Diabetes Obesity and Metabolism·Jones et al.·Meta-Analysis
In 2016, the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, was shown in the LEADER study to prevent cardiovascular events in type 2 diabetes.1 The majority of GLP-1 receptor agonists developed subsequently have shown similar effects,2 including the recent SELECT trial of subcutaneous semaglutide in obese individuals with cardiovascular disease but without diabetes.3 The latter study adds to compelling evidence that the cardiovascular, as well as renal, protective effects of GLP-1 receptor agonists are not primarily dependent on glucose-lowering. It is sobering to appreciate that these cardiovascular outcome trials, which have had a major impact on clinical practice, were mandated by regulatory bodies, and the strikingly positive outcomes were generally unanticipated. Several direct and indirect mechanisms have been postulated to account for the cardio-renoprotective properties of GLP-1 receptor agonists.2 Hypertension, a major risk factor for cardiovascular disease, occurs in the majority of people with type 2 diabetes, and its treatment represents a major focus of management. Perhaps surprisingly, none of the cardiovascular outcome trials was specifically designed to assess the effects of GLP-1 receptor agonists on blood pressure, and there is also a lack of information about the methodology used to evaluate blood pressure in these studies. An antihypertensive effect of GLP-1 receptor agonists has, however, been consistently evident, e.g. initially in phase 3 (LEAD) trials, then confirmed in LEADER.1 It is generally accepted that GLP-1 receptor agonists induce a modest, but potentially clinically meaningful, 2-6 mmHg reduction in systolic blood pressure in hypertensive individuals. This reduction is evident 2-3 weeks after initiating treatment (i.e. before the occurrence of significant weight loss). In contrast, there is little, if any, effect on diastolic blood pressure, and systolic blood pressure does not fall as much in normotensive individuals. GLP-1 receptor agonists also induce modest (2-4 beats/min) tachycardia, irrespective of the presence of hypertension. These effects of GLP-1 receptor agonists on blood pressure are supported by Rivera et al.,4 who performed a systematic review and meta-analysis of randomized controlled trials relating to the effects of four GLP-1 receptor agonists, semaglutide subcutaneously, exenatide once weekly, liraglutide and dulaglutide, on blood pressure in both type 2 diabetes and obesity without type 2 diabetes.4 Not surprisingly, Rivera et al. report marked inconsistencies in the design and duration of these studies; moreover, 31 of 63 related to liraglutide. While a previous analysis suggested that blood pressure reduction did not contribute to the cardiovascular benefits observed in LEADER,1 this issue remains contentious. Based primarily on the outcomes of animal studies, heterogeneous mechanisms, including increased natriuresis and endothelial-dependent arterial relaxation, may underlie the blood pressure-lowering effect of GLP-1 receptor agonists.2 Numerous factors are known to affect the accurate measurement of blood pressure, many of which have been incorporated into current guidelines for the diagnosis and management of hypertension.5 These include the timing of measurement (morning or night), setting (office or home) and posture of the individual (sitting, supine or standing); moreover, continuous ambulatory monitoring provides more insights than single point measurement.5 It is also recognized that blood pressure may be influenced by age, sex and body weight. Although some guidelines suggest that blood pressure monitoring should be undertaken following an overnight fast, there has generally been a lack of attention to the timing of blood pressure measurements in relation to meals. None of the studies reported by Rivera et al.4 evaluated the impact of GLP-1 receptor agonists on postprandial blood pressure. This is an important consideration because postprandial hypotension [currently defined as a fall in systolic blood pressure of ≥20 mmHg within 2 h of the start of a meal (or to <90 mmHg when baseline systolic blood pressure is >100 mmHg)] has been shown in a number of epidemiological studies to be a major cause of both morbidity and mortality,6-8 predisposing to syncope, falls, coronary events and stroke.6, 8 For example, a recent meta-analysis indicated that postprandial hypotension is associated with a 52% increase in the risk of combined cardiovascular disease outcomes and all-cause mortality.8 It is generally not appreciated that the prevalence of postprandial hypotension is high, occurring in about 25-40% of people with type 2 diabetes,9 50% of nursing home residents7 and about 15-30% of apparently ‘healthy’ older people.10 Not surprisingly, the magnitude of the postprandial fall is greater when baseline systolic blood pressure is higher.6 Postprandial hypotension occurs much more frequently in type 2 diabetes than orthostatic hypotension, despite being less well recognized. To some extent, this reflects the absence of an effective treatment for postprandial hypotension, resulting in a dearth of intervention studies that are required to clarify the clinical significance of postprandial hypotension. Postprandial hypotension is, however, not an unexpected phenomenon; meal ingestion is associated with an approximate doubling of intestinal blood flow, which, in health, leads to a substantial increase in heart rate to maintain blood pressure.6 Accordingly, a fall in blood pressure is