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Alfred Penfornis,1 Béatrice Fiquet,2 Jean Frédéric Blicklé,3 Sylvie Dejager2,4 1Department of Endocrinology and Diabetology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes Cedex, France; 2Clinical Affairs, Novartis Pharma SAS, Rueil-Malmaison, France; 3Department of Internal Medicine and Diabetology, Strasbourg University Hospital, Strasbourg, France; 4Department of Diabetology, Metabolism and Endocrinology, Pitié-Salpétrière Hospital, Paris, France Background: Few data exist examining the management of elderly patients with type 2 diabetes mellitus and renal impairment (RI). This observational study assessed the therapeutic management of this fragile population. Methods: Cross-sectional study: data from 980 diabetic patients ≥75 years with renal disease are presented. Results: Patients had a mean age of 81 years (range 75–101) with long-standing diabetes (15.4 years) often complicated (half with macrovascular disease). Mean estimated glomerular filtration rate was 43 mL/min/1.73 m2 and 20% had severe RI. Mean hemoglobin A1c was 7.4%. Anti-diabetic therapy was oral based for 51% of patients (60% $2 oral anti-diabetic drugs [OAD]) and insulin based for 49% (combined with OAD in 59%). OAD included metformin (47%), sulfonylureas (26%), glinides (19%), and DPP-4 inhibitors (31%). Treatments were adjusted to increasing RI, with less use of metformin, sulfonylureas, and DPP-4 inhibitors, and more glinides and insulin in severe RI. In all, 579 (60%) of these elderly patients with comorbidities had hemoglobin A1c

Bruno Detournay,1 Serge Halimi,2,3 Julien Robert,1 Céline Deschaseaux,4 Sylvie Dejager5,6 1Cemka-Eval, Bourg-la Reine, France; 2Department of Diabetology, Endocrinology and Nutrition, Grenoble University Hospital Center, Grenoble, France; 3University Joseph Fourier, Grenoble, France; 4Novartis Pharma SAS, Market Access Department, Rueil-Malmaison, France; 5Novartis Pharma SAS, Medical and Scientific Affairs, Rueil Malmaison, France; 6Department of Diabetology, Metabolism and Endocrinology, Pitié-Salpétrière Hospital, Paris, France Aim: We aimed to compare the frequency of severe hypoglycemia leading to hospitalization (HH) and emergency visits (EV) for any cause in patients with type 2 diabetes mellitus exposed to dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4-i) versus those exposed to insulin secretagogues (IS; sulfonylureas or glinides). Methods: Data were extracted from the EGB (Echantillon Généraliste des Bénéficiaires) database, comprising a representative sample of ~1% of patients registered in the French National Health Insurance System (~600,000 patients). Type 2 diabetes mellitus patients exposed to regimens containing either a DPP4-i (excluding treatment with IS, insulin, or glucagon-like peptide 1 analog) or IS (excluding treatment with insulin and any incretin therapy) between 2009 and 2012 were selected. HH and EV during the exposure periods were identified in both cohorts. A similar analysis was conducted considering vildagliptin alone versus IS. Comparative analyses adjusting for covariates within the model (subjects matched for key characteristics) and using multinomial regression models were performed. Results: Overall, 7,152 patients exposed to any DPP4-i and 1,440 patients exposed to vildagliptin were compared to 10,019 patients exposed to IS. Eight patients (0.11%) from the DPP4-i cohort and none from the vildagliptin cohort (0.0%) were hospitalized for hypoglycemia versus 130 patients (1.30%) from the IS cohort (138 hospitalizations) (P=0.02 and P

