight gain, peripheral oedema, or gastrointestinal side-effects. Results: In the Belgian population, 37.8% of patients in the vildagliptin group and 32.8% in the comparator group had a decrease in HbA1c of .0.3% without the predefined tolerability issues of hypoglycemia, weight gain, oedema or, gastrointestinal complaints (primary endpoint), resulting in an unadjusted odds ratio of 1.24 (95% CI: 0.96–1.61). Mean HbA1c change from baseline was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort. Overall, vildagliptin was well tolerated with similarly low incidences of total adverse events (14.9% versus 14.5% in the compactor group) and serious adverse events (2.7% versus 2.5% in the comparator group). Conclusion: In this EDGE subgroup of Belgian patients with type 2 diabetes who do not achieve the glycemic targets with monotherapy, a similar trend as in the global EDGE study was observed. Adding vildagliptin as a second oral glucose-lowering agent resulted in lowering HbA1c to ,7% without weight gain, hypoglycemia or peripheral oedema in a higher proportion of patients than comparator oral antidiabetic drugs, with no differences in the reported number of adverse events. Keywords: Type 2 diabetes mellitus, Vildagliptin, Observational study, Add-on therapy
Introduction Type 2 diabetes (T2D) mellitus is a chronic disease characterized by insulin resistance and relative insulin deficiency.1 Current clinical practice guidelines recommend a stepwise treatment pathway for diabetic patients.1 Initial management includes lifestyle changes, aimed at increasing exercise and dietary modification. If blood glucose levels are not adequately controlled by these measures, pharmacological intervention will be necessary. At present, different classes of oral glucose-lowering agents are available,
Correspondence to: C. Mathieu, I.G. – Endocrinologie, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Email: chantal. [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000018
some affecting mainly insulin resistance, such as metformin or glitazones, others mainly affecting insulin secretion like the sulfonylureas. A recent class of oral glucose-lowering drugs are the dipeptidyl peptidase-4 (DPP-4) inhibitors, that inhibit the inactivation of glucagon-like peptide-1 and gastric inhibitory polypeptide by DPP-4, allowing glucagon-like peptide-1 and gastric inhibitory polypeptide to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Guidelines advocate initiating pharmacological glucose-lowering therapy in T2D by metformin, based on the effects of metformin on diabetes complications demonstrated in the UKPDS2 and its
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cost-efficacy profile. However, as diabetes is a progressive disease, it becomes over time increasingly difficult to manage blood glucose levels with one therapy alone. What this second oral agent should be is unclear and clinicians should choose on the basis of effectiveness, tolerability, cost, and patient profile.1 Vildagliptin is a DPP-4 inhibitor, for which efficacy as a glucose-lowering agent in patients with T2D has been demonstrated in randomized, double-blind, multicentre trials.3–8 Vildagliptin has a low risk of hypoglycemia, is weight-neutral overall, and is generally well tolerated. The Novartis-sponsored EDGE study (the observational Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) was a prospective, 1-year, worldwide, real-life observational study that compared vildagliptin to other oral antidiabetic agents in patients who failed to achieve target blood glucose levels with monotherapy.9 It was one of the largest real-life studies of T2D treatments conducted to date. The present report is a prespecified post-hoc subanalysis of the Belgian data, assessing effectiveness and tolerability of vildagliptin combinations versus all other oral antidiabetic drugs for patients enrolled in the EDGE study in Belgium (n51793).
Methods Study design Between 2008 and 2011, EDGE enrolled 45 868 patients in 27 countries from Europe, Central and Latin America, Asia, and Middle East. Adult patients (aged .18 years) with T2D who required oral combination therapy as add-on to monotherapy to reach glycemic targets were enrolled. Of these, 1793 patients were enrolled from 335 sites in Belgium. Patients were recruited in primary, secondary, as well as tertiary care centres. Patients became eligible for the study only after an add-on treatment was chosen by their physician based on the patient’s need. According to this choice, patients were included in one of two groups: vildagliptin in combination with another oral antidiabetic drug and all other oral glucose-lowering combinations, including any sulphonylurea, thiazolidinedione, glinide, alpha-glucosidase inhibitor, or metformin, but excluding any DPP-4 inhibitor. Data were collected at baseline and at any time point in the next 12 months, with a required reporting at 12 months. Further details about the study design, assessments, and data collection are provided in Mathieu et al.9
Effectiveness and tolerability endpoints The primary endpoint (PEP) was defined as the proportion of patients having a treatment response (HbA1c reduction from baseline to month 12 .0.3%) 172
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and no tolerability findings (peripheral oedema, hypoglycemic event, discontinuation due to a gastrointestinal (GI) event, or weight gain >5%).10 Patients who could not be categorized as a success or failure were considered non-evaluable. Non-evaluable patient data were considered failures in calculation of the odds ratio (OR) for success. The study also evaluated the following secondary effectiveness endpoints (SEPs): SEP 1: treatment response without any of the following tolerability findings (hypoglycemia, weight gain, oedema, or gastrointestinal complaints); SEP 2: treatment response without >3% weight gain at 12 months or hypoglycemic event; SEP 3: in patients with baseline HbA1c >7.0%, attainment of target HbA1c level of ,7.0% at month 12 endpoint, without >3% weight gain at 12 months or hypoglycemic event. Hypoglycemia was defined on the basis of symptoms suggestive of hypoglycemia that resolved promptly on the administration of oral carbohydrate. Safety was assessed by adverse event reporting and measurement of specific laboratory values. Specific attention was given to hepatic safety on the basis of signals of liver toxicity for vildagliptin in early studies. All these combined endpoints were defined in agreement with the European Medicines Agency when this post-marketing study on vildagliptin was designed.
