Markus Dworak

Treatment persistence, hypoglycaemia and clinical outcomes in type 2 diabetes patients with dipeptidyl peptidase-4 inhibitors and sulphonylureas: a primary care database analysis

To investigate therapy persistence, frequency of hypoglycaemia and macrovascular outcomes among type 2 diabetes patients with dipeptidyl peptidase‐4 (DPP‐4) inhibitors (DPP‐4) and sulphonylureas (SU).

Effect of vildagliptin compared to glimepiride on postprandial proinsulin processing in the β cell of patients with type 2 diabetes mellitus

This study compared the effect of Glimepiride versus Vildagliptin on β‐cell function and the release of intact proinsulin (PI) in patients with type 2 diabetes mellitus. Patients on metformin monotherapy were randomized to add on treatment with Vildagliptin or Glimepiride. A standardized test meal was given at baseline, after 12 and 24 weeks of treatment. Insulin, PI and blood glucose values were measured in the fasting state and postprandial for 300 min. Fasting PI levels significantly decreased in the Vildagliptin group. The area under the curve for the postprandial release of PI decreased during Vildagliptin and increased during Glimepiride treatment. The proinsulin to insulin ratio declined in the Vildagliptin group, whereas it did not change significantly in the Glimepiride group. Addition of Vildagliptin to ongoing Metformin treatment reconstitutes the disproportionality of the proinsulin to insulin secretion from the β cell.

Efficacy and safety of vildagliptin in clinical practice-results of the PROVIL-study

AIM To investigate efficacy and safety of vildagliptin compared to other oral antidiabetics in clinical practice in Germany. METHODS In this prospective, open, observational study, patients with type 2 diabetes mellitus (T2DM) previously on oral monotherapy were selected by their treating physician to receive either vildagliptin add-on to metformin (cohort 1), vildagliptin + metformin single-pill combination (SPC) (cohort 2) or another dual combination therapy with oral antidiabetic drugs (OADs) (cohort 3). According to routine clinical practice, interim examinations occurred every 3 mo: at baseline, after approximately 3 mo and after approximately 6 mo. Parameters documented in the study included demographic and diagnostic data, history of T2DM, data on diabetes control, vital signs, relevant prior and concomitant medication and disease history. Efficacy was assessed by changes in HbA1c and fasting plasma glucose (FPG) 3 mo and 6 mo after initiation of dual combination therapy. Safety was assessed by adverse event reporting and measurement of specific laboratory values (serum creatinine, total bilirubin, alanine aminotransferase, aspartate aminotransferase, creatine kinase). RESULTS Between October 2009 and January 2011, a total of 3881 patients were enrolled in this study. Since 47 patients were withdrawn due to protocol violations, 3834 patients were included in the statistical analysis. There were no relevant differences between the three cohorts concerning age, body weight and body mass index. Average diabetes duration was approximately 6 years and mean HbA1c was between 7.6% and 7.9% at baseline. Antidiabetic treatment was recorded in 3648 patients. Patients were treated with vildagliptin add-on to metformin (n = 603), vildagliptin + metformin (SPC) (n = 2198), and other oral OADs including combinations of metformin with sulfonylurea (n = 370), with glitazones (n = 123), other dipeptidyl peptidase-4 inhibitors (n = 99). After 6 mo of treatment, the absolute decrease in HbA1c (mean ± SE) was significantly more pronounced in patients receiving vildagliptin add-on to metformin (-0.9% ± 0.04%) and vildagliptin + metformin (SPC) (-0.9% ± 0.03%) than in patients receiving other OADs (-0.6% ± 0.04%; P < 0.0001). In addition, significant cohort differences were observed for the improvement in FPG after 6 mo treatment (vildagliptin add-on to metformin: -291 mg/L ± 18.3 mg/L; vildagliptin +metformin (SPC): -305 mg/L ± 9.6 mg/L; other antidiabetic drugs: -209 mg/L ± 14.0 mg/L for (P < 0.0001). Moderate decreases in body weight (absolute difference between last control and baseline: mean ± SE) were observed for patients in all cohorts (vildagliptin add-on to metformin: -1.4 kg ± 0.17 kg; vildagliptin + metformin (SPC): -1.7 kg ± 0.09 kg; other OADs: -0.8 kg ± 0.13 kg). No significant differences in adverse events (AEs) and other safety measures were observed between the cohorts. When performing an additional analysis by age (patients < 65 years vs patients ≥ 65 years), there was no relevant difference in the most common AEs between the two age groups and the AE profile was similar to that of the overall patient population. CONCLUSION Clinical practice confirms that vildagliptin is an effective and well-tolerated treatment in combination with metformin in T2DM patients.

Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study

The 12‐month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)‐based immunosuppression to a CNI‐free everolimus (EVR)‐based regimen showed numerically better renal function. Here, we present the five‐yr follow‐up data.

