Which oral antidiabetic drug to combine with metformin to minimize the risk of hypoglycemia when initiating basal insulin?: A randomized controlled trial of a DPP4 inhibitor versus insulin secretagogues.

We conducted a pilot study to evaluate two therapeutic strategies at the time of insulin initiation in type 2 diabetic patients insufficiently controlled with metformin+insulin-secretagogues (IS, sulfonylureas or glinides). Patients were randomized to remain under the same dual therapy or to receive metformin+DPP4 inhibitors while starting insulin. Similar glycemic control was achieved in both groups. However less hypoglycemia was observed with DPP4 inhibitors despite higher doses of insulin.

Near normal HbA1c with stable glucose homeostasis: the ultimate target/aim of diabetes therapy.

Achieving near normal glucose homeostasis implies that all components of dysglycemia that are present in diabetes states be eliminated. Reducing ambient/overall hyperglycemia is a pre-requisite to eliminate the risk of development and progression of diabetes complications. More controversially however, are the relative and related contributions of postprandial glucose excursions, glucose variability, hypoglycemia and the dawn phenomenon across the spectrum of dysglycemia. For instance, it is likely that the dawn phenomenon contributes to ambient hyperglycemia and that postprandial glucose excursions are at the cross road of ambient hyperglycemia and glucose variability with glucose fluctuations as causative risk factors for hypoglycemia. Proof-of-concept trials such as the ongoing FLAT-SUGAR study are necessary for gaining further insight into the possible harmful effects of some of these features such as excessive glycemic variability and glucose excursions, still considered to be of minor relevance by several diabetologists. Whether their role will be more thoroughly proven through further intervention trials with "hard" endpoints, remains to be seen. In the meantime more consideration should be given to medications aimed at concomitantly reducing ambient/overall hyperglycemia and those additional abnormal glycemic features of dysglycemia.

The dawn phenomenon in type 2 diabetes: how to assess it in clinical practice?

AIM: The study was aimed at determining whether the dawn phenomenon in type 2 diabetes (T2D) can be predicted and quantified using simple and easily accessible glucose determinations. METHODS: A total of 210 non-insulin-treated persons with T2D underwent continuous glucose monitoring (CGM). The dawn phenomenon was quantified as the absolute increment from the nocturnal glucose nadir to the pre-breakfast value (Δdawn, mg/dL). Pre-lunch (preL) and pre-dinner (preD) glucose, and their averaged values (preLD), were compared with the nocturnal nadir. These pre-meal values were subtracted from the pre-breakfast values. The differences obtained (Δpre-mealL, Δpre-meal D and Δpre-meal LD) were correlated with Δdawn values. The receiver operating characteristic (ROC) curve was used to select the optimal Δpre-meal value that best predicted a dawn phenomenon, set at a threshold of 20mg/dL. RESULTS: All pre-meal glucose levels and differences from pre-breakfast values (Δpre-meal) significantly correlated (P<0.0001) with the nocturnal nadir and Δdawn values, respectively. The strongest correlations were observed for the parameters averaged at preL and preD time points: r=0.83 for preLD and r=0.58 for Δpre-meal LD. ROC curve analysis indicated that the dawn phenomenon at a threshold of 20mg/dL can be significantly predicted by a Δpre-meal LD cut off value of 10mg/dL. The relationship between Δdawn (Y, mg/dL) and Δpre-meal LD (X, mg/dL) was Y=0.49 X+15. CONCLUSION: The self-monitoring of preprandial glucose values at the three main mealtimes can predict the presence/absence of the dawn phenomenon, and permits reliable assessment of its magnitude without requiring continuous overnight glucose monitoring.

Residual dysglycemia when at target HbA(1c) of 7% (53mmol/mol) in persons with type 2 diabetes.