Analysis of primary and secondary effectiveness and tolerability endpoints This post-hoc analysis provides mainly descriptive statistics. Inference is provided for primary and secondary endpoints. For these, the probability of success was analysed using a binary logistic regression model to calculate OR with 95% confidence intervals (CIs). The OR expresses odds in favor of success with vildagliptin relative to odds in favor of success with comparator oral glucose-lowering agents. In this post-hoc analysis, only the unadjusted OR is provided. HbA1c drop was adjusted with HbA1c baseline by using ANCOVA model.
Results Patient populations and baseline characteristics A total of 1793 Belgian patients at 335 study locations participated in this prospective observational study. Approximately four patients were included in the vildagliptin cohort for every patient in the comparison cohort (4 : 1 ratio, 1436 patients in the vildagliptin cohort and 357 patients in comparator cohort). One hundred and forty-one patients (109 in the vildagliptin and 32 in the comparator cohort) were excluded due to inadequate source documentation, or problems with quality or accuracy of data entry. The intention-to-treat (ITT) population, used
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for baseline demographics and safety analyses, comprised 1327 patients newly receiving dual therapy including vildagliptin (vildagliptin group) and 325 patients receiving a new non-DPP-4 inhibitor oral glucose-lowering agent added to prior monotherapy (comparator group). The PP population was a subset of the ITT population used for the analyses of effectiveness endpoints and comprised 1318 patients in the vildagliptin and 323 patients in the comparator cohort. Discontinuation occurred in 191/1327 (14.4%) ITT patients in the vildagliptin and 41/325 (12.6%) ITT patients in the comparator group. Table 1 presents baseline characteristics of the ITT population. Vildagliptin patients tended to be younger and more obese, with a higher HbA1c and a longer duration of diabetes. However, none of these differences were statistically significant. There were no differences between the two cohorts concerning cardiovascular risk factors, for instance, hypertension and lipid disorders or pre-existing macrovascular complications (around 20% had preexisting macrovascular complications). Table 2 summarizes the combination treatment initiated at enrollment. In the vast majority of patients, the index medication was metformin (98.2% in the vildagliptin group versus 77.8% in the comparator group). The most frequent combination therapy in the comparator cohort was metforminsulphonylurea (73.2%).
Primary and secondary endpoints In the Belgian population 37.8% of patients in the vildagliptin group and 32.8% of patients in the comparator group had a decrease in HbA1c of .0.3% without the predefined tolerability issues. OR (unadjusted) was 1.24 (95% CI: 0.96–1.60). Mean HbA1c change from baseline was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort. SEP 3 (reaching HbA1c,7% without >3% weight gain or hypoglycemic event) was reached in 22.0% in the vildagliptin cohort and in 19.1% in the comparator cohort. OR (unadjusted) was 1.20 (95% CI: 0.86–1.68) (Table 3).
Second-line OAD’s in real world Belgian patients
Safety analysis The incidence of adverse events was similar in the vildagliptin and comparator cohorts (14.9% and 14.5%, respectively) (Table 4). The highest incidences of reported adverse events in both cohorts were in gastrointestinal disorders and infections and infestations. The incidence of hypoglycemia was almost five times lower in the vildagliptin group (0.4% versus 1.8% in the comparator group). In both cohorts, the proportion of patients reporting serious adverse events was very low (2.7% of the overall population reported any serious adverse event). The serious adverse events were distributed evenly between vildagliptin (2.7%) and comparator-treated patients (2.5%).