Martine Duclos,1,2 Sylvie Dejager,3,4 Nicolas Postel-Vinay,5 Sylvie di Nicola,6 Stéphane Quéré,7 Béatrice Fiquet4,5 1Department of Sport Medicine and Functional Explorations, University-Hospital (CHU), G Montpied Hospital; INRA, UNH, CRNH Auvergne, 2Nutrition Department, University of Auvergne, Clermont-Ferrand, Auvergne, 3Department of Endocrinology and Metabolism, La Pitié-Salpétrière Hospital, Paris, 4Clinical and Scientific Affairs, Novartis Pharma SAS, Rueil-Malmaison, 5Department of Hypertension, Georges Pompidou European Hospital, Paris, 6Biostatistics, Inferential, Paris, 7Biostatistics, Novartis Pharma SAS, Rueil-Malmaison, France Background: Although physical activity (PA) is key in the management of type 2 diabetes (T2DM) and hypertension, it is difficult to implement in practice. Methods: Cross-sectional, observational study. Participating physicians were asked to recruit two active and four inactive patients, screened with the Ricci-Gagnon (RG) self-questionnaire (active if score ≥16). Patients subsequently completed the International Physical Activity Questionnaire. The objective was to assess the achievement of individualized glycated hemoglobin and blood pressure goals (

Alfred Penfornis,1 Jean Frédéric Blicklé,2 Béatrice Fiquet,3 Stéphane Quéré,4 Sylvie Dejager3 1Department of Endocrinology-Metabolism and Diabetology-Nutrition, Jean Minjoz Hospital, University of Franche-Comté, Besançon, France; 2Department of Internal Medicine and Diabetology, Strasbourg University Hospital, Strasbourg, France; 3Clinical Affairs, Novartis Pharma SAS, Rueil-Malmaison, France; 4BioStatistics, Novartis Pharma SAS, Rueil-Malmaison, France Background and aim: Chronic kidney disease (CKD) is frequent in type 2 diabetes mellitus (T2DM), and therapeutic management of diabetes is more challenging in patients with renal impairment (RI). The place of metformin is of particular interest since most scientific societies now recommend using half the dosage in moderate RI and abstaining from use in severe RI, while the classic contraindication with RI has not been removed from the label. This study aimed to assess the therapeutic management, in particular the use of metformin, of T2DM patients with CKD in real life. Methods: This was a French cross-sectional observational study: 3,704 patients with T2DM diagnosed for over 1 year and pharmacologically treated were recruited in two cohorts (two-thirds were considered to have renal disease [CKD patients] and one-third were not [non-CKD patients]) by 968 physicians (81% general practitioners) in 2012. Results: CKD versus non-CKD patients were significantly older with longer diabetes history, more diabetic complications, and less strict glycemic control (mean glycated hemoglobin [HbA1c] 7.5% versus 7.1%; 25% of CKD patients had HbA1c ≥8% versus 15% of non-CKD patients). Fifteen percent of CKD patients had severe RI, and 66% moderate RI. Therapeutic management of T2DM was clearly distinct in CKD, with less use of metformin (62% versus 86%) but at similar mean daily doses (~2 g/d). Of patients with severe RI, 33% were still treated with metformin, at similar doses. For other oral anti-diabetics, a distinct pattern of use was seen across renal function (RF): use of sulfonylureas (32%, 31%, and 20% in normal RF, moderate RI, and severe RI, respectively) and DPP4-i (dipeptidyl peptidase-4 inhibitors) (41%, 36%, and 25%, respectively) decreased with RF, while that of glinides increased (8%, 14%, and 18%, respectively). CKD patients were more frequently treated with insulin (40% versus 16% of non-CKD patients), and use of insulin increased with deterioration of RF (19%, 39%, and 61% of patients with normal RF, moderate RI, and severe RI, respectively). Treatment was modified at the end of the study-visit in 34% of CKD patients, primarily to stop or reduce metformin. However, metformin was stopped in only 40% of the severe RI patients. Conclusion: Despite a fairly good detection of CKD in patients with T2DM, RI was insufficiently taken into account for adjusting anti-diabetic treatment. Keywords: therapeutic management, metformin, sulfonylureas, renal disease, type 2 diabetes

Anja Schweizer,1 Serge Halimi,2,3 Sylvie Dejager4 1Novartis Pharma AG, Basel, Switzerland; 2Department of Diabetology, Endocrinology and Nutrition, University Hospital of Grenoble, France; 3Joseph Fourier University, Grenoble, France; 4Novartis Pharma SAS, Rueil-Malmaison, France Abstract: A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting. Keywords: dipeptidyl peptidase-4, incretin, type 2 diabetes mellitus, hypoglycemia

