Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review

AimsGlucagon-like peptide 1 receptor agonists (GLP-1RA) improve glycemic control and promote weight loss in type 2 diabetes (DM2) and obesity. We identified studies describing the metabolic benefits of GLP-1RA in end-staged kidney disease (ESKD) and kidney transplantation.Data synthesisWe searched for randomized controlled trials (RCTs) and observational studies that investigated the metabolic benefits of GLP-1RA in ESKD and kidney transplantation. We summarized the effect of GLP-1RA on measures of obesity and glycemic control, examined adverse events, and explored adherence with therapy. In small RCTs of patients with DM2 on dialysis, liraglutide for up to 12 weeks lowered HbA1c by 0.8%, reduced time in hyperglycemia by ∼2%, lowered blood glucose by 2 mmol/L and reduced weight by 1–2 kg, compared with placebo. In prospective studies inclusive of ESKD, 12 months of semaglutide reduced HbA1c by 0.8%, and contributed to weight losses of 8 kg. In retrospective cohort studies in DM2 and kidney transplantation, 12 months of GLP-1RA lowered HbA1c by 2%, and fasting glucose by ∼3 mmol/L compared with non-use, and in some reports, weight losses of up to 4 kg were described. Gastrointestinal (GI) side effects were most commonly reported, with hypoglycemia described with GLP-1RA in hemodialysis, particularly in those using insulin.ConclusionsGLP-1RA are growing in popularity in those with DM2 and obesity. In small RCTs and observational cohort studies modest glycemic and weight benefits have been described in ESKD and transplantation, but GI side effects may limit adherence. Larger and longer term studies of GLP-1RA remain important.     

胰高血糖素样肽-1类似物治疗2型糖尿病的研究进展

胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1RA）艾塞那肽（exenatide）和利拉鲁肽（liraglutide）的作用机制是增加胰岛素分泌,抑制胰高血糖素释放,减轻胰岛素抵抗,抑制食欲并减缓胃排空。这些降糖作用具有葡萄糖浓度依赖性可避免严重低血糖。除了有确切的降糖作用外,还有降血压、保护心血管、减轻脂肪肝、调脂和减轻体质量的作用,动物实验中,这类药物有助于保护β细胞功能,可以安全地与二甲双胍、磺酰脲类药物、噻唑烷二酮类和胰岛素联合治疗糖尿病,其代表性药物利拉鲁肽和艾塞那肽为控制高血糖和降低体质量提供了另一种治疗选择。     

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patients

Summary Glucagon-like peptide 1 (GLP-1) (7-36 amide) is a physiological incretin hormone that is released after nutrient intake from the lower gut and stimulates insulin secretion at elevated plasma glucose concentrations. Previous work has shown that even in Type 2 (non-insulin-dependent) diabetic patients GLP-1 (7-36 amide) retains much of its insulinotropic action. However, it is not known whether the magnitude of this response is sufficient to normalize plasma glucose in Type 2 diabetic patients with poor metabolic control. Therefore, in 10 Type 2 diabetic patients with unsatisfactory metabolic control (HbA_lc 11.6±1.7%) on diet and sulphonylurea therapy (in some patients supplemented by metformin or acarbose), 1.2 pmol ×kg^–1×min^–1 GLP-1 (7-36 amide) or placebo was infused intravenously in the fasting state (plasma glucose 13.1±0.6 mmol/l). In all patients, insulin (by 17.4±4.7 nmol ×1^–1×min; p=0.0157) and C-peptide (by 228.0±39.1 nmol×1^–1×min; p=0.0019) increased significantly over basal levels, glucagon was reduced (by -1418±308 pmol ×1^–1×min) and plasma glucose reached normal fasting concentrations (4.9±0.3 mmol/l) within 4 h of GLP-1 (7-36 amide) administration, but not with placebo. When normal fasting plasma glucose concentrations were reached insulin returned towards basal levels and plasma glucose concentrations remained stable despite the ongoing infusion of GLP-1 (7-36 amide). Therefore, exogenous GLP-1 (7-36 amide) is an effective means of normalizing fasting plasma glucose concentrations in poorly-controlled Type 2 diabetic patients. The glucose-dependence of insulinotropic actions of GLP-1 (7-36 amide) appears to be retained in such patients.     