Discussion EDGE is one of the largest prospective observational studies of T2D treatment reported to date.9 This study was designed to reflect real life to the maximum, gathering information on efficacy and safety of vildagliptin as a second-line glucose-lowering agent in T2D patients. Overall, the Belgian cohort reached the PEP in a lower proportion of patients (36.8% compared with 53.9% in the global EDGE population). This difference was observed both in the vildagliptin (37.8% versus 55.4% globally) and in the comparator arm (32.8% versus 51.3% globally). The difference was also present in SEP3, the most clinically relevant endpoint, with 22.1% of vildagliptin-treated patients reaching the target compared to 35.1% worldwide and 19.1% of comparator-treated patients versus 23.2% worldwide. Mean HbA1c change from baseline in Belgium was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort, which did not reach statistical significance. In the overall EDGE study, vildagliptin in combination with another therapy was shown to achieve a 1.19% reduction in HbA1c from baseline and in the comparator group there was a reduction of 0.99%. This difference was highly statistically significant (P,0.001).9 A possible explanation for the different performance of the Belgian cohort lies in the profile of the Belgian EDGE patients. The Belgian population in EDGE was substantially older (64.4 years versus 57.8 years),
Table 1 Demographic and patient baseline characteristics (ITT population) Characteristic
Vildagliptin
Comparator
Total
Mean6SD or n (%)
n51327
n5325
N51652
Age (years) Gender, n (%) Male Female BMI (kg/m2) Baseline HbA1c (%) Duration of T2DM (years)
64.1610.8
65.7611.1
64.4610.9
763 (57.5) 564 (42.5) 30.465.5 8.461.3 6.965.3
171 (52.6) 154 (47.4) 29.765.6 8.061.3 6.665.2
934 (56.5) 718 (43.5) 30.365.5 8.361.3 6.865.3
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Table 2 Medication distribution (ITT population) Vildagliptin cohort* (n51326)
Comparator cohort (n5325)
Treatments
Patients, n (%)
Treatments
Patients, n (%)
Index/add-on therapy TZD/vildagliptin SU/vildagliptin Metformin/vildagliptin Glinide/vildagliptin
2 (0.2) 20 (1.5) 1302 (98.1) 2 (0.2)
Index/add-on therapy SU/TZD Metformin/TZD Metformin/SU Glinide/SU Glinide/metformin
3 (0.9) 15 (4.6) 238 (73.2) 5 (1.5) 64 (19.8)
Note: *For one patient in the vildagliptin cohort, it was not possible to identify the index medication.
more obese (BMI: 30.3 kg/m2 versus 29.0 kg/m2), had a longer history of diabetes (6.8 years versus 5.5 years) with a poorer baseline control (HbA1c 8.3% versus 8.2% worldwide) and had more diabetes complications (27.6% versus 7.7%) than the overall study population, suggesting more advanced diabetes. Another important contributor to the difference may be ethnicity. Whereas the Belgian population was mostly Caucasian (97.6%), only 47.8% of patients were Caucasian in global EDGE. When subanalysing regional differences worldwide, vildagliptin seemed to be more efficacious in Latin America, India, and the Middle East. Differences in underlying mechanisms leading to T2D, in particular the contribution of beta-cell failure, are known to exist in different ethnic populations and are known to contribute to differences in response to pharmaceutical agents.11 Finally, a difference in ‘reporting eagerness’ may exist in different areas of the world, considering the strikingly higher adverse event rates reported in EDGE-Belgium (14.8% versus 5.4% worldwide). The strength of the EDGE study and the Belgian substudy is that it brings real-life data on the status of diabetes care globally and in our region. EDGE sadly confirms that tight glycemic control is difficult to establish. Despite the international guidelines to intensify glucose-lowering therapy in a timely
manner, a major finding of EDGE was the confirmation of the high prevalence of suboptimal glycemic control in patients with T2D in real life. Many patients are still not achieving glycemic goals, despite an observed trend towards better control. Clinical inertia is present worldwide, average baseline HbA1c before adding second-line therapy is 7.961.3% in Europe and worldwide 8.261.3%.9 Belgium scored even worse with a mean baseline HbA1c of 8.361.3%. This is an important finding indicating that in particular in the early stages of T2D, Belgian general practitioners and endocrinologists are not aggressive enough in the treatment of diabetes. The Belgian substudy of EDGE therefore emphasizes the need to spread chronic disease management initiatives that have been implemented in our country to improve T2D care (e.g. Zorgtrajecten/Trajets de soins) to earlier stages of the disease. In particular, increasing efforts will be needed to implement the current guidelines. Incretin-based agents have a peculiar mechanism of action associated with lack of hypoglycemia and no weight gain; these characteristics may facilitate early therapy intensification and help to attain established goals.12 The EDGE study, and in particular the Belgian substudy, has several weaknesses, mainly ensuing from its strength, namely, its size and real world nature. First, because a real-life reflection was sought,
Table 3 Primary and secondary efficacy and tolerability endpoints
Primary end point (PEP) Decrease HbA1 .0.3%, no hypoglycemia, no weight gain, no discontinuation for GI events, no peripheral oedema Secondary end point 3 (SEP 3) HbA1c,7% at EOS without proven hypoglycemic events or weight gain >3% population and baseline HbA1c.7%
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Success rate comparator
n51318 (PEP)
n5323 (PEP)
n51221 (SEP)
n5262 (SEP)
OR unadjusted (95% CI)
498 (37.8)
106 (32.8)
1.24 (0.96–1.60)
269 (22.0)
50 (19.1)
1.20 (0.86–1.68)
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Table 4 Adverse events by primary system class and cohort (ITT population) Primary system organ class (SOC)
Total Vildagliptin
Comparator
n (%) Blood and lymphatic system disorders Cardiac disorders Ear and labyrinth disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning, and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant, and unspecified Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders Social circumstances Surgical and medical procedures Vascular disorders
N5375 2 (0.7) 12 (4.0) 7 (2.3) 6 (2.0) 38 (12.7) 14 (4.7) 1 (0.3) 3 (1.0) 66 (22.0) 13 (4.3) 10 (3.3) 15 (5.0) 24 (8.0) 11 (3.7) 26 (8.7) 7 (2.3) 4 (1.3) 3 (1.0) 14 (4.7) 14 (4.7) 1 (0.3) 1 (0.3) 8 (2.7)
0 2 (2. 7) 0 1 (1.3) 11 (14.7) 5 (6.7) 1 (1.3) 1 (1.3) 14 (18.7) 3 (4.0) 1 (1.3) 8 (10.7) 7 (9.3) 0 4 (5.3) 3 (4.0) 0 2 (2.7) 5 (6.7) 5 (6.7) 0 0 2 (2.7)
2 (0.53) 14 (3.73) 7 (1.87) 7 (1.87) 49 (13.07) 19 (5.07) 2 (0.53) 4 (1.07) 80 (21.33) 16 (4.27) 11 (2.93) 23 (6.13) 31 (8.27) 11 (2.93) 30 (8.0) 10 (2.67) 4 (1.07) 5 (1.33) 19 (5.07) 19 (5.07) 1 (0.27) 1 (0.27) 10 (2.67)
Note: Adverse events were coded according to MedDRA version 14.0. Primary SOCs are presented alphabetically. A patient with multiple occurrences of an AE under one cohort is counted only once in the AE category. A patient with multiple adverse events within a primary system organ class is counted only once in the total row for that cohort.