indicative of inadequate cardiovascular compensation.6 The pathophysiology of postprandial hypotension is incompletely understood, but several factors appear important in addition to the increase in small intestinal blood flow, including autonomic nerve function and the release of gastrointestinal hormones.6 Both the prevalence of postprandial hypotension and the magnitude of the fall have been shown to be greater when the rate of gastric emptying is relatively more rapid.9, 10 There is an approximate four-fold variation in gastric emptying between healthy individuals, and it is now appreciated that accelerated, rather than delayed, gastric emptying is characteristic of both uncomplicated type 2 diabetes and obesity.11 Moreover, slowing of gastric emptying by dietary12 or pharmacological13-15 interventions has been shown to attenuate the magnitude of the fall in systolic blood pressure and may abolish it. Postprandial changes in blood pressure are of particular relevance to the use of GLP-1 receptor agonists; persuasive evidence has shown that native GLP-113, 16 and both short-14, 17, 18 and long-acting15 GLP-1 receptor agonists have the capacity to diminish the postprandial fall in blood pressure in both healthy people and those with type 2 diabetes. It was initially shown that intravenous infusion of GLP-1(7-36), at a dose of 0.9 pmol/kg markedly attenuated the hypotensive response to an intraduodenal infusion of glucose (3 kcal/min) in healthy older people16 and a 75 g oral glucose drink in type 2 diabetes.13 In the latter study, the effect of GLP-1(7-36) on diminishing the fall in blood pressure was associated with a substantial reduction in both superior mesenteric artery blood flow and the rate of gastric emptying.13 These observations underpinned the therapeutic potential for GLP-1 receptor agonists in the management of postprandial hypotension, which has been supported by subsequent studies.17, 18 Accordingly, in uncomplicated type 2 diabetes, an intravenous infusion of the short-acting GLP-1 receptor agonist, exenatide (twice daily) was shown to markedly attenuate the fall in blood pressure induced by a mixed meal.18 A subsequent study, published in this journal, established ‘proof-of-principle’ for the use of the short-acting GLP-1 agonist, lixisenatide, in the management of postprandial hypotension.14 An acute dose of only 10 μg lixisenatide (half the dose characteristically used in the management of type 2 diabetes) was shown predictably to slow gastric emptying of a 75 g glucose drink but also prevent the postprandial fall in blood pressure in both healthy older individuals and those with type 2 diabetes. Long-acting GLP-1 receptor agonists, contrary to previous dogma, are now recognized to have a variable but sustained effect to slow gastric emptying,15, 19, 20 and the long-acting agonist, exenatide, given once weekly for 8 weeks, was recently shown to attenuate the postprandial fall in systolic blood pressure following a mashed potato meal in type 2 diabetes.15 While the ‘chronic’ effects of short- and longer-acting GLP-1 receptor agonists on postprandial blood pressure remain to be determined, it would not be surprising if they proved useful in the management of postprandial hypotension. Moreover, a reduction in postprandial hypotension may be relevant to the beneficial cardiovascular effects of GLP-1 receptor agonists. Given the seminal importance of elevated blood pressure as a cardiovascular risk factor, its pivotal relevance to pathological conditions such as postprandial hypotension,8 and the effects shown by GLP-1 receptor agonists on both fasting and postprandial blood pressure, we believe that the assessment of the effects of GLP-1 receptor agonists on blood pressure should be optimized. This would involve the use of standardized, state-of-the-art methodology, including ambulatory recording and evaluation of meal-induced changes in blood pressure. Such innovation is, from our perspective, overdue. Moreover, the resulting insights will probably be of relevance to an improved understanding of the cardioprotective effects of GLP-1 receptor agonists. KLJ: wrote the first draft of the manuscript. All authors: edited, reviewed and approved the final version. KLJ salary is supported by a University of Adelaide William T Southcott Senior Research Fellowship. TW is supported by a Mid-Career Fellowship from The Hospital Research Foundation. CSM is supported by an Early Career Fellowship provided by the National Health and Medical Research Council of Australia. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. KLJ holds stocks options with Glyscend Therapeutics. TW has received travel support from Novartis and Sanofi and research funding from Novartis. CKR has received research funding from Novartis and Sanofi, honoraria for lectures from Eli Lilly, and participated in advisory boards for Glyscend Therapeutics. MAN has been member on advisory boards or consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma and Structure Therapeutics (ShouTi, Gasherbrum), received grant support from Merck, Sharp & Dohme, and has served on the speakers' bureau of Eli Lilly & Co., Menarini/Berlin Chemie, Merck, Sharp & Dohme, Medscape, Medical Learning Institute and NovoNordisk. MH has participated in the advisory boards and/or symposia for Inova and has received honoraria for this activity; he is a shareholder with Mirum Pharmaceuticals and has stock options with Glyscend Therapeutics. CSM has no conflicts of interest to declare. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15631. Not applicable.
