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Bad Mergentheim, Germany

Making appropriate treatment decisions for patients newly diagnosed with type 2 diabetes mellitus (T2DM) and severe hyperglycemia (glycated hemoglobin [HbA1c]>10% or fasting plasma glucose≥250 mg/dL) presents a formidable challenge to primary care physicians. Extreme defects in insulin secretion make it unlikely that these patients will achieve glycemic targets with metformin monotherapy. Additionally, uncontrolled hyperglycemia is associated with an increased risk of short-term acute complications, such as hyperosmolar coma, and long-term complications affecting the micro- and macrovasculature. Thus, severely hyperglycemic patients require prompt, intensive treatment to re-establish glycemic control. Current guidelines indicate that either initial insulin therapy or initial combination therapy with metformin plus non-insulin drug(s) are the treatments of choice for these challenging-to-treat patients. This mini-review examines the clinical evidence supporting these two treatment options, with particular reference to the findings of a phase 3 study of treatment with an initial combination of metformin plus the dipeptidyl peptidase-4 inhibitor, linagliptin. Intensive insulin therapy can induce sustained euglycemia and improve beta-cell function in newly diagnosed patients. However, insulin use is associated with an increased risk of adverse events, such as hypoglycemia and weight gain. These potentially serious side effects cause concern among patients and physicians, and are a major barrier to initiating and maintaining adherence to insulin treatment. In the phase 3 study, open-label treatment of severely hyperglycemic patients (HbA1c≥11.0%) with linagliptin plus metformin resulted in a mean change in HbA1c of -3.7%±1.7%. This combination therapy was generally well tolerated with most adverse events being of mild or moderate intensity; asymptomatic hypoglycemia was reported by just 1 of 66 (1.5%) patients. These findings provide evidence in support of linagliptin plus metformin as a well-tolerated and effective treatment alternative to insulin for new-onset patients with T2DM and severe hyperglycemia.


Haak T.,Diabetes Center Mergentheim | Meinicke T.,Boehringer Ingelheim | Jones R.,Boehringer Ingelheim | Weber S.,Boehringer Ingelheim | And 2 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Aims: To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes. Methods: In this 24-week, double-blind, placebo-controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) ≥11.0% were not eligible for randomization and received open-label linagliptin + high-dose metformin. Results: The placebo-corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was -1.7% (-2.0, -1.4) for linagliptin + high-dose metformin, -1.3% (-1.6, -1.1) for linagliptin + low-dose metformin, -1.2% (-1.5, -0.9) for high-dose metformin, -0.8% (-1.0, -0.5) for low-dose metformin and -0.6 (-0.9, -0.3) for linagliptin (all p < 0.0001). In the open-label arm, the mean change in HbA1c from baseline (11.8%) was -3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted. Conclusions: Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia. © 2012 Blackwell Publishing Ltd.


Haak T.,Diabetes Center Mergentheim | Meinicke T.,Boehringer Ingelheim | Jones R.,Boehringer Ingelheim | Weber S.,Boehringer Ingelheim | And 2 more authors.
International Journal of Clinical Practice | Year: 2013

Objective: To determine the efficacy and safety of linagliptin in initial combination with metformin in patients with type 2 diabetes. Methods: This 1-year randomised, double-blind study was an extension of a 6-month randomised controlled trial, in which adults with type 2 diabetes received one of six treatment regimens (linagliptin 2.5 mg plus metformin 500 mg bid, linagliptin 2.5 mg plus metformin mg 1000 bid, metformin 1000 mg bid, metformin 500 mg bid, linagliptin 5 mg qd or placebo). In the extension, patients in the first three treatment groups continued their regimen (non-switched group, n = 333) while the metformin 500 mg bid, linagliptin 5 mg qd and placebo groups were re-randomised to one of the three continuing regimens (switched group, n = 233). Results: All three non-switched groups maintained reductions in glycosylated haemoglobin (HbA1c; mean ± standard deviation reductions across the 1.5-year period: linagliptin 2.5 plus metformin 1000 bid, -1.63 ± 1.05%; linagliptin 2.5 plus metformin 500 bid, -1.32 ± 1.06%; metformin 1000 bid, -1.25 ± 0.91%) while the switched groups showed additional HbA1c reductions. During the extension, there were no clinically meaningful changes in body weight in any group. Adverse event rates were similar between groups, with most events being mild or moderate, and the incidence of investigator-defined hypoglycaemia was low, with no severe events. Discussion: Initial combination of linagliptin and metformin was well tolerated over the 1-year extension period, with low risk of hypoglycaemia, and improved glycaemic control vs. metformin alone. Conclusion: The initial combination of linagliptin and metformin appears to provide a useful treatment option in patients whose blood glucose levels are increased to an extent that metformin monotherapy may not achieve treatment targets. © 2013 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.