Potent glycogenic effect of GLP-1(7–36)amide in rat skeletal muscle

Summary GLP-1(7–36)amide is an intestinal posttranslational proglucagon product released mainly after carbohydrate ingestion, the glucose dependent insulinotropic and antidiabetogenic actions of which have been documented. In this work, by exploring whether GLP-1(7–36)amide has any effect on the glucose metabolism of the muscle, we have observed that this peptide, at physiological concentrations, exerts in this tissue an increment of the d-[U-¹⁴C] glucose incorporated into glycogen, which is accompanied by an increase in the glycogen synthase a activity; also, it stimulates both glucose oxidation and lactate formation. These data indicate that the skeletal muscle is one of the target tissues for GLP-1(7–36)amide, where its insulin-like effect explains, at least in part, its plasma glucose lowering action; thus, GLP-1(7–36)amide may well be implicated in the physiological control of glucose homeostasis after meals, not only by acting as an incretin, but also by directly promoting glucose disposal.Abbreviations KRB Krebs-Ringer bicarbonate buffer, pH 7.4 - EDTA ethylenedinitrilo tetraacetic acid, disodium salt dihydrate - BSA bovine serum albumin     

Cardioprotective properties of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: A systematic review

Background and aimsCardiovascular disease is one of the main contributors for the mortality in type 2 diabetes mellitus (T2DM) patients. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) had shown cardiovascular benefits which may be advantageous to reduce mortality in T2DM patients. This systematic review focused on analyzing the effects of GLP-1 RAs on cardiovascular outcomes.MethodsWe conducted an extensive search through JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. All related studies assessing the use of GLP-1 RAs in T2DM patients from inception up to October 2020 were screened. Any cardioprotective properties as the outcomes were obtained.ResultsA total of six studies (4 randomized, 2 observational) with a total of 182.205 patients were included in this review. The GLP-1 RAs used were either liraglutide or exenatide in combination with antihypertensive or antilipidemic drugs. All studies showed that GLP-1 RA significantly caused weight loss and improved cardiac functional capacity by increasing left ventricular ejection fraction and reducing end-systolic and end-diastolic left ventricle volume. GLP-1 RA also improved myocardial blood flow without affecting myocardial glucose uptake. However, GLP-1 RA failed to show its effect in reducing blood pressure and improving lipid profiles.ConclusionsDespite the limited number of studies, consistent data showed that GLP-1 RA has several cardioprotective properties.     

A beneficial role of GLP-1 receptor agonist therapy in ABCC8-MODY (MODY 12)

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes resulting from a mutation in a single gene. ABCC8-MODY is caused by mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), a regulatory component of the ATP-sensitive potassium (K_ATP) channel found in beta cells. In ABCC8-MODY, mutations in the ABCC8 gene interfere with insulin secretion in response to glucose. Recent evidence suggests that therapy with GLP-1 receptor agonists (GLP-1 RAs) may be beneficial in ABCC8-MODY. This report presents a successful treatment of a 49-year-old woman diagnosed with ABCC8-MODY using the GLP-1 RA semaglutide. The patient, who had been previously receiving insulin therapy, experienced significant improvements in glycemic control and weight loss after transitioning to semaglutide. GLP-1 RAs potentially enhance insulin secretion in ABCC8-MODY by activating multiple signaling pathways involved in insulin secretion. The report highlights the potential of GLP-1 RA therapy as an alternative to sulfonylureas and insulin for individuals with ABCC8-MODY. GLP-1 RAs have previously demonstrated benefits in other forms of MODY. Understanding the molecular mechanisms through which GLP-1 RAs promote insulin secretion, including their effects on KATP channels and activation of PKA and Epac signaling, offers valuable insights into their therapeutic effects.     

All-cause mortality and cardiovascular outcomes with sodium-glucose Co-transporter 2 inhibitors,glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes

Aim

To assess the relationship of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP-1RA) and their combination (SGLT2i + GLP-1RA) with 5-year risk of all-cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes.

Materials and Methods

Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP-1RA and SGLT2i + GLP-1RA) were compared against a control cohort (no SGLT2i/GLP-1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP-1RA, n = 186 841; SGLT-2i + GLP-1RA, n = 108 504). A sub-analysis comparing combination and monotherapy cohorts was also performed.

