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Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride). In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) 6·5–10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1–4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284. 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA1c (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (–0·16% [SE 0·03]) and glimepiride groups (–0·36% [0·03]; difference 0·20%, 97·5% CI 0·09–0·30), meeting the predefined non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23–0·91, p=0·0213). The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient. Boehringer Ingelheim.

Sitagliptin (Januvia, Merck Pharmaceuticals) is a dipeptidyl-peptidase inhibitor (DPP-4 inhibitor) that has recently been approved for the therapy of type 2 diabetes. Like other DPP-4 inhibitors its action is mediated by increasing levels of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Sitagliptin is effective in lowering HbA1c, and fasting as well as postprandial glucose in monotherapy and in combination with other oral antidiabetic agents. It stimulates insulin secretion when hyperglycemia is present and inhibits glucagon secretion. In clinical studies it is weight neutral. This article gives an overview of the mechanism of action, the pharmacology, and the clinical efficacy and safety of sitagliptin in type 2 diabetes therapy.

Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18–85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA1C) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762. We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2–18·6], hazard ratio 0·748 [0·623–0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA1c concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. Eli Lilly and Company; Amylin Pharmaceuticals.

Dipeptidyl-peptidase-IV (DPP-4) inhibitors are oral antidiabetic agents that can be administered as monotherapy in patients with contraindications to metformin or metformin intolerance, and in combination with other oral compounds and/or insulin. DPP-4 inhibitors act in a glucose-dependent manner and only increase insulin secretion and inhibit glucagon secretion under hyperglycemic conditions. Renal impairment is frequent in type 2 diabetes as a result of microvascular complications and diabetes treatment, and options in these patients are limited. Linagliptin is a DPP-4 inhibitor with a hepatobiliary route of elimination. In comparative studies, it was noninferior to metformin and sulfonylureas in lowering glycated hemoglobin (HbA1c) and improving glycemic parameters. It can be used throughout all stages of renal impairment without dose adjustments. This review gives an overview of linagliptin in various stages of chronic kidney disease and has a focus on efficacy and safety parameters from clinical studies in patients with impaired renal function. These data are interpreted in the context of type 2 diabetes therapy in general.

Novel therapeutic options for type 2 diabetes mellitus based on the action of the incretin hormone glucagon-like peptide (GLP)-1 were introduced in 2005. As injectable GLP-1 receptor agonists acting on the GLP-1 receptor, exenatide and liraglutide are available in many countries. In type 2 diabetes treatment, incretin-based therapies are attractive and more commonly used because of their mechanism of action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by these agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycaemia. Furthermore, GLP-1 receptor agonists allow weight loss and lower systolic blood pressure. This review gives a brief overview of the mechanism of action and summarizes the clinical data available on exenatide and liraglutide as established substances. It further highlights the clinical study data of exenatide once weekly as the first long-acting GLP-1 receptor agonist and covers other new long acting GLP-1 receptor agonists currently in clinical development. The placement of GLP-1 receptor agonists in the treatment algorithm of type 2 diabetes is discussed.