AIMS: To understand the composition of the residual dysglycemia when HbA1c is between 6.5% (48mmol/mol) and 7% (53mmol/mol), representing the definition of diabetes and the recommended treatment goal, respectively. METHODS: One hundred persons with type 2 diabetes and a HbA1c<7% (53mmol/mol), treated with diet alone and/or oral hypoglycemic agents underwent continuous glucose monitoring (CGM) and were further divided into two subgroups 1 (n=50) and 2 (n=50) according to whether the HbA1c was <6.5% (48mmol/mol) or 6.5-6.9% (48-52mmol/mol), respectively. A similar analysis was performed in those on diet alone: subgroups A (n=34, HbA1c<6.5%, 48mmol/mol) and B (n=10, HbA1c 6.5-6.9%, 48-52mmol/mol). The residual dysglycemia determined from the CGM was assessed using glucose exposures defined as areas under curves (AUCs) and mean glucose values. RESULTS: Averaged 2-h postprandial glucose value (averaged PPG, mmol/L, mean±SD) and postprandial glucose exposure (AUCpp, mean±SD, mmol·L(-1)·h) were significantly higher in subgroup 2 (mean HbA1c=6.7%, 50mmol/mol) than in subgroup 1 (mean HbA1c=6.0%, 42mmol/mol): averaged PPG=8.1±1.3 versus 7.3±1.3mmol/L (p<0.002); AUCpp=23.5±8.6 versus 16.2±8.6 (p<0.0001). The percentages of persons with averaged PPG≥7.8mmol/L were 52% and 24% (p<0.01) in subgroups 2 and 1, respectively. Similar results were observed in those (subgroups A and B) who were on diet alone. CONCLUSIONS: The residual dysglycemia in type 2 diabetes with HbA1c between 6.5 and 6.9% (48-52mmol/mol) inclusive is mainly due to remnant abnormal postprandial glucose excursions. Consequently, HbA1c<6.5% (48mmol/mol) is an achievable goal with therapeutic measures aimed at reducing postmeal glucose when the HbA1c is at 7% (53mmol/mol).

Real-life comparison of DPP4-inhibitors with conventional oral antidiabetics as add-on therapy to metformin in elderly patients with type 2 diabetes: the HYPOCRAS study.

AIM: Despite half of all type 2 diabetes mellitus (T2DM) patients being over 65 and treatment being complicated by an elevated risk of iatrogenic hypoglycaemia, information about antidiabetic treatment is scarce in this age group. This prospective observational study compares DPP4-inhibitors (DPP4-i) with conventional oral antidiabetic drugs (COAD) in the real-life treatment of elderly patients with T2DM uncontrolled on metformin alone. METHODS: Two treatment cohorts (DPP4-i and COAD, constituted on the basis of the GP decision of add-on therapy at the 1st visit) were compared after 6months. The primary objective was to assess the incidence of hypoglycaemic episodes in relationship with glycaemic control assessed by HbA(1c) level. RESULTS: Demographics and disease history were comparable between the two cohorts (DPP4-i, n=931 and COAD, n=257) at baseline. The incidence of hypoglycaemia/severe hypoglycaemia was significantly higher over 6months in the COAD cohort (20.1%/2.4% vs. 6.4%/0.1%; P<0.001) whereas similar improvements were observed in glycaemic control with HbA(1c) down from 7.9% to 7.0% (COAD) and 6.9% (DPP4-i). The 7% target was reached without hypoglycaemia in more patients in the DPP4-i than in COAD cohort (59.7% vs. 45.5%; P<0.001). Patients in both cohorts who experienced hypoglycaemia more frequently had a pre-existing diabetic complication. The COAD was more likely to be discontinued (6.6% vs. 1.6%; P<0.001). CONCLUSION: This large cohort study of elderly T2DM patients in France shows that the incidence of hypoglycaemia was three times higher in patients prescribed a COAD versus a DPP4-i after 6months while both treatments induced satisfactory glycaemic control.

Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study.

