Andreas Brønden

Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin.

Metformin is an oral antihyperglycaemic drug used in the first‐line treatment of type 2 diabetes. Metformins classic and most well‐known blood glucose‐lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose‐lowering gut incretin hormone glucagon‐like peptide‐1 (GLP‐1), which may contribute to metformins glucose‐lowering effect in patients with type 2 diabetes. The mechanisms behind metformin‐induced increments in GLP‐1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP‐1 secretion directly and/or indirectly and that metformin prolongs the half‐life of GLP‐1. Also, it has been suggested that metformin may potentiate the glucose‐lowering effects of GLP‐1 by increasing target tissue sensitivity to GLP‐1. The present article critically reviews the possible mechanisms by which metformin may affect GLP‐1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose‐lowering actions of metformin.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

CONTEXT Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. OBJECTIVE We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN A double-blinded, randomized study. SETTING The study was conducted at a specialized research unit. PARTICIPANTS Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). INTERVENTION On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. MAIN OUTCOME MEASURES Plasma levels of GLP-1. RESULTS CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CONCLUSIONS CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

Exenatide: pharmacokinetics, clinical use, and future directions

ABSTRACT Introduction: The first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use. Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations. Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D.

Cardiovascular safety and benefits of GLP-1 receptor agonists

ABSTRACT Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years. Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits. Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging – and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.

Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential

Sevelamer is a calcium‐free and metal‐free phosphate‐binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid‐lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These ‘novel’ effects are most probably derived from the bile acid‐binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose‐lowering effect of the drug.

Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes: A review

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well‐described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long‐acting GLP‐1RAs, but the risk–benefit ratio emerging from studies evaluating the effect of long‐acting GLP‐1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long‐acting GLP‐1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP‐1‐induced retardation of gastric emptying. In contrast, the short‐acting GLP‐1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short‐acting GLP‐1RAs are all derived from small open‐label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP‐1RAs, in particular short‐acting GLP‐1RAs, as add‐on to insulin in the treatment of type 1 diabetes.

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Bile acids are amphipathic water‐soluble steroid‐based molecules best known for their important lipid‐solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose‐lowering potential. Among a variety of gluco‐metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut‐derived incretin hormone glucagon‐like peptide‐1 (GLP‐1), possibly via the transmembrane receptor Takeda G‐protein‐coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion, and discusses whether bile acid‐induced GLP‐1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium‐dependent bile acids transporter, and bile acid sequestrants – old, new and neglected glucose‐lowering drugs – improve glucose metabolism.

Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer

Sevelamer, a non‐absorbable amine‐based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid‐binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose‐lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.

The bile acid‐sequestering resin sevelamer eliminates the acute GLP‐1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein‐coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon‐like peptide‐1 (GLP‐1) secretion and glucose metabolism. The aim of the present study was to assess the GLP‐1 secretory and gluco‐metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid‐sequestering resin, sevelamer, in patients with type 2 diabetes.

Single-Dose Metformin Enhances Bile Acid–Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes

Context: Despite a position as the first‐line pharmacotherapy in type 2 diabetes, the glucose‐lowering mechanisms of metformin remain to be fully clarified. Gut‐derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon‐like peptide‐1 (GLP‐1) secretion, have been proposed. Objective: The aim of this study was to assess the GLP‐1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single‐dose administration of metformin in patients with type 2 diabetes. Design: Randomized, placebo‐controlled, and double‐blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin‐treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg−1 × min−1) or saline. Main Outcome Measure: Plasma GLP‐1 excursions as measured by baseline‐subtracted area under the curve. Results: Single‐dose metformin further enhanced bile acid‐mediated induction of GLP‐1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP‐1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin‐induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP‐1‐mediated induction of insulin secretion or suppression of glucagon was observed. Conclusions: Metformin elicited an enhancement of the GLP‐1 response to cholecystokinin‐induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.