Results

The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all-cause mortality (SGLT2i 0.49, 0.48-0.50; GLP-1RA 0.47, 0.46-0.48; combination 0.25, 0.24-0.26), hospitalization (0.73, 0.72-0.74; 0.69, 0.68-0.69; 0.60, 0.59-0.61) and acute myocardial infarct (0.75, 0.72-0.78; 0.70, 0.68-0.73; 0.63, 0.60-0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub-analysis showed a significant risk reduction in all-cause mortality for combination therapy versus SGLT2i (0.53, 0.50-0.55) and GLP-1RA (0.56, 0.54-0.59).

Conclusions

SGLT2i, GLP-1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all-cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5-year all-cause mortality when compared directly against either monotherapy.     

Effects of the GLP-1 receptor agonist lixisenatide on postprandial glucose and gastric emptying – preclinical evidence

In addition to promoting glucose homeostasis, glucagon-like peptide 1 (GLP-1) has a number of extra-pancreatic effects that regulate appetite and body weight. GLP-1 delays gastric emptying, which is vital for postprandial glucose (PPG) control. As GLP-1 is rapidly degraded by protease dipeptidyl peptidase-4, a number of degradation-resistant GLP-1 receptor agonists (GLP-1RAs) have been developed for the treatment of Type 2 diabetes mellitus. These agents can be broadly categorized as being short- or long-acting, based on their pharmacokinetic profile. Short-acting agonists predominantly affect PPG and delay gastric emptying in a sustained manner, whereas long-acting agents largely affect fasting plasma glucose and their delay in gastric emptying appears to be subjected to tachyphylaxis. Lixisenatide is a “short-acting” once-daily prandial GLP-1RA. This review provides an overview of the preclinical studies that are currently available and that evaluate the efficacy of lixisenatide on gastric emptying and PPG levels. The preclinical evidence outlined in this review supports the efficacy of lixisenatide in reducing PPG excursions and delaying gastric emptying. Furthermore, in contrast to long-acting agents, the actions of lixisenatide do not appear to be subjected to tachyphylaxis.     

A Plethora of GLP-1 Agonists: Decisions About What to Use and When

Incretin-based therapies are important addition to our armamentarium for the treatment of type 2 diabetes (T2DM). There are six Glucagon-like peptide-1 receptor agonists (GLP-1RAs) which have received regulatory approval for clinical use. The short-acting GLP-1RAs include exenatide twice daily, liraglutide once daily, and lixisenatide once daily. The approved long-acting GLP-1RAs are administered weekly and are exenatide, albiglutide, and dulaglutide. Although all of these therapies lower hemoglobin A1C (HbA1C), there also are unique features of GLP-1RAs that have been made manifest from clinical trial data with regard to weight-loss efficacy, fasting and post-prandial glucose control, cardiovascular safety and protection, and gastrointestinal and injection adverse effects. It is imperative to consider these features when tailoring the choice of a GLP-1RA to patient specific characteristics.     

Glucagon-like peptide-1 receptor agonists versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trials

To compare the effect and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RA) with insulin therapy on type 2 diabetes mellitus (T2DM) patients inadequately controlled with metformin and/or sulfonylurea. A systematic literature search on MEDLINE, Embase and Cochrane for randomized controlled trials (RCTs) was conducted using specific search terms 'GLP-1 insulin type 2 diabetes clinical trials' and eight eligible studies were retrieved. Data on mean change in haemoglobin A1c (HbA1C), weight loss, fasting plasma glucose (FPG), incidence of hypoglycaemia and gastrointestinal adverse events were extracted from each study and pooled in meta-analysis. Data on postprandial plasma glucose (PPG) and adverse events were also described or tabulated. Data from eight RCTs enrolling 2782 patients were pooled using a random-effects model. The mean net change [95% confidence interval (CIs)] for HbA1c, weight loss and FPG for patients treated with GLP-1 RA as compared with insulin was -0.14% (-2 mmol/mol) [95% CI; (-0.27, -0.02)%; p = 0.03]; -4.40 kg [95% CI; (-5.23, -3.56) kg; p < 0.01] and 1.18 mmol/l [95% CI; (0.43, 1.93) mmol/l; p < 0.01], respectively, with negative values favouring GLP-1 and positive values favouring insulin. The GLP-1 group was associated with a greater reduction in PPG than the insulin group. Overall, hypoglycaemia was reported less in the GLP-1 group [Mantel-Haenszel odds ratio (M-H OR) 0.45 (0.27, 0.76); p < 0.01], while there was no significant difference in occurrence of severe hypoglycaemia [M-H OR 0.65 (0.29,1.45); p = 0.29]. A significantly higher number of gastrointestinal adverse events were reported with GLP-1 group [M-H OR 15.00 (5.44,41.35) p < 0.01]. GLP-1 RA are promising new agents compared with insulin. Further prospective clinical trials are expected to fully evaluate the long-term effectiveness and safety of these therapies within the T2DM treatment paradigm.     