AIM: To compare continuous glucose monitoring (CGM) profiles on vildagliptin versus sitagliptin in addition to metformin, in patients with inadequately controlled type 2 diabetes mellitus (HbA(1c) 6.5-8.0%). METHODS: A multicenter, prospective, randomised, open-label study with blinded endpoint analysis. CGM data acquired over three days--firstly on metformin alone and then 8 weeks after the addition of either vildagliptin (n=14) or sitagliptin (n=16)--were blinded and analyzed centrally. RESULTS: In comparable populations with a mean baseline HbA1c of 7.1%, 24-hour glucose variability--measured by mean amplitude of glucose excursions and standard deviation of mean glucose concentration--showed similar improvement on both drugs versus metformin alone. In contrast, a series of predefined parameters reflecting daily glycaemic control--mean 24-hour blood glucose concentration, and the times spent in the optimal glycaemic range (70-140 mg/dL) and above the hyperglycaemic thresholds of 140 and 180 mg/dL together with the corresponding AUC values--were significantly improved from baseline only in the vildagliptin arm. In addition, overall hyperglycaemia (AUC[24 h] > 100 mg/dL) significantly dropped from baseline on vildagliptin [-37%] but not on sitagliptin [-9%], while postprandial hyperglycaemia (AUC[0-4 h] × 3) was significantly reduced on both, and basal hyperglycaemia (overall--postprandial hyperglycaemia was reduced only on vildagliptin [-41%; P = 0.04]). CONCLUSIONS: The addition of a DPP-4 inhibitor significantly reduced glycaemic variability with no difference between the two drugs. However, vildagliptin induced better circadian glycaemic control than sitagliptin with a significant decrease on overall hyperglycemia, mainly driven by reduction on basal hyperglycaemia.

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans.

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.

Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: a pooled analysis from a database of clinical trials.

AIM: To report the experience with vildagliptin in a patient population with type 2 diabetes mellitus (T2DM) ≥75 years. METHODS: Efficacy data from seven monotherapy and three add-on therapy to metformin studies, respectively, of ≥24 weeks duration were pooled; effects of 24 weeks of treatment with vildagliptin (50 mg bid) in patients ≥75 years were assessed in these two pooled datasets. Safety data were pooled from 38 studies of ≥12 to ≥104 weeks duration; adverse events (AEs) profiles of vildagliptin (50 mg bid) were evaluated relative to a pool of comparators; 301 patients ≥75 years were analysed. Data in patients <75 years are provided as a reference. RESULTS: Mean age of the elderly population was 77 years. Changes in haemoglobin A1c (HbA1c) with vildagliptin in the patient group ≥75 years were -0.9% from a baseline of 8.3% in monotherapy (p < 0.0001) and -1.1% from a baseline of 8.5% in add-on therapy to metformin (p = 0.0004), and these reductions were similar to those seen in the younger patients. The corresponding weight changes in the elderly patients were -0.9 kg (p = 0.0277) and -0.2 kg [not significant (NS)], respectively, and no confirmed hypoglycaemic events, including no severe events, were reported. AEs, drug-related AEs, serious adverse events (SAEs) and deaths were reported with a lower frequency in older patients receiving vildagliptin than comparators [133.9 vs. 200.6, 14.5 vs. 21.8, 8.8 vs. 16.5 and 0.0 vs. 1.7 events per 100 subject year exposure (SYE), respectively], and the incidence of discontinuations due to AEs was similar in the two groups (7.2 vs. 7.5 events per 100 SYE, respectively). The safety profile of vildagliptin was overall similar in younger and older patients. CONCLUSIONS: Vildagliptin was effective and well-tolerated in type 2 diabetic patients ≥75 years (mean age 77 years).

GLP-1: what is known, new and controversial in 2010?