Real-life efficacy and safety of vildagliptin compared with sulfonylureas as add-on to metformin in patients with type 2 diabetes mellitus in Germany

Abstract Objective: Metformin is an established first-line treatment for type 2 diabetes mellitus (T2DM) patients, but intensification of oral anti-diabetes therapy is usually required over time. A large observational study of 45,868 T2DM patients in 27 countries (EDGE) was conducted to compare the effectiveness and safety of vildagliptin as add-on therapy to another oral anti-diabetes drug (OAD) vs other dual OAD combinations. This report presents results from a post-hoc analysis of patients in Germany who received vildagliptin or a sulfonylurea (SU) in combination with metformin. Research design and methods: Patients inadequately controlled with monotherapy became eligible only after the add-on treatment was finalized. Patients included were assigned to receive either vildagliptin or another OAD (SUs, thiazolidinediones, glinides, α-glucosidase inhibitors, or metformin; DPP-4 inhibitors or glucagon-like peptide-1 [GLP-1] mimetics/analogs were excluded). The primary end-point was the proportion of patients achieving a reduction in HbA1c >0.3% without peripheral edema, hypoglycemia, discontinuation due to gastrointestinal event, or weight gain ≥5%. Results: Of 8887 patients enrolled in Germany, 6439 received vildagliptin and 971 received SUs as add-on to metformin. The primary end-point was reached in 34.9% and 29.6% of patients in the vildagliptin and SU groups, respectively, with an unadjusted odds ratio of 1.27 (95% CI = 1.09, 1.47; p = 0.001). HbA1c decreased in both cohorts from baseline (−0.7% with vildagliptin vs −0.5% with SUs), with a mean between-group difference of −0.2% (95% CI = −0.22, −0.09). The number of hypoglycemic events was 4-fold higher in the SU group than in the vildagliptin group (vildagliptin = 0.11%; SU = 0.41%). Conclusions: In a real-life setting, vildagliptin was associated with a numerically greater reduction in HbA1c, less hypoglycemia, and more patients reaching target HbA1c without hypoglycemia or weight gain compared with SUs. Open-label design and under reporting of adverse events are limitations of this post hoc analysis.

Vildagliptin versus insulin in patients with type 2 diabetes mellitus inadequately controlled with sulfonylurea: results from a randomized, 24 week study

Abstract Objective: There is limited evidence to guide the selection of second-line anti-hyperglycemic agents in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with sulfonylurea monotherapy and are intolerant to metformin. We compared the efficacy and safety of vildagliptin 50 mg qd and Neutral Protamine Hagedorn (NPH) insulin qd in such patients. Methods: This was a 24 week, multicenter, randomized, open-label study. The co-primary endpoints were (i) proportion of patients achieving HbA1c <7.0% without any confirmed hypoglycemic events (HEs) or weight gain ≥3% (composite endpoint); (ii) rate of confirmed HEs. Treatment satisfaction was assessed using the TSQM-9 questionnaire at study end. Results: A total of 162 patients were randomly assigned to vildagliptin (n = 83) and NPH insulin (n = 79). Similar proportion of patients achieved the composite endpoint in vildagliptin versus NPH insulin group (35.4% versus 34.2%; OR 0.985; 95% CI 0.507, 1.915; p = 0.96). After 24 weeks, 48.8% of patients in the vildagliptin group and 60.8% in the NPH insulin group achieved HbA1c <7.0%; 13.4% in the vildagliptin group and 29.1% in the insulin group had at least one confirmed HE; while 11.0% in the vildagliptin group and 22.8% in the insulin group experienced weight gain. The rate of confirmed HEs was significantly lower in patients receiving vildagliptin versus NPH insulin (1.3 versus 5.1 events per year). The TSQM-9 score for ‘convenience’ at week 24 increased significantly more with vildagliptin than with NPH insulin. Conclusions: Addition of vildagliptin and NPH insulin resulted in a similar number of patients reaching HbA1c target without HEs or weight gain in T2DM patients inadequately controlled with sulfonylurea. The addition of vildagliptin to sulfonylurea could be considered as a treatment option prior to intensification with insulin, with the advantages of a lower HE rate and greater patient convenience. Study results are limited by a higher drop-out rate in the vildagliptin arm.

Pill Burden in Patients With Type 2 Diabetes in Germany: Subanalysis From the Prospective, Noninterventional PROVIL Study

IN BRIEF Type 2 diabetes and its associated comorbidities often require polypharmacotherapy, which may result in poor adherence to treatment. This study evaluated, using subjective patient and physician questionnaire surveys, the impact of pill burden and its associated consequences on patients treated with vildagliptin as add-on to metformin, a fixed-dose combination of vildagliptin/metformin, or another dual oral antidiabetic therapy. Patients’ responses were also analyzed by age (<65 or ≥65 years). The surveys revealed that a high pill count in antidiabetic therapy constitutes a large burden for patients with type 2 diabetes. Treating physicians are aware of the problems that result from a high pill burden, and a majority of them prefer prescribing fixed-dose combinations that have better efficacy and tolerability to reduce pill burden.