Sylvie Dejager,1 Anja Schweizer,2 James E Foley31Novartis Pharma SAS, Rueil Malmaison, France; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAAbstract: The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, vildagliptin, as monotherapy have been widely confirmed in a large body of clinical studies of up to 2 years’ duration in various populations with type 2 diabetes mellitus. This paper reviews the data supporting the use of vildagliptin in monotherapy. Consideration based on baseline glycated hemoglobin levels and age is given to patient segments where metformin is not appropriate. In addition, although prediabetes is not an indication, this manuscript briefly reviews some of the existing data showing that the mechanisms at work in diabetic populations are active in patients currently classified as prediabetic, with impaired glucose tolerance or impaired fasting glucose. Finally, the rationale for vildagliptin dosing frequency in monotherapy is discussed. In summary, this review aims to define where in community practice the use of vildagliptin as monotherapy is most desirable, focusing on segments of the population with type 2 diabetes mellitus that might receive the greatest benefit from vildagliptin in the management of their disease.Keywords: vildagliptin, type 2 diabetes, dipeptidyl peptidase-4 inhibitors, monotherapy, elderly

Anja Schweizer1, Sylvie Dejager2, James E Foley3, Wolfgang Kothny31Novartis Pharma AG, Basel, Switzerland; 2Novartis Pharma SAS, Rueil-Malmaison, France; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAAim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs), of vildagliptin based on a large pooled database of Phase II and III clinical trials.Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks' duration. AE profiles of vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths.Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas.Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.Keywords: type 2 diabetes, dipeptidyl peptidase-4, edema, safety, vildagliptin

The present study was a 52-week extension of a previously published, multi-center, randomized, parallel-group study. The aim of this extension study was to compare the efficacy and tolerability of vildagliptin and metformin in drug-na�ve patients with type 2 diabetes over 104 weeks. The extension population comprised 305 patients randomized to vildagliptin (100 mg daily) and 158 patients randomized to metformin (2 000 mg daily). Pioglitazone was added as rescue medication if fasting glucose was >10 mmol/l; data from patients receiving rescue medication were excluded from the primary analysis. Baseline HbA1c averaged 8.4�0.1% in patients randomized to vildagliptin and 8.8�0.1% in those randomized to metformin. The adjusted mean change from baseline to study endpoint was −1.0�0.1% in vildagliptin-treated patients and −1.5�0.1% in those receiving metformin (p<0.001 vs. vildagliptin). These results were similar to those reported after the 1-year core phase of the study. The adjusted mean changes in body weight from baseline to endpoint were 0.5�0.4 kg and −2.5�0.5 kg in the vildagliptin and metformin groups, respectively. One or more adverse event (AE) was reported by 82.2% of patients receiving vildagliptin and by 87.3% of those receiving metformin (p<0.001). Gastrointestinal AEs were more common in patients receiving metformin (45.6%) than in those receiving vildagliptin (25.0%, p<0.001 vs. metformin). One hypoglycemic event occurred after strenuous exercise in a single patient receiving vildagliptin (0.3%). In conclusion, both vildagliptin and metformin monotherapy provided clinically meaningful decreases in HbA1c over 2 years in drug-na�ve patients with type 2 diabetes. Vildagliptin was weight neutral, while weight loss was observed with metformin; however, metformin was associated with significantly worse gastrointestinal tolerability. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of vildagliptin in elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Efficacy data from five double-blind, randomized, placebo- or active-controlled trials of >or=24 weeks' duration were pooled. Effects of 24-week vildagliptin monotherapy (100 mg daily) were compared in younger (<65 years, n = 1,231) and older (>or=65 years, n = 238) patients. Safety data from eight controlled clinical trials of >or=12-weeks' duration were pooled; adverse event profiles in younger (n = 1,890) and older (n = 374) patients were compared. RESULTS: Mean baseline A1C and fasting plasma glucose (FPG) were significantly lower in older (70 years: 8.3 +/- 0.1% and 9.6 +/- 0.1 mmol/l, respectively) than in younger (50 years: 8.7 +/- 0.0% and 10.5 +/- 0.1 mmol/l, respectively) patients. Despite this, the adjusted mean change from baseline (AMDelta) in A1C was -1.2 +/- 0.1% in older and -1.0 +/- 0.0% in younger vildagliptin-treated patients (P = 0.092), and the AMDelta in FPG was significantly larger in older (-1.5 +/- 0.2 mmol/l) than in younger (-1.1 +/- 0.1 mmol/l, P = 0.035) patients. Body weight was significantly lower at baseline in older (83.4 +/- 1.0 kg) than in younger (92.0 +/- 0.6 kg) patients. Weight decreased significantly in the older subgroup (AMDelta -0.9 +/- 0.3 kg, P = 0.007), whereas smaller, nonsignificant decreases occurred in younger patients (AMDelta -0.2 +/- 0.1 kg). Adverse event rates were slightly higher in older than in younger subgroups but were lower among older, vildagliptin-treated subjects (63.6%) than in the pooled active comparator group (68.1%). Vildagliptin treatment did not increase adverse events among older patients with mild renal impairment (62.0%). Hypoglycemia was rare (0.8%) in the elderly patients, and no severe events occurred. CONCLUSIONS: Vildagliptin monotherapy was effective and well tolerated in treatment-naive elderly patients. [ABSTRACT FROM AUTHOR]