Over the past 2 years, more than 1300 manuscripts have been published on glucagon-like peptide-1 (GLP-1) and yet, what do we know about it for sure? The European Club for the Study of GLP-1 (EuCSGLP-1) has debated the latest controversies concerning GLP-1, including both fundamental and clinical aspects, and concluded that the control of glucose metabolism by GLP-1 requires paracrine activation of the enteric nervous system to regulate numerous physiological functions. This involves-but is not limited to-the endocrine pancreas, liver, cardiovascular system, gastric-emptying and the brain. For this reason, the role of GLP-1 as an endocrine hormone has come under question. As systemic concentration of the peptide was not thought to be relevant to its physiological action, it was proposed that dipeptidyl peptidase-4 (DPP4) inhibitors would involve the control of enteric, rather than circulating, DPP4 activity to effectively regulate glycaemia. In any case, the concomitant insulinotropic and glucagonostatic roles of GLP-1 were believed to be of equal importance to glucose control. Another important question was related to the role of GLP-1 on beta cell apoptosis, regeneration and differentiation in type 2 diabetic patients. Although evidence in vitro showed that GLP-1 controls these functions, such effects remain elusive in humans in vivo. Nevertheless, the consensus was that GLP-1 could control glucose responsiveness, one of the first impaired physiological functions at the onset of diabetes. The therapeutic efficiency of GLP-1 would be related to the initial restoration of glucose competence, while an increase of beta cell mass has not yet been demonstrated. From a clinical and fundamental point of view, it was concluded that, at the onset of diabetes, an initial triggering of GLP-1 secretion-by metformin coupled with a DPP4 inhibitor-would help to activate the gut-peripheral axis and, hence, restore adequate regulation of glycaemia. GLP-1 analogues would certainly be helpful in association with long-acting insulin (albeit off-label) in patients with impaired beta cells and GLP-1 secretory potential. However, a reliable and routine feasible test to systematically assess dynamic insulin secretion is essential. More important, factors that influence therapeutic response, such as compliance and lifestyle, as well as pharmacokinetics and dosing, disease duration, age, gender, ethnicity, patients' clinical characteristics, autonomic nervous system integrity and genotype characteristics also need to be considered. A few innovative perspectives have been debated, such as the recently discovered cardiovascular protective effects of the native GLP-1 peptide and its degradation product GLP-1(9-36), as well as the neuroprotection offered by GLP-1. Although still considered speculative, these perspectives remain hopeful and promising.

How patients' attitudes and opinions influence self-care behaviours in type 2 diabetes. Insights from the French DIABASIS Survey.

AIM: This study evaluated the profiles of patients with type 2 diabetes (T2DM) to identify sets of opinions and attitudes towards the disease that might influence self-care behaviours. METHODS: Altogether, 1,092 patients with T2DM, aged 45 or older from a large representative French cohort, completed a self-questionnaire exploring their knowledge and perceptions of diabetes, its impact on various aspects of daily life and self-management practices. Canonical and cluster analyses were used to identify sets of homogeneous 'profiles' of patients linking attitudes and opinions to specific disease-related behaviours (such as changes in lifestyle, drug compliance, treatment satisfaction, impact on everyday life and weight gain). RESULTS: Demographics of the T2DM study population were previously reported along with the main results (60% male; mean age: 66 years; mean age at diagnosis: 55 years; mean BMI: 29kg/m(2)). Five distinct patient types emerged from the typological approach: 'committed' (25%); 'carefree' (23%); 'bitter' (19%); 'disheartened' (19%); and 'overwhelmed' (15%). Each patient type defined a set of attitudes and beliefs towards T2DM that influenced disease-related behaviours, leading to different degrees of diabetes self-management. CONCLUSION: The DIABASIS survey provides important information for diabetes care by identifying distinct patients' profiles that express different degrees of difficulty in implementing self-management. For this reason, patients in each category require different kinds of customized support from their physician to induce behavioural changes that may be key in improving their metabolic control.

Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study.

AIM: To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. METHODS: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. RESULTS: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline > or =0.5% or HbA1c < or =6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. CONCLUSIONS: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.

Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population.