EDGE was not carried out in the typical ‘clinical trial’ specialist centres, but in smaller centres and in primary care practices, involving a large number of physicians. As a consequence of this spread, the absence of financial incentives to intensively monitor the patients and the systematic absence of study nurses, incomplete data were more frequent than in randomized controlled trials. Discontinuation occurred in 191/1327 (14.4%) ITT patients in the vildagliptin and 41/325 (12.6%) ITT patients in the comparator group. However, the investigators handled this phenomenon with the utmost rigor as patients with missing data were considered failures, probably underestimating rather than overestimating obtained effectiveness results for vildagliptin-treated patients. Second, great care was taken to leave full therapeutic freedom to prescribing physicians, as patients were only included into the study after the choice of the second agent was made. Still, study inclusion was not balanced, with approximately four patients accrued in the vildagliptin cohort for every patient in comparison cohort (4 : 1 ratio, 1436 patients in the vildagliptin cohort and 357 patients in comparator cohort). Worldwide ratio was 2 : 1 favoring vildagliptin. This imbalance does not reflect the reality in prescribing of DPP-4 inhibitors worldwide and surely not in our country. One explanation for this could be that participating physicians were more eager to observe the action of the new drug.
In conclusion, this study demonstrated that in analogy to findings in the worldwide EDGE study, vildagliptin is both efficacious and safe when used as a second oral glucose-lowering agent in the Belgian cohort of type 2 diabetic patients. In clinical practice, vildagliptin thus proves a valid option for use in combination with metformin or any other oral glucose-lowering drug in patients with T2D who require combination therapy. Treatment with vildagliptin is simple with two doses of 50 mg per day, without need of titration or home blood glucose monitoring. It can be used in patients with renal impairment in a dose of 50 mg per day. In Belgium, vildagliptin (GalvusH) is currently reimbursed for the treatment of T2D after treatment failure (HbA1c.7% or 53 mmol/mol) with monotherapy with metformin or sulphonylurea (intolerance or contraindication for metformin) during three months or in patients as monotherapy with KDOQI stage 4 or 5 kidney disease. The EDGE-Belgium substudy importantly confirms the existence of clinical inertia leading to insufficient intensification of glucose-lowering therapy in type 2 diabetic patients failing monotherapy of oral antidiabetic agents.
Disclaimer Statements Contributors Funding EDGE was funded and monitored by Novartis Pharma AG
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Conflicts of interest Daci Evis is the current Therapeutic Area Head, cardiovascular and metabolism, Integrated Hospital Care, Novartis Pharma Belgium. Ethics approval The protocol for EDGE was approved by all local Independent Review Boards (IRBs) or Ethics Committees.
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References 1 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79. 2 UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65. 3 Bader G, Schweizer A. Vildagliptin more effectively achieves a composite endpoint of HbA1c ,7% without hypoglycaemia or weight gain compared with SUYs: a pooled analysis of clinical trials. Diabetologia. 2012;55(Suppl 1):S356-Abstract 862. 4 Bolli G, Dotta F, Colin L, Minic B, Goodman M. Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Obes Metab. 2009;11:589–5. 5 Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to
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metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2008;10:82–90. Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahre´n B, Byiers S, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2009;11:157–66. Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet Med. 2010;27:318–26. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9:166–74. Mathieu C, Barnett AH, Brath H, Conget I, de Castro JJ, Go¨ke R, et al. Effectiveness and tolerability of oral glucose-lowering therapies in type 2 diabetes. A real-life worldwide observational study (EDGE). Int J Clin Pract. 2013;67:947–56. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight adults and obesity in adults. Bethesda, MD: NIH; 1998. Available from: http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.htm accessed 07 June 2013. Bhopal RS. A four-stage model explaining the higher risk of Type 2 diabetes mellitus in South Asians compared with European populations. Diabet Med. 2013;30:35–42. Nicolucci A, Rossi MC. Incretine-based therapies: a new potential treatment approach to overcome clinical inertia in type 2 diabetes. Acta Biomed. 2008;79:184–91.