Patient preference and tolerability of a DPP-4 inhibitor versus a GLP-1 analog in patients with type 2 diabetes mellitus inadequately controlled with metformin: a 24-week, randomized, multicenter, crossover study

Objective: The present study aimed to assess the patient preference and tolerability of oral dipeptidyl peptidase-4 inhibitor (vildagliptin) versus injectable glucagon-like peptide-1 analog (liraglutide) in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. Methods: This 24-week, randomized, multicenter, crossover study, patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy with hemoglobin A1c (HbA1c) ⩾6.5% and ⩽9.0% were randomized in a crossover manner to receive either vildagliptin/metformin single-pill combination (SPC) 50/1000 mg twice daily (n = 32) or 1.2 mg liraglutide as an add-on to metformin (0.6 mg [weeks 0–1] followed by 1.2 mg [weeks 2–12] once daily/1000 mg twice daily) (n = 30) for the first 12 weeks. Results: Patient preference at week 24 was similar, with 51.7% (n = 31) patients preferring vildagliptin/metformin SPC compared with 48.3% (n = 29) preferring liraglutide as an add-on to metformin therapy (p = 0.449). Post hoc analyses showed that more elderly patients (⩾65 years) preferred vildagliptin (65%; n = 13) over liraglutide (35%; n = 7) therapy. Liraglutide was associated with better improvement in fasting plasma glucose (–21.5 mg/dl versus –3.4 mg/dl) and HbA1c (–0.5% versus –0.3%) levels. Fewer adverse events were reported with vildagliptin/metformin SPC (n = 16) compared with liraglutide as add-on to metformin treatment (n = 46). Conclusions: In this pilot study, although both vildagliptin and liraglutide therapies were preferred similarly by the patients and showed effective control of glycemia over 12 weeks, vildagliptin was associated with fewer adverse events and was preferred more by elderly patients.

Early insights into the characteristics and evolution of clinical parameters in a cohort of patients prescribed sacubitril/valsartan in Germany

ABSTRACT Objectives: This study aimed to provide early insights into sacubitril/valsartan (sac/val) prescription patterns and the demographic and clinical characteristics of patients prescribed sac/val in primary care and cardiology settings in Germany. Methods: The study used electronic medical records from the German IMS® Disease Analyzer database. Patients with ≥1 prescription for sac/val during 1 January–31 December 2016 (n = 1643) were identified and followed up for ≤12 months from first prescription. Patients with ≥1 heart failure (HF) diagnosis during the study period, ≥1 additional HF diagnosis in the full history of the database, and ≥1 prescription for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a β-blocker during the study period, without a prescription for sac/val (n = 25,264), were included as a reference cohort. Changes in clinical parameters in the 12 months before and after sac/val initiation were investigated and compared with those from the PARADIGM-HF study. Results: The characteristics of patients prescribed sac/val more closely resembled those of patients enrolled in PARADIGM-HF (e.g. younger age, higher proportion of men than women, lower systolic blood pressure) than patients in the reference cohort. Most patients were initiated on the lowest dose of sac/val irrespective of clinical setting. Significant decreases (p < 0.001) in NT-proBNP and glycated haemoglobin levels were observed following sac/val initiation. Conclusions: Patients prescribed sac/val had similar baseline demographics and clinical characteristics to those from PARADIGM-HF, and most patients were initiated on the lowest dose. Changes in clinical parameters before and after initiation mirrored findings from the PARADIGM-HF study.

Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts

ABSTRACT Despite significant therapeutic advances in heart failure (HF) therapy, the morbidity and mortality associated with this disease remains unacceptably high. The concept of metabolic dysfunction as an important underlying mechanism in HF is well established. Cardiac function is inextricably linked to metabolism, with dysregulation of cardiac metabolism pathways implicated in a range of cardiac complications, including HF. Modulation of cardiac metabolism has therefore become an attractive clinical target. Cardiac metabolism is based on the integration of adenosine triphosphate (ATP) production and utilization pathways. ATP itself impacts the heart not only by providing energy, but also represents a central element in the purinergic signaling pathway, which has received considerable attention in recent years. Furthermore, novel drugs that have received interest in HF include angiotensin receptor blocker‐neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT‐2) inhibitors, whose favorable cardiovascular profile has been at least partly attributed to their effects on metabolism. This review, describes the major metabolic pathways and concepts of the healthy heart (including fatty acid oxidation, glycolysis, Krebs cycle, Randle cycle, and purinergic signaling) and their dysregulation in the progression to HF (including ketone and amino acid metabolism). The cardiac implications of HF comorbidities, including metabolic syndrome, diabetes mellitus and cachexia are also discussed. Finally, the impact of current HF and diabetes therapies on cardiac metabolism pathways and the relevance of this knowledge for current clinical practice is discussed. Targeting cardiac metabolism may have utility for the future treatment of patients with HF, complementing current approaches.