oxyntomodulin and Renal-Insufficiency--Chronic

Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Topics: Administration, Oral; Body Weight; Cardiovascular Diseases; Comorbidity; Decision Making; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hemoglobins; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Liver; Metformin; Obesity; Renal Insufficiency, Chronic; Research Design; Risk; Stomach

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are highly effective at lowering hemoglobin A1c (HbA1c) and facilitating weight loss. Four agents in the GLP-1 RA class, albiglutide, liraglutide, dulaglutide, and semaglutide, also have cardioprotective effects. However, subcutaneous administration of these agents remains a major reason for their underutilization. A new coformulation of semaglutide with sodium N-[8-(2-hydroxybenzoyl) amino caprylate (SNAC) is the first oral GLP-1 RA reviewed by the U.S. Food and Drug Administration (FDA). The SNAC technology prevents destruction of semaglutide in the stomach and facilitates transcellular absorption through the gastric membrane enabling semaglutide to reach systemic circulation intact. The oral formulation of semaglutide was studied in the PIONEER trials, demonstrating similar efficacy to the presently available GLP-1 RAs with regard to HbA1c lowering and weight loss. Although the PIONEER 6 trial suggests positive effects on cardiovascular mortality with oral semaglutide, these benefits may not fully be appreciated until the completion of the SOUL trial.

Topics: Administration, Oral; Caprylates; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Delivery Systems; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic

There are roughly 30 million Americans diagnosed with diabetes mellitus (DM), with nearly 95% of these cases being type 2 (T2)-DM. The American Diabetes Association continues to recommend metformin as the first-line initial treatment of T2DM, in combination with lifestyle modifications; yet, many require multiple therapies to achieve adequate glycemic control. In patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, adding a glucagon-like peptide 1 receptor agonist is a preferred treatment option; however, many patients are apprehensive about injecting medications. Semaglutide is the first oral option in this life-saving medication class. The purpose of this article was to review the pharmacology, clinical trials, safety profile, along with recommended dosing and costs, of oral semaglutide used for managing patients with T2DM.. A search through the PubMed, MEDLINE and Cochrane libraries was conducted for literature published from January 2017 through December 2020, using the key word semaglutide. Articles were selected if they were related to the approval of oral semaglutide or provided novel clinical information regarding this drug entity in its oral dosage formulation.. Three Phase II studies of the pharmacokinetic properties and Phase III trials from the PIONEER series were ultimately selected, as these trials were thought to provide pivotal information to the US Food and Drug Administration for the approval of oral semaglutide.. On review of the literature, it appeared that semaglutide is a viable option in treating T2DM. The use of this medication has been associated with glycosylated hemoglobin lowering similar to that with the injectable medication in its same class. Semaglutide was also showed some potential in preventing cardiovascular events as well as increasing weight loss.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose-adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m(2)) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population.

Topics: Adamantane; Biguanides; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptides; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Meglumine; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Dialysis; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Triazoles; Uracil; Vildagliptin

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.. FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.. Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.. FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Topics: Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Kidney; Renal Insufficiency, Chronic

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.. In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m. SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.

Topics: Aged; Atherosclerosis; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulins; Male; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe CKD, dulaglutide (DU) treatment slowed decline in eGFR compared with insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and BP. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups.. Participants with T2DM and CKD categories 3-4 were randomized (1:1:1) to 0.75 or 1.5 mg DU weekly or IG daily as basal therapy, with titrated insulin lispro, for 1 year. The time to occurrence of the composite outcome of ≥40% eGFR decline, ESKD, or death due to kidney disease was compared using a Cox proportional-hazards model.. Patients treated with 1.5 mg DU weekly versus IG daily for 1 year had a lower risk of ≥40% eGFR decline or ESKD events in the overall study population (5% versus 11%; hazard ratio, 0.45; 95% CI, 0.20 to 0.97;. Treatment with 1.5 mg DU weekly was associated with a clinically relevant risk reduction of ≥40% eGFR decline or ESKD compared with IG daily, particularly in the macroalbuminuria subgroup of participants with T2DM and moderate-to-severe CKD.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Glargine; Recombinant Fusion Proteins; Renal Insufficiency, Chronic