Making appropriate treatment decisions for patients newly diagnosed with type 2 diabetes mellitus (T2DM) and severe hyperglycemia (glycated hemoglobin [HbA1c] >10% or fasting plasma glucose ≥250 mg/dL) presents a formidable challenge to primary care physicians. Extreme defects in insulin secretion make it unlikely that these patients will achieve glycemic targets with metformin monotherapy. Additionally, uncontrolled hyperglycemia is associated with an increased risk of short-term acute complications, such as hyperosmolar coma, and long-term complications affecting the micro- and macrovasculature. Thus, severely hyperglycemic patients require prompt, intensive treatment to re-establish glycemic control. Current guidelines indicate that either initial insulin therapy or initial combination therapy with metformin plus non-insulin drug(s) are the treatments of choice for these challenging-to-treat patients. This mini-review examines the clinical evidence supporting these two treatment options, with particular reference to the findings of a phase 3 study of treatment with an initial combination of metformin plus the dipeptidyl peptidase-4 inhibitor, linagliptin. Intensive insulin therapy can induce sustained euglycemia and improve beta-cell function in newly diagnosed patients. However, insulin use is associated with an increased risk of adverse events, such as hypoglycemia and weight gain. These potentially serious side effects cause concern among patients and physicians, and are a major barrier to initiating and maintaining adherence to insulin treatment. In the phase 3 study, open-label treatment of severely hyperglycemic patients (HbA1c ≥11.0%) with linagliptin plus metformin resulted in a mean change in HbA1c of -3.7% ± 1.7%. This combination therapy was generally well tolerated with most adverse events being of mild or moderate intensity; asymptomatic hypoglycemia was reported by just 1 of 66 (1.5%) patients. These findings provide evidence in support of linagliptin plus metformin as a well-tolerated and effective treatment alternative to insulin for new-onset patients with T2DM and severe hyperglycemia. © 2012 Springer Healthcare.


Petrak F.,Ruhr University Bochum | Herpertz S.,Ruhr University Bochum | Albus C.,University of Cologne | Hermanns N.,Diabetes Center Mergentheim | And 7 more authors.
BMC Psychiatry | Year: 2013

Background: Depression is common in diabetes and associated with hyperglycemia, diabetes related complications and mortality. No single intervention has been identified that consistently leads to simultaneous improvement of depression and glycemic control. Our aim is to analyze the efficacy of a diabetes-specific cognitive behavioral group therapy (CBT) compared to sertraline (SER) in adults with depression and poorly controlled diabetes.Methods/Design: This study is a multi-center parallel arm randomized controlled trial currently in its data analysis phase. We included 251 patients in 70 secondary care centers across Germany. Key inclusion criteria were: type 1 or 2 diabetes, major depression (diagnosed with the Structured Clinical Interview for DSM-IV, SCID) and hemoglobin A1C >7.5% despite current insulin therapy. During the initial phase, patients received either 50-200 mg/d sertraline or 10 CBT sessions aiming at the remission of depression and enhanced adherence to diabetes treatment and coping with diabetes. Both groups received diabetes treatment as usual. After 12 weeks of this initial open-label therapy, only the treatment-responders (50% depression symptoms reduction, Hamilton Depression Rating Scale, 17-item version [HAMD]) were included in the subsequent one year study phase and represented the primary analysis population. CBT-responders received no further treatment, while SER-responders obtained a continuous, flexible-dose SER regimen as relapse prevention. Adherence to treatment was analyzed using therapeutic drug monitoring (measurement of sertraline and N-desmethylsertraline concentrations in blood serum) and by counting the numbers of CBT sessions received. Outcome assessments were conducted by trained psychologists blinded to group assignment. Group differences in HbA1c (primary outcome) and depression (HAMD, secondary outcome) between 1-year follow-up and baseline will be analyzed by ANCOVA controlling for baseline values. As primary hypothesis we expect that CBT leads to significantly greater improvement of glycemic control in the one year follow-up in treatment responders of the short term phase.Discussion: The DAD study is the first randomized controlled trial comparing antidepressants to a psychological treatment in diabetes patients with depression.The study is investigator initiated and was supported by the 'Förderprogramm Klinische Studien (Clinical Trials)' and the 'Competence Network for Diabetes mellitus' funded by the Federal Ministry of Education and Research (FKZ 01KG0505). © 2013 Petrak et al.; licensee BioMed Central Ltd.

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