EMERGING THERAPIES: DRUGS AND REGIMENS Diabetes Care 1 Christopher K. Rayner,1,2 Linda E. Watson,1 Effects of Sustained Treatment Liza K. Phillips,1,3 Kylie Lange,1 Michelle J. Bound,1 Jacqueline Grivell,1 With Lixisenatide on Gastric Tongzhi Wu,1,3 Karen L. Jones,1,3 Michael Horowitz,1,3 Ele Ferrannini,4 Emptying and Postprandial Domenico Trico,` 5 Silvia Frascerra,6 Glucose Metabolism in Type 2 Andrea Mari,7 and Andrea Natali6 Diabetes: A Randomized Controlled Trial https://doi.org/10.2337/dc20-0190 OBJECTIVE Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a “short-acting” GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. RESEARCH DESIGN AND METHODS 1Centre of Research Excellence for Translating A total of 30 patients with metformin-treated type 2 diabetes underwent assessment Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) 2Department of Gastroenterology and Hepatol- aftera75-gglucosedrink,beforeandafter8weeks’treatmentwithlixisenatide(20mg ogy, Royal Adelaide Hospital, Adelaide, Australia subcutaneously daily) or placebo, in a double-blind randomized parallel design. 3Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia RESULTS 4CNR Institute of Clinical Physiology, Pisa, Italy 5Department of Surgical, Medical and Molecular Gastric retention of the glucose drink was markedly increased after lixisenatide Pathology and Critical Care Medicine, University versus placebo (ratio of adjusted geometric means for area under curve [AUC] over of Pisa, Pisa, Italy 240min of 2.19[95%CI 1.82, 2.64;P< 0.001]), associatedwith substantial reductions 6Department of Clinical and Experimental Med- in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC icine, University of Pisa, Pisa, Italy 7CNR Institute of Neuroscience, Padua, Italy for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P 5 0.003) and P 5 Corresponding author: Christopher K. Rayner, insulin ( 0.032), but not endogenous glucose production, over 120 min after oral [email protected] glucose intake. Postprandial glucose lowering over 240 min was strongly related to Received 27 January 2020 and accepted 28 April the magnitude of slowing of gastric emptying by lixisenatide (r 520.74, P 5 0.002) 2020 and to the baseline rate of emptying (r 5 0.52, P 5 0.048) but unrelated to b-cell Clinical trial reg. no. ACTRN12616001059459, function (assessed by b-cell glucose sensitivity). www.anzctr.org.au This article contains supplementary material online CONCLUSIONS at https://doi.org/10.2337/figshare.12245516. Eight weeks’ treatment with lixisenatide is associated with sustained slowing of © 2020 by the American Diabetes Association. gastric emptying and marked reductions in postprandial glycemia and appearance Readers may use this article as long as the work is properly cited, the use is educational and not for of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially fi fi pro t, and the work is not altered. More infor- represent an effective long-term therapy for speci cally targeting postprandial mation is available at https://www.diabetesjournals glucose excursions. .org/content/license. Diabetes Care Publish Ahead of Print, published online May 29, 2020 2 Gastric Emptying With Sustained Lixisenatide Diabetes Care Early intervention to achieve good gly- The evolution of type 2 diabetes is Study Design cemic control in type 2 diabetes can characterized by progressive b-cell After enrolment, participants were ran- reduce the risk of micro- and potentially failure, which entails a loss of insulin domized to treatment with lixisenatide macrovascular complications but entails secretory capacity and, eventually, a re- or placebo in a double-blind parallel risks, particularly for insulin therapy, of duction in b-cell mass (16). A therapy that design. Patients attended our Clinical weight gain and hypoglycemia (1). Re- targets postprandial glycemia, without Research Facility for a baseline study cent guidelines recommend an individ- the requirement to stimulate insulin se- where a glucose drink was administered ualizedapproachtotheselectionof cretion, is an attractive therapeutic op- (day 0) before commencing treatment second-line pharmacological treatment tion, and there is recent evidence that with daily subcutaneous injections from after metformin (2). In the majority of lixisenatide maintains its efficacy for day 1 to day 56. They attended the type 2 patients in the community, who lowering HbA1c across the spectrum of laboratory for a second study on the have relatively modest elevation of gly- b-cell function in patients with type 2 last day of treatment (day 