Aims To evaluate the ability of vildagliptin and metformin to sustain reductions in HbA1c over a 1-year treatment period in drug-naïve patients with Type 2 diabetes (Type 2 DM). Methods Double-blind, randomized, multicentre, active-controlled, parallel-group study of 52-week treatment with vildagliptin (100 mg daily, n = 526) or metformin (titrated to 2000 mg daily, n = 254) in drug-naïve patients (baseline HbA1c = 7.5–11.0%). HbA1c was measured periodically over 1 year. Results Vildagliptin and metformin each rapidly decreased HbA1c from an equal baseline of 8.7%. Most of the HbA1c reduction was attained by week 12, and the efficacy was sustained throughout 1-year treatment with both agents. At the study end, significant HbA1c reductions from baseline were seen with both vildagliptin (–1.0 ± 0.1%, P < 0.001) and metformin (–1.4 ± 0.1%, P < 0.001); however, statistical non-inferiority of 50 mg vildagliptin twice daily to 1000 mg metformin twice daily was not established. Body weight did not change during the 1-year treatment with vildagliptin (0.3 ± 0.2 kg, P = 0.17) and decreased in metformin-treated patients (–1.9 ± 0.3 kg, P < 0.001). The proportion of patients experiencing an adverse event was 70.1 vs. 75.4% in patients receiving vildagliptin and metformin, respectively. The proportion of patients experiencing a gastrointestinal adverse event was twofold higher in the metformin group, driven by a 3–4-fold greater incidence of diarrhoea, nausea and abdominal pain. The incidence of hypoglycaemia was similarly low in both groups (< 1%). Conclusions A clinically meaningful decrease in HbA1c that was sustained throughout a 1-year treatment in drug-naïve patients with Type 2 DM was seen with both metformin and vildagliptin monotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267). RESULTS: Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by -1.1 +/- 0.1% (P < 0.001) and -1.3 +/- 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference

The article focuses on the results of clinical trials on the efficacy and tolerability of vildagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in improving glycemic control in type 2 diabetes (T2DM) patients across ethnic groups. The study states that the A1C glycosylated hemoglobin level in all subgroups has decreased with no clinically meaningful difference among groups. It concludes that vildagliptin showed consistent efficacy and tolerability regardless of ethnicity.