Department of Endocrinology, UZ Leuven, Belgium, 2N.V. Novartis Pharma S.A., Vilvoorde, Belgium
Aim: To assess the efficacy and safety of vildagliptin versus other oral glucose-lowering drugs added to antidiabetic monotherapy in Belgian patients with type 2 diabetes mellitus, in comparison to the global EDGE study results. Methods: This is a pre-specified post-hoc subanalysis of the Belgian patient cohort from a worldwide 1-year observational study that compared the effectiveness and tolerability of vildagliptin to other oral antidiabetic agents in type 2 diabetes patients failing monotherapy with oral glucose-lowering agents (EDGE). A total of 1793 Belgian patients were enrolled. Physicians could add any oral antidiabetic drug and patients entered either into the vildagliptin or the comparator cohort. The primary effectiveness and tolerability endpoint was defined as the proportion of patients having a treatment response (HbA1c reduction from baseline to month 12 endpoint .0.3%) without hypoglycemia, weight gain, peripheral oedema, or gastrointestinal side-effects. Results: In the Belgian population, 37.8% of patients in the vildagliptin group and 32.8% in the comparator group had a decrease in HbA1c of .0.3% without the predefined tolerability issues of hypoglycemia, weight gain, oedema or, gastrointestinal complaints (primary endpoint), resulting in an unadjusted odds ratio of 1.24 (95% CI: 0.96–1.61). Mean HbA1c change from baseline was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort. Overall, vildagliptin was well tolerated with similarly low incidences of total adverse events (14.9% versus 14.5% in the compactor group) and serious adverse events (2.7% versus 2.5% in the comparator group). Conclusion: In this EDGE subgroup of Belgian patients with type 2 diabetes who do not achieve the glycemic targets with monotherapy, a similar trend as in the global EDGE study was observed. Adding vildagliptin as a second oral glucose-lowering agent resulted in lowering HbA1c to ,7% without weight gain, hypoglycemia or peripheral oedema in a higher proportion of patients than comparator oral antidiabetic drugs, with no differences in the reported number of adverse events. Keywords: Type 2 diabetes mellitus, Vildagliptin, Observational study, Add-on therapy
Introduction Type 2 diabetes (T2D) mellitus is a chronic disease characterized by insulin resistance and relative insulin deficiency.1 Current clinical practice guidelines recommend a stepwise treatment pathway for diabetic patients.1 Initial management includes lifestyle changes, aimed at increasing exercise and dietary modification. If blood glucose levels are not adequately controlled by these measures, pharmacological intervention will be necessary. At present, different classes of oral glucose-lowering agents are available,
Correspondence to: C. Mathieu, I.G. – Endocrinologie, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Email: chantal. [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000018
some affecting mainly insulin resistance, such as metformin or glitazones, others mainly affecting insulin secretion like the sulfonylureas. A recent class of oral glucose-lowering drugs are the dipeptidyl peptidase-4 (DPP-4) inhibitors, that inhibit the inactivation of glucagon-like peptide-1 and gastric inhibitory polypeptide by DPP-4, allowing glucagon-like peptide-1 and gastric inhibitory polypeptide to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Guidelines advocate initiating pharmacological glucose-lowering therapy in T2D by metformin, based on the effects of metformin on diabetes complications demonstrated in the UKPDS2 and its
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cost-efficacy profile. However, as diabetes is a progressive disease, it becomes over time increasingly difficult to manage blood glucose levels with one therapy alone. What this second oral agent should be is unclear and clinicians should choose on the basis of effectiveness, tolerability, cost, and patient profile.1 Vildagliptin is a DPP-4 inhibitor, for which efficacy as a glucose-lowering agent in patients with T2D has been demonstrated in randomized, double-blind, multicentre trials.3–8 Vildagliptin has a low risk of hypoglycemia, is weight-neutral overall, and is generally well tolerated. The Novartis-sponsored EDGE study (the observational Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) was a prospective, 1-year, worldwide, real-life observational study that compared vildagliptin to other oral antidiabetic agents in patients who failed to achieve target blood glucose levels with monotherapy.9 It was one of the largest real-life studies of T2D treatments conducted to date. The present report is a prespecified post-hoc subanalysis of the Belgian data, assessing effectiveness and tolerability of vildagliptin combinations versus all other oral antidiabetic drugs for patients enrolled in the EDGE study in Belgium (n51793).
