Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Extra Glycemic Impacts of GLP-1 Receptor Agonists: Benefits of a Class Effect?

GLP-1 receptor agonists are approved for the treatment of type 2 diabetes, and more recently for obesity treatment. The glucagon-like-peptide-1 (GLP-1) is a glucose dependent hormone produced by intestinal cells, which is involved in insulin secretion and glucagon suppression. This hormone controls glucose plasma levels and reduces food intake. Additional effects were reported in slowing gastric emptying and in inducing satiety. In clinical practice, theGLP-1 receptor agonists are associated with significant reductions in glycosylated hemoglobin (HbA1c) and weight loss, despite showing a low risk of hypoglycemia. Beneficial effects have also been observed on blood pressure and lipid profile. The most common side effects associated with GLP-1 receptor agonists are gastro-intestinal motility disorders, such as nausea, vomiting and diarrhea, which are not associated with long-term health risks. Therefore, GLP-1 receptor agonists represent a relevant medication for type 2 diabetes, whose benefits may go far beyond glycemic control.

Efficacy and Safety of Basal-Supported Prandial GLP-1 Receptor Agonist Therapy

Aim: To assess the safety and efficacy of basal-supported prandial GLP-1 receptor agonist therapy (BPT)* in type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM, who had previously received insulin injection therapy and who had had their treatment switched to BPT (liraglutide), were retrospectively recruited. The efficacy of BPT was assessed by determining changes in HbA1c, body weight and total daily insulin dose from baseline to 4 months after BPT initiation. Safety was assessed by comparing the frequency of hypoglycemic episodes at baseline and after 4 months. The Wilcoxon test was used to analyze changes in parameters throughout the study period. Results: Twenty-nine patients, previously treated with basal-supported oral therapy (BOT), basal-bolus insulin, or pre-mixed insulin, were recruited. When analyzed together, there was no change in HbA1c throughout the study period, but body weight decreased (baseline 68.8 ± 13.2 kg vs. month 4 67.3 ± 13.1 kg;p < 0.001). Total daily insulin dose decreased after 4 months (baseline 24.4 ± 15.5 U/day vs. month 4 14.7 ± 9.2 U/day;p < 0.001), and there was no change in the frequency of hypoglycemic episodes. Analysis was conducted within sub-groups based on previous treatment modality. In the BOT group, HbA1c decreased from baseline after 2 months and body weight did not change throughout the study period. In both the basal-bolus insulin group and the pre-mixed insulin group, HbA1c remained steady throughout and there was a decrease in body weight. No change in the frequency of hypoglycemia was observed in any of the sub-groups. Conclusion: BPT in T2DM was associated with weight loss without changes in glycemic control over 4 months, suggesting that it may be an effective and safe therapy.

Research Progress in the Effect Evaluation of GLP1-1 Agonists

Glucagon-like peptide-1(GLP-1)promotes insulin secretion,inhibits glucagon secretion,and repairs pancreatic islet cell function to enhance islet cell proliferation and regeneration.Furthermore,it includes a mechanism for weight loss and angiocarpy protection.This study covers the comparison of GLP-1 agonists with DPP-4 inhibitors and GLT-2 inhibitors,the mechanism of GLP-1 agonists,and its research possibilities based on a summary of current clinical tests of GLP-1 receptor agonists.

GLP-1R Agonists Therapy for Type 2 Diabetes

Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.

Successful treatment of hyperglycemia with liraglutide in a hospitalized 27-year-old patient with schizophrenia:A case report

BACKGROUND Antipsychotics are associated with abnormalities in glucose metabolism in patients with schizophrenia. Liraglutide, a GLP-1 receptor agonist, is Food and Drug Administration approved for the treatment of type 2 diabetes mellitus. However, ways to maintain the long-term stability of psychotic symptoms and balance the disadvantages of obesity, diabetes, and other metabolic disorders caused by antipsychotic medications remain unclear. In this study, we present a case of weight gain and hyperglycemia in a schizophrenia patient who received antipsychotic polypharmacy for 6 years.CASE SUMMARY A 27-year-old man with olanzapine and sodium valproate-treated disorganized schizophrenia was admitted to a diabetes outpatient clinic. He was diagnosed with type 2 diabetes(fasting blood glucose, 20 mmol/L) and obesity(body mass index, 38.58 kg/m). The patient had been treated with glargine(40 IU/d) and metformin(1.5 g/d) and showed a poor response for 2 mo. Two years of liraglutide treatment resulted in stable blood glucose levels and weight loss in addition to a maintained stable mental status for a long time. The biological activities of GLP-1 significantly improved glucose levels and body weight in the schizophrenia patient treated with antipsychotic medications.CONCLUSION Liraglutide administration can be considered an effective alternative treatment for abnormalities in glucose metabolism in schizophrenia patients receiving antipsychotics.

Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors

SGLT-2 inhibitors(SGLT-2Is)have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases,heart failure,and diabetic kidney disease.Similarly,GLP-1 receptor agonists(GLP-1RAs)have significantly improved atherosclerotic cardiovascular outcomes.To this end,DPP-4 inhibitors(DPP-4Is)are cardiac-neutral drugs.While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is,there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is.Moreover,the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions,unlike DPP-4Is.Furthermore,the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c(8.0%-8.5%)compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c(>8.5%-9.0%).These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.

Liraglutide as Add-on to Oral Antidiabetic Agents or Insulin in Routine Practice of Patients with Type 2 Diabetes

Aims: To evaluate in a real-word routine-care practice the effect of liraglutide as add-on treatment in type 2 diabetic patients treated with oral antidiabetic agents and/or insulin. Methods: A retrospective study from 3 outpatient clinics in Copenhagen, Denmark, of all patients (n = 534) initiating treatment with liraglutide. 346 patients were treated ≥3 months. Excluded from analysis were: 107 patients changing from exenatide and 83 due to lack of clinical response or adverse events. Results: In 149 patients liraglutide was add-on to oral antidiabetic agents, most often metformin plus sulfonylurea (n = 86). Mean follow-up: 7.3 ± 3.0 months. HbA1c reduction: 1.3% ± 1.5% (15 ± 16 mmol/mol) from a baseline of 8.7% ± 1.5% (71 ± 16 mmol/mol). Weight reduction: –3.5 ± 4.9 kg from 105.2 ± 21.3 kg. Sulfonylurea treatment was stopped/dose reduced in 57% of these patients. In 114 patients liraglutide was add-on to insulin. Mean follow-up: 7.0 ± 3.1 months. HbA1c reduction: 0.8% ± 1.2% (8 mmol/mol) from a baseline of 8.7% ± 1.5% (71 ± 16 mmol/mol). Weight reduction: –5.1 ± 4.9 kg from 109.2 ± 22.1 kg. Baseline insulin dose of 83 ± 59 U/day was reduced by 28 ± 36 U/day. Insulin therapy could be stopped in 19% of these patients. Conclusions: Effects on HbA1c and weight of liraglutide as add-on to oral antidiabetic agents were not different from results previously published in randomised trials. Adding liraglutide to existing insulin regimens is an attractive treatment strategy in obese type 2 diabetic patients.

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

Advances in reducing cardiovascular risk in the management of patients with type 2 diabetes mellitus

Treatment intended to lower cardiovascular (CV) risk in patients with diabetes has always been a primary goal of diabetes treatment. Due to the subdued effects of reducing hemoglobin A1c (HbA1c) on macrovascular complications, controlling other CV risk factors such as hypertension and hyperlipidemia instead of hyperglycemia has been the mainstay treatment to improve CV outcome in patients with type 2 diabetes mellitus (T2DM) until recent years. This review is intended to summarize and compare the results from the available cardiovascular outcome trials (CVOTs) for the two classes of glucose lowering drug: sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). The results including the EMPA-REG, CANVAS program and DECLARE-TIMI 58 trials for SGLT2i, and the ELIXA, LEADER, SUSTAIN-6, EXSCEL and HARMONY trials for GLP-1 RA were summarized. The potential mechanisms of these CV beneficial effects and the optimal CV risk reduction treatment in patients with T2DM based on patient risk stratification and evidence from these CVOTs in real-world setting were discussed.

Diabetes and NAFLD:a high-risk cohort with definite therapeutic potential

Despite the fact that non-alcoholic fatty liver disease(NAFLD)and its severe clinical forms[non-alcoholic steatohepatitis(NASH)and NASH-cirrhosis]are highly prevalent in the general population,there are no licensed drugs for NAFLD,and lifestyle intervention remains the only treatment accepted by international guidelines.This is despite massive investments in research by pharmaceutical companies.In the presence of type 2 diabetes,novel anti-diabetic drugs offer an opportunity to reduce the burden of NAFLD,by adequate control of glucose and lipid metabolism,also reducing the risk of NASH progression,advanced fibrosis,and finally hepatocellular carcinoma.We extensively reviewed the literature,based either on registration studies,ad hoc randomized studies or real-world data,to define the effectiveness of anti-diabetic drugs in the treatment of NAFLD and prevention of hepatocellular carcinoma(HCC).Metformin provides the best evidence for decreased risk of HCC,pioglitazone was associated with decreased progression to fibrosis,glucagon-like peptide-1 receptor agonists offer a possible opportunity to reduce NAFLD progression coupled with a definite protection for cardiovascular outcomes,and sodium-glucose cotransporter-2 inhibitors are likely to reduce lipid burden,simultaneously reducing the risk of progressive renal and heart failure.For the latter two drug classes,the effects on NAFLD might largely explained by decreased body weight,in keeping with the beneficial effects of intensive lifestyle intervention.