AIM: To assess the cardiovascular and cerebrovascular (CCV) safety of the dipeptidyl peptidase-IV inhibitor vildagliptin. METHODS: Data were pooled from 25 Phase III studies of vildagliptin, used either as monotherapy or combination therapy, with durations of 12 weeks to > or = 2 years. The safety of vildagliptin [50 mg qd (N = 1393) or 50 mg bid (N = 6116)] was assessed relative to a pool of all comparators [both placebo and active comparators (N = 6061)]. CCV events were adjudicated in a prospective, blinded fashion by an independent CCV adjudication committee. Meta-analysis of confirmed CCV events was performed with Mantel-Haenszel risk ratios (RRs); categories included in the composite endpoint were acute coronary syndrome, transient ischaemic attack (with imaging evidence of infarction), stroke and CCV death. Subgroup analyses by age (< and > or = 65 years), gender and cardiovascular (CV) risk status [high CV risk status defined as a previous history of events in the Standard MedDRA Queries of ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events, arterial) were also carried out. In addition, unadjusted and exposure-adjusted incidences are presented for both the composite endpoint and its components. RESULTS: Relative to all comparators, the RRs for the composite endpoint were < 1 for both vildagliptin 50 mg qd [RR = 0.88; 95% CI (0.37, 2.11)] and vildagliptin 50 mg bid [RR = 0.84; 95% CI (0.62, 1.14)]. The results were consistent across subgroups defined by age, gender and CV risk status, including the higher CV risk subgroups of elderly patients [RR for vildagliptin 50 mg bid vs. all comparators = 1.04; 95% CI (0.62, 1.73)], males [RR = 0.87; 95% CI (0.60, 1.24)] or patients with a high CV risk status [RR = 0.78; 95% CI (0.51, 1.19)]. The exposure-adjusted incidences of each component of the composite endpoint for vildagliptin 50 mg bid were also lower than or similar to those of all comparators. CONCLUSIONS: In a large meta-analysis, vildagliptin was not associated with an increased risk of adjudicated CCV events relative to all comparators in the broad population of type 2 diabetes including patients at increased risk of CCV events.

Role of vildagliptin in managing type 2 diabetes mellitus in the elderly.

BACKGROUND: The prevalence of type 2 diabetes (T2DM) increases with age. Older patients have an increased likelihood for T2DM-related morbidity and mortality. The objective of this review is to provide an overview of the challenges in managing T2DM in the elderly, with an emphasis on prevention of hypoglycaemia and the role of the DPP-4 inhibitor vildagliptin in this patient population. METHODS: A search of PubMed was conducted (from 2003 to 2010) to identify English-language articles relevant to the management of elderly patients with T2DM, with an emphasis on vildagliptin treatment. A limitation of this review is that it does not provide an overview of the entire class of dipeptidyl-peptidase-4 (DPP-4) inhibitors. FINDINGS: Management of T2DM in elderly patients is complicated by numerous factors, including a high prevalence of cardiovascular risk factors and other comorbidities and a high frequency of polypharmacy issues. Hypoglycaemia may pose the greatest barrier to optimal glycaemic control in elderly patients, who are less likely to recognise and respond to hypoglycaemic episodes, leading to increased frequency and severity of events. Data on the DPP-4 inhibitor vildagliptin indicate that reductions in A1C in elderly patients are at least as good as those observed in younger patients and are achieved with minimal risk of hypoglycaemia. T2DM in older individuals is associated with relative hyperglucagonaemia and elevated postprandial glucose (PPG). Vildagliptin treatment appears to address both these defects. Vildagliptin improves the ability of alpha- and beta-cells to respond appropriately to changes in plasma glucose levels. This, in the face of high glucose levels, results in reduced inappropriate glucagon secretion and PPG excursions. In the face of low glucose, however, the protective glucagon response is well-preserved. These factors help explain the efficacy and minimal risk of hypoglycaemia observed with vildagliptin in elderly patients. CONCLUSION: The elderly population with T2DM poses unique treatment challenges and have not been particularly well-represented in clinical trials, highlighting the need for additional studies to better define appropriate glucose targets and to ascertain the best strategies for achieving and maintaining appropriate glycaemic levels. Because vildagliptin does not expose patients to hypoglycaemic risk, it seems particularly suited to oral therapy of T2DM in the elderly.

Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial.

