Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas

The gastrointestinal hormone glucagon‐like peptide‐1 (GLP‐1) lowers postprandial glucose concentrations by regulating pancreatic islet‐cell function, with stimulation of glucose‐dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP‐1 are at least as important for glucose‐lowering. GLP‐1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP‐1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP‐1 receptor agonists, which mimic the effects of GLP‐1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP‐1 receptor agonists can be broadly categorized as short‐ or long‐acting, with each having unique islet‐cell and gastrointestinal effects that lower glucose levels. Short‐acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long‐acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β‐cell function.     

Glucagon‐like peptide‐1 receptor agonists in type 2 diabetes treatment: are they all the same?

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are an important class of drugs with a well‐established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin‐4 (a compound present in Gila monster venom) or modifications of human GLP‐1 active fragment. Differences among these drugs in duration of action (ie, short‐acting vs long‐acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP‐1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short‐acting and long‐acting GLP‐1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short‐acting (ie, exenatide twice daily and lixisenatide) and long‐acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP‐1 RAs is that short‐acting agents primarily delay gastric emptying (lowering postprandial glucose) and long‐acting agents affect both fasting glucose (via enhanced glucose‐dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long‐acting GLP‐1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long‐acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.     

Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists

Currently, six glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short‐acting exenatide twice daily and lixisenatide once daily; and longer‐acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP‐1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head‐to‐head trials and one large phase II study have compared the efficacy and safety of these seven GLP‐1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short‐acting GLP‐1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer‐acting agents, whereas the longer‐acting compounds reduced plasma glucose throughout the 24‐h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP‐1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection‐site reactions than liraglutide and dulaglutide. GLP‐1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP‐1RAs and delivery methods may further expand future treatment options.     

The extra‐pancreatic effects of GLP‐1 receptor agonists: a focus on the cardiovascular,gastrointestinal and central nervous systems

The glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta‐cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP‐1 receptors are also expressed in extra‐pancreatic tissues and trial data suggest that GLP‐1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP‐1 or GLP‐1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP‐1RAs in both people with type 2 diabetes and obese people without diabetes. GLP‐1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP‐1RA‐induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP‐1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra‐pancreatic effects of GLP‐1RAs could provide multi‐factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP‐1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP‐1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.     

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short‐acting, prandial, and long‐acting GLP‐1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short‐acting prandial GLP‐1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.     

The role of glucagon‐like peptide‐1 impairment in obesity and potential therapeutic implications

The hormone glucagon‐like peptide‐1 (GLP‐1) is released from the gut in response to food intake. It acts as a satiety signal, leading to reduced food intake, and also as a regulator of gastric emptying. Furthermore, GLP‐1 functions as an incretin hormone, stimulating insulin release and inhibiting glucagon secretion from the pancreas in response to food ingestion. Evidence suggests that the action or effect of GLP‐1 may be impaired in obese subjects, even in those with normal glucose tolerance. GLP‐1 impairment may help explain the increased gastric emptying and decreased satiety signalling seen in obesity. Incretin impairment, probably associated with reduced insulinotropic potency of GLP‐1, is also characteristic of type 2 diabetes (T2D). Therefore, it is possible that incretin impairment may contribute to the pathophysiological bridge between obesity and T2D. This review summarises current knowledge about the pathophysiology and consequences of GLP‐1 and incretin impairment in obesity, and examines the evidence for an incretin‐related link between obesity and T2D. It also considers the current literature surrounding the novel use of GLP‐1 receptor agonists as a treatment for obesity in patients with normoglycaemia, prediabetes and T2D.     

Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) increase insulin release and suppress glucagon secretion in a glucose‐dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP‐1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP‐1RAs is limited. The combination of a GLP‐1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP‐1RA–insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP‐1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined.     

Glucagon‐like peptide‐1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes

Glucagon‐like peptide‐1 receptor agonist (GLP‐1RAs) labels warn about acute pancreatitis (AP) and impose upon doctors the obligation to inform patients about symptoms of AP. Here we systematically reviewed the risk of AP in randomized placebo‐controlled trials (RCTs) investigating the effect of GLP‐1RAs in type 2 diabetes. We performed a systematic review with meta‐analysis of long‐term (minimum 24 months), placebo‐controlled GLP‐1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees. Three high‐quality RCTs included a total of 9347 GLP‐1RA‐treated and 9353 placebo‐treated patients with type 2 diabetes. Compared to placebo, treatment with GLP1‐RA was not associated with increased risk of AP (Peto odds ratio 0.745 [95% CI, 0.47‐1.17]). Trial Sequential Analysis suggested that additional evidence is needed. In conclusion, this review found no evidence that treatment with GLP‐1RA increases the risk of AP in patients with type 2 diabetes.     

Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen (“treat to failure”). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti‐diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self‐monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta‐cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) is often required. Long‐ or short‐acting GLP‐1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP‐1 RAs with insulin (“treat‐to‐success” paradigm).     

Combination therapy with GLP‐1 receptor agonist and SGLT2 inhibitor

The SGLT2 inhibitors (SGLTi) and glucagon‐like‐1 receptor agonists (GLP‐1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP‐1 RAs work via anti‐atherogenic/anti‐inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits. The SGLT2i and GLP‐1 RAs also reduced macroalbuminuria, decreased the time for doubling of serum creatinine, and slowed the time to end‐stage renal disease. In this perspective, we review the potential benefit of combination SGLT2i/GLP‐1 RA therapy on metabolic‐cardiovascular‐renal disease in patients with type 2 diabetes mellitus.     

A review of glucagon‐like peptide‐1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all‐cause and CV‐related mortality. Although GLP‐1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short‐lived effect on gastric emptying and, hence, lower PPG substantially. However, current long‐term data on CV outcomes with GLP‐1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.     

Glucagon‐like peptide‐1 receptor agonists for type 2 diabetes: A rational drug development

Today, glucagon‐like peptide‐1 (GLP‐1) receptor agonists are established glucose‐lowering drugs used in the management of type 2 diabetes. Their development emerged from the understanding that a combined islet dysfunction comprising of impaired insulin secretion and exaggerated glucagon secretion is the key defect of hyperglycemia. GLP‐1 was shown to target these defects, and after the discovery that dipeptidyl peptidase‐4 inactivates native GLP‐1, several different dipeptidyl peptidase‐4‐resistant GLP‐1 receptor agonists have been developed. They are administered subcutaneously, but show differences in molecular structure, molecular size and pharmacokinetics, the latter allowing twice‐daily, once‐daily or once‐weekly administration. They have been shown to be efficient in reducing both glycated hemoglobin and bodyweight, and to be safe and highly tolerable. Cardiovascular outcomes trials have shown them to be neutral or beneficial. GLP‐1 receptor agonists are positioned as add‐ons to metformin alone or in combination with oral agents in the clinical paradigm. They are also efficient when combined with insulin, and fixed dose combinations with long‐acting insulin have been developed. Recent development includes a very long administration schedule and oral availability. The research from the first demonstration of the antidiabetic action of GLP‐1 in the early 1990s to the enormously accumulated data today represents a successful and rational development, which has been characterized by focused perseverance to establish this therapy in the management of type 2 diabetes.     

Change in glycated haemoglobin levels after initiating second‐line therapy in type 2 diabetes: a primary care database study

The aim of the present study was to compare the absolute reduction in glycated haemoglobin (HbA1c) levels at 6 months after initiating second‐line glucose‐lowering therapy in patients with type 2 diabetes treated with metformin monotherapy in general practices. A total of 7009 patients were identified (Disease Analyser Germany: January 2004 to December 2014). The patients' mean ± standard deviation (s.d.) age was 63 ± 11 years, 55.5% were male and their mean ± s.d. HbA1c level was 8.0 ± 1.6%. The initiated second‐line therapies included: dipeptidyl peptidase‐4 (DPP‐4) inhibitors (38.7%); sulphonylureas (36.3%); insulin (13.3%); glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs; 2.5%); thiazolidinediones (5%); and other agents (glinides, aldose‐reductase inhibitors; 4.1%). The mean absolute HbA1c change from baseline was ?0.9% (DPP‐4 inhibitors, ?0.9%; sulphonylureas, ?0.9%; insulin, ?1.1%; GLP‐1RAs, ?0.7%; thiazolidinediones, ?0.9%; and other, ?0.7%; all p < 0.001). Overall, 58% of patients reached the HbA1c target of <7% (DPP‐4 inhibitors, 61.7%; sulphonylureas, 56.7%; insulin, 45.6%; GLP‐1RAs, 62.2%; thiazolidinediones, 69.7%; and other, 57.5%). Compared with sulphonlyureas, DPP‐4 inhibitors, GLP‐1RAs and thiazolidinediones were associated with an increased odds of reaching HbA1c <7% [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.09–1.40; OR 1.43, 95% CI 1.01–2.04; and OR 1.70, 95% CI 1.30–2.23, respectively], whereas insulin was related to a lower odds (0.66, 95% CI 0.55–0.78). In conclusion, in patients with type 2 diabetes very similar reductions in HbA1c after 6 months of second‐line therapy were achieved regardless of the type of therapy.     