Vildagliptin is a potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes (T2DM) by increasing α-and β-cell responsiveness to glucose. Phase 3 trials with vildagliptin enrolled a substantial number of persons age ≥65 years, allowing us to examine whether there were any age-associated differences in efficacy or tolerability with this new agent. Summarized below are baseline (BL) values and adjusted mean A A1C, FPG and body weight (BW), and the general safety profile of vildagliptin monotherapy (100 mg daily; 50 mg bid or 100 mg qd) using 24-wk pooled data from 2 placebo-controlled trials and 3 active-controlled trials. Relative to the younger subgroup, in older patients vildagliptin decreased A1C and FPG to a somewhat greater degree, from significantly lower baseline values, and vildagliptin significantly decreased body weight only in the older subgroup. Vildagliptin was well tolerated in older patients, with a low risk of hypoglycemia (and no severe events). Specific AEs occurring in ≥5% of older or younger subgroups, respectively, were constipation (5.6%, 2.2%), nasopharyngitis (5.9%, 6.8%), dizziness (6.3%, 5.2%) and headache (3.7%, 6.2%). Conclusion: vildagliptin represents a good therapeutic option for treating elderly patients with T2DM. [ABSTRACT FROM AUTHOR]

Vildagliptin is a potent and selective DPP-4 inhibitor that improves glycemic control in patients (pts) with type 2 diabetes (T2DM) by increasing α-and β-cell responsiveness to glucose. In Phase 3 monotherapy trials with vildagliptin, 1682 drug-naïve pts with T2DM were randomized to vildagliptin 100 mg daily (either 50 mg bid, n=1280 or 100 mg qd, n=402). At baseline mean age = 53.2 y, BMI = 32.2 kg/m² and disease duration = 2.3 y. Summarized below are baseline values and adjusted mean changes from baseline to endpoint in A1C, FPG, and body weight (BW) using 24-wk pooled data from 2 placebo-controlled trials and 3 active-controlled trials. Also shown are the percentages of pts achieving ADA target A1C (<7.0%) at endpoint, achieving a reduction of at least 0.7%, and experiencing I or more confirmed hypoglycemic episodes (symptoms with SMPG < 56 mg/dL). Similar efficacy was observed with vildagliptin 100 mg qd and 50 mg bid. Vildagliptin 100 mg daily decreased A1C by 1.0% and FPG by 20 mg/dL, with no weight gain. Conclusion: in patients with T2DM failing diet and exercise, vildagliptin monotherapy exhibits robust efficacy without weight gain and with minimal risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

The ADA recommends a target A1C <7.0% to minimize risk of microvascular complications in patients (pts) with type 2 diabetes (T2DM), but a minority achieve this goal. Vildagliptin is a potent and selective DPP-4 inhibitor that improves glycemic control by increasing both α- and β-cell responsiveness to glucose. We examined the efficacy of vildagliptin in bringing patients to A1C goal (<7%) as monotherapy, as add-on to metformin (MET) and in initial combination therapy with pioglitazone (PIO). The proportion of patients reaching goal is dependent on the baseline A1C, therefore data are presented for all subjects and for those with a baseline A1C <8%. In two 24-wk placebo-(PBO) controlled monotherapy trials in drug-naive pts (pooled data), target A1C was achieved by 40% of pts receiving vildagliptin 100 mg vs. 20% of pts receiving PBO; in pts with baseline (BL) A1C ≤8.0%, more than half of pts receiving vildagliptin reached goal. These data were confirmed in a larger pooled analysis of all (5) phase 3 monotherapy trials; in pts with BL A1C ≤8.0% (mean ≈ 7.6%) 60% of pts receiving vildagliptin 100 mg daily achieved A1C <7.0%. When vildagliptin 100 mg qd was given as initial combination with PIO 30 mg qd, 65% of pts receiving the combination achieved endpoint A1C <7.0% vs 43% of pts receiving either PIO or vildagliptin alone. As add-on to MET, 4-fold more pts got to goal with vildagliptin 100 mg/d than with PBO; in pts with BL A1C ≤8.0%, 54% of pts receiving vildagliptin attained the goal vs 13% of those receiving PBO added to MET. Conclusions: Twice as many pts achieved the ADA goal A1C of <7.0% with vildagliptin monotherapy compared to PBO, whereas 4-times more pts reached goal when vildagliptin was added to MET. Two-thirds of patients achieved an endpoint A1C <7.0% when initially treated with the combination of vildagliptin/PIO (100 mg/30 mg qd). [ABSTRACT FROM AUTHOR]