Methods Study design Between 2008 and 2011, EDGE enrolled 45 868 patients in 27 countries from Europe, Central and Latin America, Asia, and Middle East. Adult patients (aged .18 years) with T2D who required oral combination therapy as add-on to monotherapy to reach glycemic targets were enrolled. Of these, 1793 patients were enrolled from 335 sites in Belgium. Patients were recruited in primary, secondary, as well as tertiary care centres. Patients became eligible for the study only after an add-on treatment was chosen by their physician based on the patient’s need. According to this choice, patients were included in one of two groups: vildagliptin in combination with another oral antidiabetic drug and all other oral glucose-lowering combinations, including any sulphonylurea, thiazolidinedione, glinide, alpha-glucosidase inhibitor, or metformin, but excluding any DPP-4 inhibitor. Data were collected at baseline and at any time point in the next 12 months, with a required reporting at 12 months. Further details about the study design, assessments, and data collection are provided in Mathieu et al.9
Effectiveness and tolerability endpoints The primary endpoint (PEP) was defined as the proportion of patients having a treatment response (HbA1c reduction from baseline to month 12 .0.3%) 172
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and no tolerability findings (peripheral oedema, hypoglycemic event, discontinuation due to a gastrointestinal (GI) event, or weight gain >5%).10 Patients who could not be categorized as a success or failure were considered non-evaluable. Non-evaluable patient data were considered failures in calculation of the odds ratio (OR) for success. The study also evaluated the following secondary effectiveness endpoints (SEPs): SEP 1: treatment response without any of the following tolerability findings (hypoglycemia, weight gain, oedema, or gastrointestinal complaints); SEP 2: treatment response without >3% weight gain at 12 months or hypoglycemic event; SEP 3: in patients with baseline HbA1c >7.0%, attainment of target HbA1c level of ,7.0% at month 12 endpoint, without >3% weight gain at 12 months or hypoglycemic event. Hypoglycemia was defined on the basis of symptoms suggestive of hypoglycemia that resolved promptly on the administration of oral carbohydrate. Safety was assessed by adverse event reporting and measurement of specific laboratory values. Specific attention was given to hepatic safety on the basis of signals of liver toxicity for vildagliptin in early studies. All these combined endpoints were defined in agreement with the European Medicines Agency when this post-marketing study on vildagliptin was designed.
Analysis of primary and secondary effectiveness and tolerability endpoints This post-hoc analysis provides mainly descriptive statistics. Inference is provided for primary and secondary endpoints. For these, the probability of success was analysed using a binary logistic regression model to calculate OR with 95% confidence intervals (CIs). The OR expresses odds in favor of success with vildagliptin relative to odds in favor of success with comparator oral glucose-lowering agents. In this post-hoc analysis, only the unadjusted OR is provided. HbA1c drop was adjusted with HbA1c baseline by using ANCOVA model.
Results Patient populations and baseline characteristics A total of 1793 Belgian patients at 335 study locations participated in this prospective observational study. Approximately four patients were included in the vildagliptin cohort for every patient in the comparison cohort (4 : 1 ratio, 1436 patients in the vildagliptin cohort and 357 patients in comparator cohort). One hundred and forty-one patients (109 in the vildagliptin and 32 in the comparator cohort) were excluded due to inadequate source documentation, or problems with quality or accuracy of data entry. The intention-to-treat (ITT) population, used
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for baseline demographics and safety analyses, comprised 1327 patients newly receiving dual therapy including vildagliptin (vildagliptin group) and 325 patients receiving a new non-DPP-4 inhibitor oral glucose-lowering agent added to prior monotherapy (comparator group). The PP population was a subset of the ITT population used for the analyses of effectiveness endpoints and comprised 1318 patients in the vildagliptin and 323 patients in the comparator cohort. Discontinuation occurred in 191/1327 (14.4%) ITT patients in the vildagliptin and 41/325 (12.6%) ITT patients in the comparator group. Table 1 presents baseline characteristics of the ITT population. Vildagliptin patients tended to be younger and more obese, with a higher HbA1c and a longer duration of diabetes. However, none of these differences were statistically significant. There were no differences between the two cohorts concerning cardiovascular risk factors, for instance, hypertension and lipid disorders or pre-existing macrovascular complications (around 20% had preexisting macrovascular complications). Table 2 summarizes the combination treatment initiated at enrollment. In the vast majority of patients, the index medication was metformin (98.2% in the vildagliptin group versus 77.8% in the comparator group). The most frequent combination therapy in the comparator cohort was metforminsulphonylurea (73.2%).
Primary and secondary endpoints In the Belgian population 37.8% of patients in the vildagliptin group and 32.8% of patients in the comparator group had a decrease in HbA1c of .0.3% without the predefined tolerability issues. OR (unadjusted) was 1.24 (95% CI: 0.96–1.60). Mean HbA1c change from baseline was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort. SEP 3 (reaching HbA1c,7% without >3% weight gain or hypoglycemic event) was reached in 22.0% in the vildagliptin cohort and in 19.1% in the comparator cohort. OR (unadjusted) was 1.20 (95% CI: 0.86–1.68) (Table 3).
Second-line OAD’s in real world Belgian patients
Safety analysis The incidence of adverse events was similar in the vildagliptin and comparator cohorts (14.9% and 14.5%, respectively) (Table 4). The highest incidences of reported adverse events in both cohorts were in gastrointestinal disorders and infections and infestations. The incidence of hypoglycemia was almost five times lower in the vildagliptin group (0.4% versus 1.8% in the comparator group). In both cohorts, the proportion of patients reporting serious adverse events was very low (2.7% of the overall population reported any serious adverse event). The serious adverse events were distributed evenly between vildagliptin (2.7%) and comparator-treated patients (2.5%).