脑室给予胰升糖素样肽GLP－1（7－36）对大鼠血糖及血糖调节激素的影响

采用给禁食大鼠脑室灌注溶于不同溶剂中的ＧＬＰ－１（７－３６）的方法，观察ＧＬＰ－１在中枢对大鼠血糖及血糖调节激素浓度的影响。结果表明：脑室灌注溶于生理盐水的ＧＬＰ－１与单纯灌注生理盐水相比，血糖无明显变化，但１小时后，血中胰岛素、胰升糖素浓度均明显降低；脑室灌注溶于３０％葡萄糖的ＧＬＰ－１与单纯灌注３０％葡萄糖相比，血糖明显升高，在３０’、４５’、６０’有显著性差异，血中胰岛素浓度明显低于对照组，胰升糖素浓度无变化。这些实验说明ＧＬＰ－１参与了中枢神经系统对胰岛分泌激素功能的调节。     

Effect of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese adults without diabetes: A meta-analysis of placebo-controlled randomized trials

Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the risk of any cardiovascular event in adults with overweight or obesity and without diabetes. We conducted a random-effects meta-analysis of placebo-controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430 patients were included, of which 7702 (67%) were submitted to treatment with GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%) and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascular event (RR = 0.81, CI 0.70-0.92; p = .001). In overweight or obese adults without diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our findings support the use of GLP-1 RA for reducing the cardiovascular risk of these patients.     

Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA

Purpose of Review

In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits.

Recent Findings

SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system.

Summary

This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.

     

Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

Since the first glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) was approved in 2005 (exenatide twice daily) for type 2 diabetes (T2D), the class has developed with newer compounds having more pronounced effects on glycaemic control and body weight. Also, administration regimes have become more convenient with once weekly injections, and recently an oral administration has become available. Large-scale randomized controlled cardiovascular (CV) outcome trials (CVOTs) have shown that GLP-1RA therapy can reduce the risk of CV disease (CVD) in high-risk individuals with T2D. In addition, GLP-1RAs may have renal benefits driven by new-onset macroalbuminuria, although no effect on hard renal endpoints has been found. Subsequently, the place for GLP-1RA therapy has changed over recent years, with most societies endorsing GLP-1RA therapy in patients with established or high risk of CVD independently of glycaemia. Initiation of GLP-1RA therapy can be complex due to differences in efficacy, side effects and safety profiles as well as administration forms within the class. Implementing guideline recommendations into ideal patient selection may be challenging both in specialty and non-specialty settings. To ensure adequate and proactive use of modern glucose-lowering medications in the treatment of T2D, it is essential to recognize patients with high risk or documented CVD. The present review provides an overview of the efficacy and benefits of the currently available GLP-1RA compounds. Furthermore, we review the results from recent large-scale CVOTs in a clinical context and suggest improving the implementation of GLP-1RA therapy across specialties to improve overall patient selection.     

Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

Summary The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in 4 separate protocols: 1) i. v. infusion of glucose (25 g) alone, 2) glucose together with i. v. GLP-1 infusion, and 3) and 4) glucose together with i. v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP-1 and GIP concentrations (low dose) obtained were comparable with those of the patients. With GLP-1, infusion of a total of 33.4 ± 1.3 g glucose was required to obtain plasma glucose concentrations similar to those obtained by glucose infusion alone; with low GIP, 28.0 ± 1.2 g and with high GIP 38.4 ± 3.5 g. Insulin concentrations increased 10-fold with GLP-1 compared with i. v. glucose alone, but less with high and low GIP. In contrast, C-peptide concentrations were similar after GLP-1 and high GIP. After termination of i. v. glucose the lowest glucose concentrations were 4.5 (3.7–4.9) (median, range) for glucose alone; 2.4 (1.9–2.8) mmol/l with GLP-1; 3.7 (2.6–4.0) with low GIP and 3.3 (2.1–4.2 ) with high GIP. Thus, the exaggerated GLP-1 response to nutrients in patients with accelerated gastric emptying could be responsible for their high incidence of postprandial reactive hypoglycaemia. [Diabetologia (1998) 41: 1180–1186] Received: 23 February 1998 and in revised form: 18 May 1998     

The association between GLP-1 receptor agonist and diabetic ketoacidosis in the FDA adverse event reporting system

Background and aimsIn 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) and food and drug administration (FDA) of the United States of America (US) suggested that the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RA) and diabetic ketoacidosis (DKA) deserved attention. This study is aiming to assess the association between GLP-1RA and DKA/ketosis in the FDA Adverse Event Reporting System (FAERS) database.Methods and resultsUsing FAERS database, we firstly extract the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculate proportional reporting ratios (PRRs). We then mined each FAERS file from 2004 Q1 to 2020 Q4 and obtained detailed information on DKA reports. From the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019, there are 1382 DKA cases (1491 ketosis cases) associated with GLP-1RA in the FAERS database. There was a slight disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95%CI 1.24–1.79, p < 0.001) after excluding the impact of SGLT2i, T1D and insulin. Any disproportionality disappeared after selecting the GLP-1RA combined with insulin for comparison.ConclusionsWhen GLP-1RA not combined with insulin, the disproportionality of DKA reports associated with GLP-1RA was observed. Our analysis mined the FAERS database to provide evidence and highlight the potential association between DKA adverse events and GLP-1RA therapy that clinicians tend to overlook.     

改善心血管和肾脏结局的新型抗高血糖药物临床应用中国专家建议

动脉粥样硬化性心血管病(ASCVD)和(或)慢性肾脏病(CKD)不但是2型糖尿病(T2DM)常见合并疾病,也是T2DM患者致残和致死的首要原因。近年来一系列临床研究证据表明,新型抗高血糖药物胰高糖素样肽-1受体激动剂(GLP-1 RA)和钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)类药物能显著改善心血管和肾脏结局的临床获益,且安全性良好。为促使T2DM的治疗模式从单纯控制血糖转移到改善心血管和肾脏临床结局,中国心血管病学、内分泌学、肾脏病学和神经病学专家组成的专家组梳理了GLP-1 RA或SGLT2i的心血管保护的临床证据、可能机制和常见不良反应,提出了对这两类药物在临床实践中的合理定位、应用建议和注意事项,鼓励临床医师在临床实践中对T2DM患者及早启动并长期维持能够改善心血管和肾脏结局的新型抗高血糖药物治疗。     

Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 in hibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.     

A case of hyperinsulinemia due to hypersecretion of incretin]

A 65-year-old male presented with postprandial hypoglycemic episodes. He had normal glucose tolerance, but plasma glucose reached a hypoglycemic level of 31 mg/dl at 120 min during 75 g oral glucose tolerance test. He had markedly increased insulin response to oral glucose but not to intravenous glucose, intravenous arginine or intravenous glucagon. Hyperresponse of insulin after oral but not intravenous glucose suggested the possible involvement of insulinotropic hormonal factor in the gut (incretin) in hyperinsulinemia of this patient. Therefore we evaluated the secretory response of glucagon like peptide-1 (GLP-1), a most likely candidate for incretin, to oral and intravenous glucose administration. Plasma GLP-1 response to oral glucose was almost five times greater than that of normal subjects. On the other hand, there was no significant response in plasma GLP-1 after intravenous glucose. These results suggest that hypersecretion of GLP-1 may be responsible for the hyperinsulinemia after oral glucose in this patient.     

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis

AimsThe risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates.Materials and methodsWe searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication.ResultsA total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI] = 0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i.ConclusionsIn women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.