Network Meta-Analysis on the Effects of Finerenone Versus SGLT2 Inhibitors and GLP-1 Receptor Agonists on Cardiovascular and Renal Outcomes in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease
Yaofu ZhangLi JiangJunheng WangTongxin WangChieh ChienWeijun HuangXiaozhe FuYonghua XiaoQiang FuShidong WangJinxi Zhao
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Abstract Objective: To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis.Methods: Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the three drugs indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI).Results: In all, 17 RCTs were selected, including 51,496 patients. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal events and hospitalization for heart failure (HHF) (RR [95%CI]; 0.88 [0.80-0.97], 0.86 [0.79–0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95%CI]; 0.84 [0.78–0.90]), renal events (RR [95%CI]; 0.67 [0.60–0.74], HHF (RR [95%CI]; 0.60 [0.53–0.68]), all-cause death (ACD) (RR [95%CI]; 0.89 [0.81–0.91]) and cardiovascular death (CVD) (RR [95%CI]; 0.86 [0.77–0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95%CI]; 0.88 [0.80–0.97]). As for renal outcomes and HHF, SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95%CI]; 1.29 [1.13–1.47], 1.31 [1.07–1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95%CI]; 1.36 [1.16–1.59], 1.49 [1.18–1.89], respectively). It can be concluded that all three kinds of drugs were comparable in MACE, ACD and CVD. When the risk of cardiovascular events arise in DM patients with CKD, SGLT2i，finerenone and GLP-1 analogues can be considered, as all three drugs share resemblance in the ability of lowering cardiovascular risks, but should renal events becomes a priority, then SGLT2i should be recommended. Compared with placebo, there was a trend toward reduction in ACD with finerenone (RR [95%CI]; 0.90 [0.80–1.00]). GLP-1 RA did not reduce the risk of renal events, HHF, CVD and ACD, but the analysis based on chemical structure showed that a GLP-1 analogues, liraglutide (RR [95%CI]; 0.79 [0.67–0.92], 0.69 [0.52–0.90], 0.76 [0.62–0.93], respectively) showed significant effect in HHF, CVD and ACD, while an exendin-4 analogues, exenatide (RR [95%CI]; 1.10 [0.83–1.46], 1.19 [0.84–1.69], 1.10 [0.87–1.39], respectively), did not.Conclusions: In patients with T2DM and CKD, finerenone led to a risk reduction in MACE, renal events and HHF, SGLT2i were associated with a decreased risk of cardiovascular and renal events. GLP-1 RA were associated with a decreased risk of MACE. And all three kinds of drugs were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significantly reduced cardiovascular events compared with exendin-4 analogues.Keywords:
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Exenatide was the first approved incretin mimetic,which acts like the naturally occurring hormone glucagon like peptide-1 in vivo.Exenatide has been shown to decrease fasting and postprandial glucose levels.This review describes the anti-type 2 diabetes and development of exenatide.
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Glucagon-like peptide (GLP)-1 agonists are one of the newer classes of medications for use in type 2 diabetes. There are currently three GLP-1 agonists on the market: exenatide twice daily, liraglutide, and exenatide extended release (ER). Exenatide ER is a new weekly formulation of exenatide. Exenatide ER reduces glycosylated hemoglobin by 1.6%, with fewer gastrointestinal side effects compared with twice-daily exenatide. Like other GLP-1 agonists, exenatide ER can be used in combination with metformin, sulfonylureas, or thiazolidinediones. Patients should be assessed for risk of pancreatitis and renal impairment. Education about proper administration technique is vital with the novel delivery system. Prescribers may also consider the use of exenatide ER to improve medication adherence in patients who have successfully tolerated exenatide twice daily or use in patients who have gastrointestinal side effects with exenatide twice daily. Exenatide is a reasonable option that can be added to the regimen of a patient with type 2 diabetes.
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Exenatide is a new antidiabetic glucagon-like peptide-1 receptor agonist. In addition to its hypoglycemic effect, exenatide may have a potential protective benefit on vascular endothelial function. This study attempted to compare the effects of exenatide and traditional antidiabetic drug metformin treatment on endothelial function in overweight patients with type 2 diabetes.Ninety overweight patients with newly diagnosed type 2 diabetes were recruited; 45 patients received exenatide (Exe) treatment and 45 patients received metformin (Met) treatment for 12 weeks. The control groups included 37 overweight and 24 non-overweight individuals. The parameters of glucose and lipid metabolism and endothelial function were measured before and after treatment. Vascular endothelial dysfunction was measured by reactive hyperemia index.Newly diagnosed patients with type 2 diabetes had more serious vascular endothelial dysfunction than both overweight and normal-weight control groups. The levels of body mass index, glucose, HbA1c, homeostasis model assessment insulin resistance, and homeostasis model assessment β-cell function were improved significantly by both exenatide and metformin treatment. Both exenatide and metformin treatment can improve vascular endothelial function (Exe group: 1.67 ± 0.52 vs 1.98 ± 0.67, P < 0.05; Met group: 1.68 ± 0.29 vs 1.82 ± 0.24, P < 0.05). Exenatide treatment was no less effective than metformin in improving endothelial function (0.31 ± 0.70 vs 0.13 ± 0.24, P > 0.05).Newly diagnosed patients with type 2 diabetes may have vascular endothelial dysfunction. Both exenatide and metformin treatment can improve vascular endothelial dysfunction, and exenatide was no less effective than metformin treatment.
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Exenatide is an FDA-approved glucose-lowering peptide drug for the treatment of type 2 diabetes by subcutaneous injection. To address the issues on the inconvenience for patient use and the difficulty of oral administration of peptide drugs, chemical cross-linking of two pH-responsive biomaterials, alginate and hyaluronate, was carried out to prepare a new material for the encapsulation of exenatide as a form of microspheres. The exenatide-loaded microspheres exhibited spherical structures with excellent loading and release behaviors in the simulated gastrointestinal tract environments. After oral administration of the microspheres in db/db mice, maximum plasma concentration of exenatide appeared at 4 hours, and blood glucose was effectively reduced to a normal level within 2 hours and maintained for another 4 hours. The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%. Collectively, the present study demonstrated the feasibility of orally delivering exenatide with the new cross-linked biomaterial and formulation, and showed therapeutic potential for clinical applications.
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Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of exenatide requires twice-daily dosing (exenatide BID), and an extended-release formulation of exenatide is now in development for use as a once-weekly injection (exenatide QW). The purpose of this report is to review the most current clinical data on the development of exenatide QW for the treatment of T2DM. In clinical trials, exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, exenatide QW caused greater improvements in glycemic control and was better tolerated than exenatide BID. Given the rapidly increasing prevalence of diabetes and obesity worldwide, exenatide QW is a promising development candidate for the treatment of T2DM.
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Two elderly patients with poorly controlled type 2 diabetes mellitus had difficulty self-managing their medications. Exenatide long-acting release (LAR), with an extended administration interval of 1 month, maintained hemoglobin A1c (HbA1c) level in the 7% range. Monthly administration of exenatide-LAR may be considered for use in carefully selected elderly individuals.
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