Discussion EDGE is one of the largest prospective observational studies of T2D treatment reported to date.9 This study was designed to reflect real life to the maximum, gathering information on efficacy and safety of vildagliptin as a second-line glucose-lowering agent in T2D patients. Overall, the Belgian cohort reached the PEP in a lower proportion of patients (36.8% compared with 53.9% in the global EDGE population). This difference was observed both in the vildagliptin (37.8% versus 55.4% globally) and in the comparator arm (32.8% versus 51.3% globally). The difference was also present in SEP3, the most clinically relevant endpoint, with 22.1% of vildagliptin-treated patients reaching the target compared to 35.1% worldwide and 19.1% of comparator-treated patients versus 23.2% worldwide. Mean HbA1c change from baseline in Belgium was 20.81% in the vildagliptin cohort and 20.75% in the comparator cohort, which did not reach statistical significance. In the overall EDGE study, vildagliptin in combination with another therapy was shown to achieve a 1.19% reduction in HbA1c from baseline and in the comparator group there was a reduction of 0.99%. This difference was highly statistically significant (P,0.001).9 A possible explanation for the different performance of the Belgian cohort lies in the profile of the Belgian EDGE patients. The Belgian population in EDGE was substantially older (64.4 years versus 57.8 years),
Table 1 Demographic and patient baseline characteristics (ITT population) Characteristic
Vildagliptin
Comparator
Total
Mean6SD or n (%)
n51327
n5325
N51652
Age (years) Gender, n (%) Male Female BMI (kg/m2) Baseline HbA1c (%) Duration of T2DM (years)
64.1610.8
65.7611.1
64.4610.9
763 (57.5) 564 (42.5) 30.465.5 8.461.3 6.965.3
171 (52.6) 154 (47.4) 29.765.6 8.061.3 6.665.2
934 (56.5) 718 (43.5) 30.365.5 8.361.3 6.865.3
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Table 2 Medication distribution (ITT population) Vildagliptin cohort* (n51326)
Comparator cohort (n5325)
Treatments
Patients, n (%)
Treatments
Patients, n (%)
Index/add-on therapy TZD/vildagliptin SU/vildagliptin Metformin/vildagliptin Glinide/vildagliptin
2 (0.2) 20 (1.5) 1302 (98.1) 2 (0.2)
Index/add-on therapy SU/TZD Metformin/TZD Metformin/SU Glinide/SU Glinide/metformin
3 (0.9) 15 (4.6) 238 (73.2) 5 (1.5) 64 (19.8)
Note: *For one patient in the vildagliptin cohort, it was not possible to identify the index medication.
more obese (BMI: 30.3 kg/m2 versus 29.0 kg/m2), had a longer history of diabetes (6.8 years versus 5.5 years) with a poorer baseline control (HbA1c 8.3% versus 8.2% worldwide) and had more diabetes complications (27.6% versus 7.7%) than the overall study population, suggesting more advanced diabetes. Another important contributor to the difference may be ethnicity. Whereas the Belgian population was mostly Caucasian (97.6%), only 47.8% of patients were Caucasian in global EDGE. When subanalysing regional differences worldwide, vildagliptin seemed to be more efficacious in Latin America, India, and the Middle East. Differences in underlying mechanisms leading to T2D, in particular the contribution of beta-cell failure, are known to exist in different ethnic populations and are known to contribute to differences in response to pharmaceutical agents.11 Finally, a difference in ‘reporting eagerness’ may exist in different areas of the world, considering the strikingly higher adverse event rates reported in EDGE-Belgium (14.8% versus 5.4% worldwide). The strength of the EDGE study and the Belgian substudy is that it brings real-life data on the status of diabetes care globally and in our region. EDGE sadly confirms that tight glycemic control is difficult to establish. Despite the international guidelines to intensify glucose-lowering therapy in a timely
manner, a major finding of EDGE was the confirmation of the high prevalence of suboptimal glycemic control in patients with T2D in real life. Many patients are still not achieving glycemic goals, despite an observed trend towards better control. Clinical inertia is present worldwide, average baseline HbA1c before adding second-line therapy is 7.961.3% in Europe and worldwide 8.261.3%.9 Belgium scored even worse with a mean baseline HbA1c of 8.361.3%. This is an important finding indicating that in particular in the early stages of T2D, Belgian general practitioners and endocrinologists are not aggressive enough in the treatment of diabetes. The Belgian substudy of EDGE therefore emphasizes the need to spread chronic disease management initiatives that have been implemented in our country to improve T2D care (e.g. Zorgtrajecten/Trajets de soins) to earlier stages of the disease. In particular, increasing efforts will be needed to implement the current guidelines. Incretin-based agents have a peculiar mechanism of action associated with lack of hypoglycemia and no weight gain; these characteristics may facilitate early therapy intensification and help to attain established goals.12 The EDGE study, and in particular the Belgian substudy, has several weaknesses, mainly ensuing from its strength, namely, its size and real world nature. First, because a real-life reflection was sought,
