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How the many antidiabetic drugs work
Published in Hugh McGavock, How Drugs Work, 2017
The remaining oral antidiabetics do not act on B cells but reduce plasma glucose by a number of other actions. Everyone involved in treating Type 2 diabetic patients should understand all of these, and how and why they can be combined with the sulfonylureas and meglitinides (see above). Metformin. This is one of the most frequently prescribed oral antidiabetics. It reduces plasma glucose first, by reducing glucose synthesis in the liver; second, by increasing insulin action in fat and muscle; and third, by reducing glucose absorption from the intestine. It will not work unless the patient's B cells are secreting some insulin. Metformin is the drug of first choice in obese Type 2 diabetes, and as the condition deteriorates, it can be combined with all of the oral antidiabetic drugs mentioned above and below, and with insulin when that is needed. It has some side-effects and should not be used in patients with renal, or hepatic or cardiac failure or in advanced chronic obstructive pulmonary disease (COPD).Pioglitazone. One of the features of Type 2 diabetes is tissue insensitivity to insulin, often called 'insulin resistance'. This involves particularly liver, muscle and fat. Insulin resistance is strongly associated with abdominal obesity. Pioglitazone reduces peripheral insulin resistance, thus 'making the most' of the remaining insulin. It also reduces glucose output by the liver. It is often combined with metformin and/or a sulfonylurea.The gliptins. Linagliptin, saxagliptin, sitagliptin and vildagliptin act in the mucous membrane of the duodenum and small intestine, causing release of peptide hormones which slow the rate of gastric emptying, reduce pancreatic glucagon secretion (A cells) and begin insulin secretion in 'anticipation' of the rise in plasma glucose which results from the meal.Exenatide. This drug must be taken by subcutaneous injection. It mimics the effects of one of the intestinal peptide hormones (see 3 above), with similar therapeutic results. It also reduces appetite, helping weight loss. Liraglutide and lixisenatide have similar actions and must also be injected subcutaneously.Acarbose. By delaying carbohydrate absorption, acarbose lowers the 'peak' of plasma glucose following a meal. Patients often dislike its side-effects (intestinal), well-described in BNF, Chapter 6.1.2.Dapagliflozin. This new drug reduces glucose reabsorption from the renal tubule (seeChapter 4), increasing urinary glucose excretion. Dapagliflozin is ineffective in even moderate renal failure.
Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes
Published in Postgraduate Medicine, 2019
The observed differences in the results from CVOTs of the different GLP-1RAs may be explained by variations in the short-acting compared to long-acting nature of the formulations, different study designs, and different patient populations [52]. Lixisenatide is a short-acting exenatide-based formulation that has a half-life of ~3 hours and the characteristics of the patient population of the ELIXA trial were very different from that of other CVOTs. Furthermore, exenatide QW is a long-acting formulation like albiglutide, dulaglutide, liraglutide, and semaglutide; however, the pragmatic study design of the EXSCEL trial was fundamentally different from the other CVOT designs and may have impacted the trial results [52]. However, a meta-analysis that included data from the LEADER, SUSTAIN-6, EXSCEL, ELIXA, HARMONY, REWIND, and PIONEER 6 studies indicated that GLP-1RAs as a class reduce the risk of three-point MACE, CV mortality, and all-cause mortality compared with placebo [53]. These findings suggest that GLP-1RAs reduce the risk of CV events over time through antiatherogenic mechanisms, including decreased BP and effects on cardiac output, anti-inflammatory pathways, endothelial function, and ischemic conditioning [53,54].
Impact of lixisenatide dose range on clinical outcomes with fixed-ratio combination iGlarLixi in patients with type 2 diabetes
Published in Current Medical Research and Opinion, 2019
Juan Pablo Frias, Martin Lorenz, Michelle Roberts, Terry Dex, Wolfgang Schmider, William Hurst, Neil Skolnik
The efficacy and safety of lixisenatide have been demonstrated in a number of clinical trials14–17,20–27. In a review of clinical studies, lixisenatide treatment produced mean reductions of 0.46–0.99% in A1C, 55.86–143.43 mg/dL in 2-hour PPG levels (through gastric emptying, its principal mechanism of action), and 56.58–127.75 mg/dL in mealtime glucose levels25. In the comprehensive phase 3 GetGoal clinical program, lixisenatide demonstrated efficacy when added to a range of background treatments in different patient populations from America, Europe, and Asia24,25. In this program, the addition of lixisenatide resulted in changes in FPG levels and weight from −21.98 to +5.41 mg/dL and from −2.96 to +0.3 kg, respectively25.
Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy
Published in Current Medical Research and Opinion, 2018
Ronald M. Goldenberg, Lori Berard
Three hundred and eleven patients were randomized to either lixisenatide (n = 154) or placebo (n = 157). Lixisenatide was administered in a stepwise dose increase to 20 µg OD. Baseline HbA1c was 8.5%. Once-daily lixisenatide significantly improved HbA1c vs placebo (LS mean changes were –0.77% for the lixisenatide group and +0.11% for the placebo group; LS mean difference vs placebo = –0.88%; p < .0001). Lixisenatide allowed more patients to achieve HbA1c < 7.0% (35.6% vs 5.2%) and ≤6.5% (17.8% vs 1.3%). Lixisenatide also had a pronounced effect on postprandial glycemic control by significantly improving 2-h PPG and glucose excursion. Furthermore, significant changes vs placebo were achieved for average 7-point self-monitored blood glucose and FPG.