AIMS: The study evaluated the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, vildagliptin, and metformin in drug-naïve elderly patients with type 2 diabetes. The primary objective was to demonstrate non-inferiority of vildagliptin vs. metformin in glycated haemoglobin (HbA1c) reduction. METHODS: This was a double-blind, randomized, multicentre, active-controlled, parallel-group study of 24-week treatment with vildagliptin (100 mg daily, n=169) or metformin (titrated to 1500 mg daily, n=166) in drug-naïve patients with type 2 diabetes aged>or=65 years (baseline HbA1c 7-9%). RESULTS: Participants had a mean age of 71 years, known duration of diabetes of 3 years and mean baseline HbA1c of 7.7%. At end-point, vildagliptin was as effective as metformin, improving HbA1c by -0.64+/-0.07% and -0.75+/-0.07%, respectively, meeting the predefined statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference

How do patients with type 2 diabetes perceive their disease? Insights from the French DIABASIS survey.

AIM: The main purpose of this survey was to describe type 2 diabetes (T2DM) from the patient's standpoint in a representative French panel in 2008. METHODS: Fourteen thousand two hundred and one individuals from the general population aged 45 or older completed a self-questionnaire exploring knowledge about diabetes; 1092 replies were from patients with T2DM. RESULTS: The prevalence of T2DM in this population was 7.7%, with demographics as follows: 60% men; mean age: 66 years; mean age at diagnosis: 55 years; mean BMI: 29 kg/m(2). Eighty-five percent of T2DM patients reported that they wanted more information about at least one aspect of the disease at diagnosis; they reported feeling anxious (30%), frightened (13%), angry (4%) or that the disease was unfair (12%). Half of the patients had modified their dietary habits but 71% found it difficult to engage in regular physical activity. Most patients (90%) were treated with drugs: 81% with oral antidiabetic drugs (OAD) (44% in monotherapy) while 19% received insulin (alone or in combination with OAD). Twenty-three percent complained of weight gain since start of current therapy (average gain of 7.3 kg). Insulin initiation represented a turning point for patients who became more aware of the disease severity, more willing to follow advice and to take greater control over their disease management. The mean time from diagnosis to insulin initiation was 13.8 years. Half of the patients perceived their disease as severe especially women, patients who initially reacted with anxiety, insulin-treated patients and those actively involved in their disease management. Some gender differences emerged: women took the disease more seriously, were more engaged in self-management, and reported a higher impact on daily life. CONCLUSIONS: DIABASIS provides important information for diabetes care by highlighting patients' views of the disease, such as distress at diagnosis, lack of adequate information to cope with this distress and the important supportive role played by the family. A deeper understanding of patients' perception of the disease would help optimize customized care.

Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy.

AIM: To examine the efficacy and safety of vildagliptin vs. glimepiride as add-on therapy to metformin in patients with type 2 diabetes mellitus in a 52-week interim analysis of a large, randomized, double-blind, multicentre study. The primary objective was to demonstrate non-inferiority of vildagliptin vs. glimepiride in glycosylated haemoglobin (HbA(1c)) reduction at week 52. METHODS: Patients inadequately controlled on metformin monotherapy (HbA(1c) 6.5-8.5%) and receiving a stable dose of metformin (mean dose 1898 mg/day; mean duration of use 36 months) were randomized 1:1 to receive vildagliptin (50 mg twice daily, n = 1396) or glimepiride (titrated up to 6 mg/day; mean dose 4.5 mg/day, n = 1393). RESULTS: Non-inferiority of vildagliptin was demonstrated (97.5% confidence interval 0.02%, 0.16%) with a mean (SE) change from baseline HbA(1c) (7.3% in both groups) to week 52 endpoint of -0.44% (0.02%) with vildagliptin and -0.53% (0.02%) with glimepiride. Although a similar proportion of patients reached a target HbA(1c) level of <7% with vildagliptin and glimepiride (54.1 and 55.5%, respectively), a greater proportion of patients reached this target without hypoglycaemia in the vildagliptin group (50.9 vs. 44.3%; p < 0.01). Fasting plasma glucose (FPG) reductions were comparable between groups (mean [SE] -1.01 [0.06] mmol/l and -1.14 [0.06] mmol/l respectively). Vildagliptin significantly reduced body weight relative to glimepiride (mean [SE] change from baseline -0.23 [0.11] kg; between-group difference -1.79 kg; p < 0.001) and resulted in a 10-fold lower incidence of hypoglycaemia than glimepiride (1.7 vs. 16.2% of patients presenting at least one hypoglycaemic event; 39 vs. 554 hypoglycaemic events, p < 0.01). No severe hypoglycaemia occurred with vildagliptin compared with 10 episodes with glimepiride (p < 0.01), and no patient in the vildagliptin group discontinued because of hypoglycaemia compared with 11 patients in the glimepiride group. The incidence of adverse events (AEs), serious AEs and adjudicated cardiovascular events was 74.5, 7.1 and 0.9%, respectively, in patients receiving vildagliptin, and 81.1, 9.5 and 1.6%, respectively, in patients receiving glimepiride. CONCLUSIONS: When metformin alone fails to maintain sufficient glycaemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks and displays a favourable AE profile, with no weight gain and a significant reduction in hypoglycaemia compared with glimepiride.

Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2 diabetes: comparison with metformin.

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-naïve 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 HbA (1c) 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 HbA (1c) over 2 years in drug-naïve 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.

Robust improvements in fasting and prandial measures of beta-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database.

AIM: To assess the effects of 24-week treatment with vildagliptin on measures of beta-cell function in a broad spectrum of drug-naïve patients with type 2 diabetes (T2DM). METHODS: Data from all double-blind, multicentre, randomized, placebo- or active-controlled trials conducted in drug-naïve patients with T2DM were pooled from all patients receiving monotherapy with vildagliptin (100 mg daily: 50 mg twice daily or 100 mg once daily, n = 1855) or placebo (n = 347). Fasting measures of beta-cell function [homeostasis model assessment of beta-cell function (HOMA-B) and proinsulin : insulin ratio] were assessed in the overall pooled monotherapy population. Standard meal tests were performed at baseline and week 24 in a subset of patients, and effects of vildagliptin (100 mg daily, n = 227) on dynamic (meal test-derived) measures of beta-cell function [insulin secretion rate relative to glucose (ISR/G) and insulinogenic indices] were assessed relative to baseline and vs. placebo (n = 29). RESULTS: In the overall population, vildagliptin significantly increased HOMA-B both relative to baseline [adjusted mean change (AMDelta) = 10.3 +/- 1.5] and vs. placebo (between-treatment difference in AMDelta = 11.5 +/- 4.5, p = 0.01) and significantly decreased the proinsulin : insulin ratio relative to baseline (AMDelta = -0.05 +/- 0.01) and vs. placebo (between-treatment difference in AMDelta = -0.09 +/- 0.02, p < 0.001). Relative to baseline, vildagliptin monotherapy significantly increased all meal test-derived parameters, and ISR/G (between-treatment difference in AMDelta = 9.8 +/- 2.8 pmol/min/m(2)/mM, p < 0.001) and the insulinogenic index(0-peak glucose) (between-treatment difference in AMDelta = 0.24 +/- 0.05 pmol/mmol, p = 0.045) were significantly increased vs. placebo. CONCLUSIONS: Vildagliptin monotherapy consistently produced robust improvements in both fasting and meal test-derived measures of beta-cell function across a broad spectrum of drug-naïve patients with T2DM. All Phase III trials described (NCT 00099905, NCT 00099866, NCT 00099918, NCT 00101673, NCT 00101803 and NCT 00120536) are registered with ClinicalTrials.gov.

Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naïve patients with Type 2 diabetes.

AIMS: To evaluate the ability of vildagliptin and metformin to sustain reductions in HbA(1c) 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 HbA(1c) = 7.5-11.0%). HbA(1c) was measured periodically over 1 year. RESULTS: Vildagliptin and metformin each rapidly decreased HbA(1c) from an equal baseline of 8.7%. Most of the HbA(1c) reduction was attained by week 12, and the efficacy was sustained throughout 1-year treatment with both agents. At the study end, significant HbA(1c) 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 HbA(1c) that was sustained throughout a 1-year treatment in drug-naïve patients with Type 2 DM was seen with both metformin and vildagliptin monotherapy.