Table 3 Primary and secondary efficacy and tolerability endpoints
Primary end point (PEP) Decrease HbA1 .0.3%, no hypoglycemia, no weight gain, no discontinuation for GI events, no peripheral oedema Secondary end point 3 (SEP 3) HbA1c,7% at EOS without proven hypoglycemic events or weight gain >3% population and baseline HbA1c.7%
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Success rate comparator
n51318 (PEP)
n5323 (PEP)
n51221 (SEP)
n5262 (SEP)
OR unadjusted (95% CI)
498 (37.8)
106 (32.8)
1.24 (0.96–1.60)
269 (22.0)
50 (19.1)
1.20 (0.86–1.68)
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Table 4 Adverse events by primary system class and cohort (ITT population) Primary system organ class (SOC)
Total Vildagliptin
Comparator
n (%) Blood and lymphatic system disorders Cardiac disorders Ear and labyrinth disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning, and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant, and unspecified Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders Social circumstances Surgical and medical procedures Vascular disorders
N5375 2 (0.7) 12 (4.0) 7 (2.3) 6 (2.0) 38 (12.7) 14 (4.7) 1 (0.3) 3 (1.0) 66 (22.0) 13 (4.3) 10 (3.3) 15 (5.0) 24 (8.0) 11 (3.7) 26 (8.7) 7 (2.3) 4 (1.3) 3 (1.0) 14 (4.7) 14 (4.7) 1 (0.3) 1 (0.3) 8 (2.7)
0 2 (2. 7) 0 1 (1.3) 11 (14.7) 5 (6.7) 1 (1.3) 1 (1.3) 14 (18.7) 3 (4.0) 1 (1.3) 8 (10.7) 7 (9.3) 0 4 (5.3) 3 (4.0) 0 2 (2.7) 5 (6.7) 5 (6.7) 0 0 2 (2.7)
2 (0.53) 14 (3.73) 7 (1.87) 7 (1.87) 49 (13.07) 19 (5.07) 2 (0.53) 4 (1.07) 80 (21.33) 16 (4.27) 11 (2.93) 23 (6.13) 31 (8.27) 11 (2.93) 30 (8.0) 10 (2.67) 4 (1.07) 5 (1.33) 19 (5.07) 19 (5.07) 1 (0.27) 1 (0.27) 10 (2.67)
Note: Adverse events were coded according to MedDRA version 14.0. Primary SOCs are presented alphabetically. A patient with multiple occurrences of an AE under one cohort is counted only once in the AE category. A patient with multiple adverse events within a primary system organ class is counted only once in the total row for that cohort.
EDGE was not carried out in the typical ‘clinical trial’ specialist centres, but in smaller centres and in primary care practices, involving a large number of physicians. As a consequence of this spread, the absence of financial incentives to intensively monitor the patients and the systematic absence of study nurses, incomplete data were more frequent than in randomized controlled trials. Discontinuation occurred in 191/1327 (14.4%) ITT patients in the vildagliptin and 41/325 (12.6%) ITT patients in the comparator group. However, the investigators handled this phenomenon with the utmost rigor as patients with missing data were considered failures, probably underestimating rather than overestimating obtained effectiveness results for vildagliptin-treated patients. Second, great care was taken to leave full therapeutic freedom to prescribing physicians, as patients were only included into the study after the choice of the second agent was made. Still, study inclusion was not balanced, with approximately four patients accrued in the vildagliptin cohort for every patient in comparison cohort (4 : 1 ratio, 1436 patients in the vildagliptin cohort and 357 patients in comparator cohort). Worldwide ratio was 2 : 1 favoring vildagliptin. This imbalance does not reflect the reality in prescribing of DPP-4 inhibitors worldwide and surely not in our country. One explanation for this could be that participating physicians were more eager to observe the action of the new drug.
In conclusion, this study demonstrated that in analogy to findings in the worldwide EDGE study, vildagliptin is both efficacious and safe when used as a second oral glucose-lowering agent in the Belgian cohort of type 2 diabetic patients. In clinical practice, vildagliptin thus proves a valid option for use in combination with metformin or any other oral glucose-lowering drug in patients with T2D who require combination therapy. Treatment with vildagliptin is simple with two doses of 50 mg per day, without need of titration or home blood glucose monitoring. It can be used in patients with renal impairment in a dose of 50 mg per day. In Belgium, vildagliptin (GalvusH) is currently reimbursed for the treatment of T2D after treatment failure (HbA1c.7% or 53 mmol/mol) with monotherapy with metformin or sulphonylurea (intolerance or contraindication for metformin) during three months or in patients as monotherapy with KDOQI stage 4 or 5 kidney disease. The EDGE-Belgium substudy importantly confirms the existence of clinical inertia leading to insufficient intensification of glucose-lowering therapy in type 2 diabetic patients failing monotherapy of oral antidiabetic agents.
Disclaimer Statements Contributors Funding EDGE was funded and monitored by Novartis Pharma AG
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Conflicts of interest Daci Evis is the current Therapeutic Area Head, cardiovascular and metabolism, Integrated Hospital Care, Novartis Pharma Belgium. Ethics approval The protocol for EDGE was approved by all local Independent Review Boards (IRBs) or Ethics Committees.
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