56), when fi cated hemoglobin (HbA1c) (3), postpran- diabetes (17). they received their nal dose of lixise- dial rather than fasting blood glucose We aimed to evaluate the effects of natide or placebo 30 min before the plays an important role in overall glyce- sustained use of lixisenatide on gastric glucose test drink. mic control (4), which is not surprising emptying, using the most accurate tech- On each of the two study days (days given that humans are predominantly in nique of scintigraphy, and on postpran- 0 and 56), patients attended our facility the postprandial state. It is now apparent dial glucose metabolism, using a dual in the morning (0800 h) after an over- that postprandial glycemia must be spe- glucose tracer technique (18), in patients night fast, having consumed a standard- cifically targeted in patients with diabe- with relatively well-controlled type 2 di- ized beef lasagne meal the previous tes, particularly in those who have only abetes treated with metformin alone. We evening. An intravenous (IV) cannula moderately elevated HbA1c with minimal hypothesized that, as a short-acting GLP-1 wasinsertedineachforearm:onefor fasting hyperglycemia (5). receptor agonist, lixisenatide would have blood sampling and the other for IV The gut-derived incretin hormone, glu- persistingeffectstoslowgastricemptying infusion of glucose tracer (bolus of 21 2 cagon-like peptide 1 (GLP-1), has several with sustained use and that this would 28 mmol z kg 6,6-[ H2]glucose, fol- actions that lower glycemia, including be a dominant mechanism by which it lowed by continuous infusion at a 2 2 slowing of gastric emptying, glucose- achieves postprandial blood glucose rate of 0.28 mmol z min 1 z kg 1 dependent stimulation of insulin, and sup- control. from t 52180 until t 5 240 min). At pression of glucagon (6–8), all of which t 525 min, a 300-mL drink was given potentially impact on the systemic ap- RESEARCH DESIGN AND METHODS while the subject sat against a g camera, pearance of orally ingested carbohydrate Subjects consisting of 75-g glucose, labeled with and the rate of endogenous glucose We recruited, by advertisement, patients 20 MBq 99mTc-calcium phytate, and also production. The rate at which nutrients with a history of type 2 diabetes of $2 containing 1.5 g [U-13C]glucose. The drink empty from the stomach is a particularly years’ duration, treated with metformin was consumed within 5 min, and scinti- important determinant of postprandial for $3 months. Responders who met graphic imaging continued for 240 min, glycemia in health and type 2 diabetes (9), eligibility criteria attended our facility with correction of data for subject move- and pharmacological agents that slow gas- for a screening visit, when fasting blood ment, radionuclide decay, and g-ray tric emptying result in a lowering of the samples were collected for blood picture, attenuation (21). Gastric retention (ex- postprandial blood glucose excursion (10). iron studies, biochemistry, and HbA1c; pressed as % of the maximum content A number of GLP-1 receptor agonists autonomic function was evaluated by of the total stomach) was calculated at have been developed for the treatment standardized cardiovascular tests (19); 15-min intervals for the first 120 min of type 2 diabetes; these differ in being and gastrointestinal symptoms were andthenhourlyuntilt 5 240 min. “short acting” (e.g., lixisenatide or ex- evaluated by questionnaire (20). Those Venous blood was sampled at frequent 21 enatide BD) or “long acting” (e.g., liraglu- with HbA1c ,6.5% (48 mmol z mol ) intervals for measurement of blood tide or exenatide QW). There is recent or .9.0% (75 mmol z mol21), estimated glucose and plasma concentrations of evidence that continuous exposure to glomerular filtration rate ,30 mL z min21, glucosetracers,insulin,C-peptide,and GLP-1is associated withtachyphylaxis for definite autonomic neuropathy, elevated glucagon. A fasting sample was also its effects on gastric emptying (11,12). liver enzymes, hospital admission for car- collected on day 56 to measure HbA1c. Consistent with this concept, postpran- diovascular disease within the previous dial glycemia appears to be better con- 6 months, previous exposure to GLP-1 Intervention trolled after several weeks’ treatment receptor agonists, or prominent gastro- On days 1–56 inclusive, each subject self- with short-acting versus long-acting GLP- intestinal symptoms or using medications administered lixisenatideor matchingpla- 1 receptor agonists, although typically in known to affect gastrointestinal motility cebo (saline) subcutaneously