Implications of Postprandial Glucose and Weight Control in People With Type 2 Diabetes Understanding and implementing the International Diabetes Federation guidelines Baptist Gallwitz , MD From the Department of Medicine IV, Eberhard-Karls-University Tübingen, Tübingen, Germany. Corresponding author: Baptist Gallwitz, baptist.gallwitz{at}med.uni-tuebingen.de . The International Diabetes Federation (IDF) recently published guidelines for the management of postmeal hyperglycemia. These guidelines were established in view of the risk of postmeal hyperglycemia for vascular events. Because of the rising incidence and prevalence of diabetes and its complications, the IDF took action to state useful strategies for the treatment of diabetes, focusing on the detection and therapy of postprandial hyperglycemia. Besides nonpharmacological measures (blood glucose self-control and diet), drugs such as short-acting insulinotropic agents (sulfonylureas and glinides), glucosidase inhibitors, insulin, and incretin-based therapies can specifically be used to act on postmeal glucose elevations. The specific action profiles of these agents are shown and discussed with respect to the IDF guidelines. POSTMEAL HYPERGLYCEMIA AS A RISK FACTOR IN TYPE 2 DIABETES Type 2 diabetes is a chronic and progressive disease that affects ∼250 million people worldwide today, with an increasing incidence in the years to come ( 1 ). With this epidemic dimension, type 2 diabetes is of global concern. Poor control of the disease is a leading cause of death in most developed countries and is associated with microvascular complications (renal failure and blindness due to retinopathy) and macrovascular complications (cardiovascular disease and stroke) as well as neurological complications such as diabetic neuropathy. Macrovascular complications are the major cause of death in type 2 diabetic patients ( 2 – 7 ). Numerous epidemiological studies have shown that postprandial hyperglycemia substantially adds to the micro- and macrovascular risk not only in type 1 and type 2 diabetes, but already in impaired glucose tolerance ( 2 – 4 , 8 ). The associations between postmeal hyperglycemia and markers of cardiovascular disease such as oxidative stress, inflammation, endothelial dysfunction, and carotid IMT have been well characterized. In addition, postprandial hyperglycemia has also been connected with the incidence of carcinomas and cognitive dysfunction in elderly type 2 diabetic patients ( 9 – 11 ). Large intervention trials … [Full Text of this Article]

Incretin based therapies have been introduced into the treatment options of type 2 diabetes a few years ago. Among them, the orally active DPP-4 inhibitors have established themselves as insulinotropic agents. Their advantage is the glucose-dependent insulinotropic action without an intrinsic risk for causing hypoglycemia. Additionally DPP-4 inhibitors have a glucose dependent glucagonostatic action contributing to improved glucose control. They are weight neutral and show a good safety and tolerability profile with comparable efficacy to sulfonylureas. Linagliptin is a novel DPP-4 inhibitor with a distinct pharmacological profile. In contrast to the other approved DPP-4 inhibitors it is eliminated by a hepatic/biliary route rather than a renal route. Therefore no dose adjustment is recommended in patients with type 2 diabetes and renal impairment. In clinical studies, it has been shown to be non-inferior to sulfonylurea treatment regarding glycemic parameters, but to possess favourable safety advantages regarding hypoglycemia frequency, body weight development and effects on cardioavascular parameters. This article gives an overview on the pharmacology of linagliptin as well as on the clinical data available.

Metformin has been recommended as first-line pharmacological therapy in type‑2 diabetes (T2D) since 1998. It was the first medication that demonstrated cardiovascular benefits in obese subjects with T2D. Efficacy and safety of metformin have since been demonstrated in further studies and in real-world data on its use in practice. The recommendation of metformin as baseline therapy has reached wide acceptance internationally. During the period 2015-2021, large cardiovascular safety trials showed superiority for cardiovascular morbidity and partly also mortality outcomes for most substances of the novel antidiabetic substance classes of GLP‑1 receptor agonists and SGLT‑2 inhibitors in people with T2D and very high cardiovascular risk or preexisting cardiovascular disease. The evidence for these two substance classes is now broader than for metformin. Therefore, the question arises as to whether it is still justified to recommend metformin generally as first-line therapy in T2D. This article provides an overview of the study data as well as an overview of the evidence-based guidelines. The status and position of metformin in the treatment of T2D are discussed.

Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.

Because of the rising incidence and prevalence of diabetes and its complications, the IDF took action to state useful strategies for the treatment of diabetes, focusing on the detection and therapy of postprandial hyperglycemia. Besides nonpharmacological measures (blood glucose self-control and diet), drugs such as shortacting insulinotropic agents (sulfonylureas and glinides), glucosidase inhibitors, insulin, and incretin-based therapies can specifically be used to act on postmeal glucose elevations. A distinct glycémie threshold for the reduction of complications has not been found; therefore, the goal of antidiabetic treatment should be to achieve nearnormoglycemia as safely as possible regarding AlC, fasting plasma glucose, and postprandial glucose concentrations.