To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist.. PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration.. Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD.. PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Placebos; Renal Insufficiency, Chronic

Dulaglutide is associated with improved cardiovascular and kidney outcomes and can be a good therapeutic option for patients with type 2 diabetes with chronic kidney disease (CKD). In this study, the effects of dulaglutide on glucose-lowering efficacy and changes in renal function were analyzed.. This retrospective study involved 197 patients with type 2 diabetes with mild-to-severe CKD treated with dulaglutide for at least 3 months between January 2017 and December 2020 at two tertiary hospitals in Korea. Changes in the creatinine-based estimated glomerular filtration rate (eGFR) and HbA1c were compared before and after the use of dulaglutide in each patient.. The number of patients and mean eGFR (mL/min/1.73 m2) in CKD 2, 3a, 3b, and 4 were 94 (75.0 ± 8.5), 46 (54.8 ± 6.3), 31 (38.8 ± 4.4), and 26 (22.5 ± 5.4), respectively. Mean HbA1c level and body mass index (BMI) at the initiation of dulaglutide were 8.9% ± 1.4% and 29.1 ± 3.6 kg/m2, the median duration of the use of dulaglutide was 16 months. The use of dulaglutide was associated with a mean decrease in HbA1c by 0.9% ± 1.5% and the glucose-lowering efficacy was similar across all stages of CKD. Also, it was associated with a reduced decline in the eGFR; the mean eGFR change after the use of dulaglutide was -0.76 mL/min/1.73 m2 per year, whereas it was -2.41 mL/min/1.73 m2 before use (paired t-test, P = 0.003). The difference was more pronounced in patients with an eGFR < 60 mL/min/1.73 m2. Subgroup analysis showed that the renal protective effect was better in patients with proteinuria, age ≤ 65 years, and HbA1c < 9.0%, but showed no association with BMI.. The use of dulaglutide provided adequate glycemic control irrespective of CKD stage and was associated with a reduced decline in the eGFR in the CKD population.

Topics: Aged; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glucagon-Like Peptides; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Kidney; Recombinant Fusion Proteins; Renal Insufficiency, Chronic; Retrospective Studies

Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes.. Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA. Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA. ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

Topics: Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Insulin Glargine; Recombinant Fusion Proteins; Renal Insufficiency, Chronic

To evaluate the effect of dulaglutide on body composition in type 2 diabetes mellitus (T2DM) patients undergoing hemodialysis (HD).. Twenty-one T2DM patients on HD, who had been treated with insulin and newly added teneligliptin (N = 10) or dulaglutide (N = 11), were enrolled. Body composition changes, such as fat mass (FM) and skeletal muscle mass (SMM), glycated albumin (GA), and insulin doses were compared before and after six months of treatment with teneligliptin or dulaglutide.. The percentage changes of GA and insulin doses were comparable between the teneliglipin and dulaglutide groups. Conversely, although FM and SMM did not change in the teneligliptin group (from 15.7 kg to 14.1 kg, P = 0.63 and 18.6 kg to 18.9 kg, P = 0.16, respectively), those in the dulaglutide group significantly decreased (from 21.9 kg to 18.9 kg, P = 0.037 and 21.0 kg to 20.2 kg, P = 0.011, respectively).. Six months of dulaglutide treatment significantly reduced not only FM but also SMM, although changes in GA and insulin doses were comparable with those in the teneligliptin group. Dulaglutide may have the effect of promoting sarcopenia; therefore, it may be carefully used in T2DM patients on HD.

Topics: Aged; Body Composition; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Male; Middle Aged; Pyrazoles; Recombinant Fusion Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Sarcopenia; Thiazolidines

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Insulin Glargine; Recombinant Fusion Proteins; Renal Insufficiency, Chronic

Topics: Diabetes Mellitus, Type 2; ErbB Receptors; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Insulin Glargine; Recombinant Fusion Proteins; Renal Insufficiency, Chronic