Augmentation of glucagon‐like peptide‐1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure

Augmentation of glucagon‐like peptide‐1 (GLP‐1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP‐1 and long‐acting GLP‐1 receptor analogues are degraded not only by dipeptidyl peptidase‐4, but also by neprilysin. This observation raises the possibilities that endogenous GLP‐1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin‐based drugs may experience important drug–drug interactions. Specifically, potentiation of GLP‐1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long‐acting GLP‐1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP‐1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP‐1 analogues, the action of neprilysin to enhance the effects of GLP‐1 may be particularly relevant in the brain, where augmentation of GLP‐1 and other endogenous peptides may act to inhibit amyloid‐induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP‐1 and GLP‐1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP‐1 and long‐acting GLP‐1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.     

Lixisenatide,a novel GLP‐1 receptor agonist: efficacy,safety and clinical implications for type 2 diabetes mellitus

Recent advances in therapies for the treatment of type 2 diabetes mellitus (T2DM) have led to the development of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), which, unlike insulin and sulphonylurea, are effective, with a low risk of hypoglycaemia. Lixisenatide is recommended as a once‐daily GLP‐1 RA for the treatment of T2DM. In persons with T2DM, lixisenatide 20 µg once‐daily given by bolus subcutaneous injection improves insulin secretion and suppresses glucagon secretion in a glucose‐dependent manner. Compared with the longer‐acting GLP‐1 RA liraglutide, lixisenatide achieved a significantly greater reduction in postprandial plasma glucose (PPG) during a standardized test breakfast in persons with T2DM otherwise insufficiently controlled on metformin alone. This is primarily due to the greater inhibition of gastric motility by lixisenatide compared with liraglutide. The efficacy and safety of lixisenatide was evaluated across a spectrum of T2DM in a series of phase III, randomized, placebo‐controlled trials known as the GetGoal programme. Lixisenatide monotherapy or as add‐on to oral antidiabetic agents or basal insulin achieved significant reductions in glycated haemoglobin, PPG and fasting plasma glucose, with either weight loss or no weight gain. The most frequent adverse events were gastrointestinal and transient in nature. Lixisenatide provides an easy, once‐daily, single‐dose, add‐on treatment to oral antidiabetic agents or basal insulin for the management of T2DM, with little or no increased risk of hypoglycaemia and a potential beneficial effect on body weight.     

Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.     

Weight loss variability with SGLT2 inhibitors and GLP‐1 receptor agonists in type 2 diabetes mellitus and obesity: Mechanistic possibilities

We are facing a global epidemic of obesity and type 2 diabetes. Weight loss, in the context of obesity and type 2 diabetes, may improve glycaemic control and weight‐related comorbidities, and in some cases, induce diabetes remission. Although lifestyle‐based weight loss strategies may be initially successful, most are not effective long‐term. There is an increasing need to consider pharmacological approaches to assist weight loss in diabetes‐obesity. Older glucose‐lowering agents may cause weight gain, whereas the newer drug classes, sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide receptor agonists (GLP‐1 RAs), concomitantly target weight loss and glycaemic control. Clinical trial data suggest that both SGLT2i and GLP1 RAs cause a mean weight loss of approximately 2 to 3 kg but real‐world evidence and clinical experience suggests a significant heterogeneity in the magnitude of the weight loss (GLP‐1 RAs) or the magnitude of the actual weight loss is significantly less than anticipated (SGLT2i). Why do some individuals lose more weight than others in response to these pharmacological treatments? This review will first explore mechanisms by which body weight is regulated through control of energy balance and its dysregulation in obesity, and then consider how these mechanisms may be modulated therapeutically with SGLT2i and GLP1 RAs.     

The challenges of achieving postprandial glucose control using closed‐loop systems in patients with type 1 diabetes

For patients with type 1 diabetes, closed‐loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal‐time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post‐meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate‐matched bolus in the post‐meal period. The latter strategy has been efficient in controlling post‐meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal‐priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag‐time. New and upcoming faster acting insulins could provide important benefits. Multi‐hormone CLS (eg, dual‐hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP‐1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined.     

GLP‐1 Receptor Agonists: Effects on Cardiovascular Risk Reduction

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease‐related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) liraglutide and exenatide are incretin‐based antidiabetes agents. This review examines CV‐associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP‐1 RAs in reducing hyperglycemia. Further, GLP‐1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.