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.     

Elucidating the glucose-lowering effect of the bile acid sequestrant sevelamer

Aim: Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes. Materials and Methods: In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH₂ or saline. Results: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH₂ increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH₂ abolished the sevelamer-induced improvement in beta-cell glucose sensitivity. Conclusions: The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH₂ we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.     

No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin

A single-blind, placebo-controlled, cross-over trial investigating possible interactions beween paroxetine, a serotonin re-uptake inhibitor, and carbamazepine (CBZ), valproate (VPA) and phenytoin (PHT) was carried out in 20 outpatients with epilepsy. Patients on long-term treatment with CBZ, VPA, or PHT were given a 7-day placebo treatment, followed by paroxetin co-treatment for 16 days. Side effects were infrequent and mild. Paroxetine caused no changes in the plasma concentrations and all values were within the recommended ranges. No changes in protein binding were found. Plasma concentrations of paroxetine at steady state (8–147 ng/ml) were in the normal range for a 30-mg daily dosing regimen. None of the patients experienced epileptic seizures during the study.     

Treatment of multiple myeloma with an intensive 5-drug combination or intermittent melphalan and prednisone; a randomised multicentre trial

In a randomised multicentre trial a combination of methylprednisolone, vincristine, CCNU, cyclophosphamide and melphalan (MOCCA) was compared with intermittent melphalan and prednisone (MP) as primary treatment in multiple myeloma. In the MP arm the refractory or relapsed patients were treated with regimen MOCCA. The MOCCA arm produced a response rate of 75% among 64 patients and the MP arm a respone rate of 54% among 66 patients. The median surival was 41 months in the MOCCA arm and 45 months in the patients primarily randomised to the MP arm. The initial response to MOCCA improved the survival, while this effect was not statistically significant in the MP arm. The results show that the median surivival does not increase if aggressive chemotherapy is employed as the first line treatment in multiple myeloma.     

Salt and nitric oxide synthase inhibition-induced hypertension: kidney dysfunction and brain anti-oxidant capacity

The specific aim of this study was to examine the effects of salt-loading on kidney function and brain antioxidant capacity. Wistar rats were divided into four groups: Control rats were given normal drinking water and no drug treatment for 2 weeks. LNNA group: rats were given normal drinking water and the nitric oxide (NO) inhibitor NG-nitro-L-arginine (L-NNA), 3 mg/kg/day. LNNA + Salt group: rats were given drinking water containing salt 2% and 3 mg/kg L-NNA. Salt group: rats were given drinking water containing salt 2% and no drug treatment. Basal blood pressure and the levels of serum BUN, creatinine, uric acid, cortisol, electrolyte, serum antioxidant capacity, and oxidative stress were measured. NO, superoxide dismutase (SOD), and catalase (CAT) levels were measured in the hypothalamus, brainstem, and cerebellum. Salt overload increased the blood pressure of the LNNA + Salt group. Salt-loading enhanced BUN, creatinine, sodium retention. High salt produced an increase in uric acid levels and a decrease in cortisol levels in serum. Additionally, the oxidative stress index in serum increased in the LNNA + Salt group. Salt-loading enhanced brain NO levels, but not SOD and CAT activity. L-NNA increased brain SOD activity, but not CAT and NO levels. In conclusion, salt-loading causes hypertension, kidney dysfunction, and enhances oxidative stress in salt-sensitive rats.     

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes

Introduction: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D).

Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit–risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide.

Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.     

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. Metformin's 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 metformin's 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.     

Does bilateral ITA grafting increase perioperative complications? Outcome of 4462 patients with bilateral versus 4204 patients with single ITA bypass.

OBJECTIVE: Superior patency of internal thoracic artery (ITA) grafting to saphenous veins is conclusive. The aim of the present study was to compare the early outcome of patients receiving either bilateral ITA (BITA) or single ITA (SITA) grafts and to identify risk factors for perioperative complications, such as obesity, diabetes mellitus, or advanced age. METHODS: All 8666 patients with isolated coronary artery bypass grafting (CABG, including emergent cases or redos) operated between January 1994 and June 2004 receiving either BITA (n=4462) or SITA (n=4204) grafting were analyzed retrospectively. Demographic data were comparable for both groups concerning mean age (65.3+/-9.4 years vs 64.9+/-9.3 years), range (35-89 years (p=0.05)), diabetes incidence (29.3% vs 2.6% (p=0.08)), dialysis-dependent renal failure (0.7% vs 0.6% (p=0.4)), preoperative ejection fraction (EF) mean (61.8% vs 61.2% (p=0.07)) but not for gender (80.4% vs 76.7% males (p=0.00)), body mass index (BMI) mean (27.2+/-3.6 vs 26.9+/-3.5 (p=0.00)), COPD (7.0% vs 8.5% (p=0.00)), and hyperlipidemia (78.3% vs 74.3% (p=0.00)). In the BITA group, right ITA (RITA) was directed preferentially to the left anterior descending artery (LAD), left ITA (LITA) to the lateral wall. In the SITA group, the LAD was revascularized with the left ITA. Additional bypasses were performed with saphenous vein grafts (SVG). RESULTS: The number of anastomoses was higher in the BITA group (3.8+/-0.9 vs 3.1+/-0.9 (p=0.00)); therefore, duration of surgery (mean: 189+/-46.3 min vs 164+/-46.2 min) and cross-clamp time (62.0+/-17.9 min vs 51.0+/-18.0 min) significantly prolonged (p=0.00). Incidence of rethoracotomy due to bleeding (2.9% vs 0.6%; p=0.00) or sternal refixation with (0.7% vs 0.2%; p=0.00) or without infection (1.4% vs 0.6%; p=0.00) was higher in the BITA group, strongly associated with diabetes mellitus and duration of surgery but not with BMI>27. Thirty-day mortality revealed 2.6% versus 3.2% (p=0.1) but was significantly lower for diabetic patients in the BITA group (3.1% vs 4.7%; p=0.00). CONCLUSIONS: CABG using both ITAs can be performed routinely with good clinical results and low mortality. Compared with single ITA grafting, sternal and bleeding complications were slightly increased. Diabetes mellitus, BITA grafting, duration of surgery but not obesity or COPD could be identified as independent risk factors for sternal complications. Dialysis-dependent renal failure, EF<30%, emergent cases, and the absence of BITA grafting were predictors for increased perioperative mortality.