Incretin-based investigational therapies for the treatment of MASLD/MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.

A Patient-Driven Approach to Manage Mealtime Insulin Titration: Tools From the AUTONOMY Study.

PURPOSE: Patient-centric methods to support diabetes management are important to overcome barriers associated with initiating mealtime insulin. This article describes the subject-driven titration tools implemented in the AUTONOMY trial to initiate and adjust mealtime insulin dose and the methods used to apply these tools in clinical practice. CONCLUSIONS: The methods used to initiate and escalate mealtime insulin in the AUTONOMY trial proved to be safe and effective, and the patient-friendly guide to self-adjusting mealtime insulin dose may mitigate the complexities associated with treatment intensification while empowering patients to reach their glycemic goals.

Evaluation of a patient self-directed mealtime insulin titration algorithm: a US payer perspective.

Objective To model the potential economic impact of implementing the AUTONOMY once daily (Q1D) patient self-titration mealtime insulin dosing algorithm vs standard of care (SOC) among a population of patients with Type 2 diabetes living in the US. Methods Three validated models were used in this analysis: The Treatment Transitions Model (TTM) was used to generate the primary results, while both the Archimedes (AM) and IMS Core Diabetes Models (IMS) were used to test the veracity of the primary results produced by TTM. Models used data from a 'real world' representative sample of patients (2012 US National Health and Nutrition Examination Survey) that matched the characteristics of US patients enrolled in the randomized controlled trial 'AUTONOMY' cohort. The base-case time horizon was 10 years. Results The modeling results from TTM demonstrated that total costs in the base-case were reduced by $1732, with savings predicted to occur as early as year 1. Results from the three models were consistent, showing a reduction in total costs for all sensitivity analyses. Limitations Data from short-term clinical trials were used to develop long-term projections. The nature of such extrapolation leads to increased uncertainty. Conclusion The results from all three models indicate that the AUTONOMY Q1D algorithm has the potential to abate total costs as early as the first year.

Insulin Lispro with Continuous Subcutaneous Insulin Infusion is Safe and Effective in Patients with Type 2 Diabetes: A Randomized Crossover Trial of Insulin Lispro Versus Insulin Aspart.

OBJECTIVE: This study provides clinical information regarding the use of insulin lispro versus insulin aspart in continuous subcutaneous insulin infusion (CSII) in adult patients with type 2 diabetes mellitus (T2D). METHODS: After a 2-week lead-in period, 122 subjects treated with CSII therapy were randomized to 32 weeks of treatment during 2 separate 16-week treatment periods (TPs) with crossover beginning with insulin lispro (n = 60) or insulin aspart (n = 62). Glycated hemoglobin A1c (HbA1c), total daily insulin dose, and weight were recorded at the end of TP1 and TP2. Adverse events (AEs) and hypoglycemic events (overall, documented symptomatic, nocturnal, or severe) were recorded throughout the TPs. Data were analyzed using statistical methods that accounted for repeated measurements. RESULTS: A total of 107 subjects completed the study; 7 discontinued in TP1 and 8 discontinued in TP2. Insulin lispro was noninferior to insulin aspart in endpoint (weeks 16 and 32) HbA1c over TP1 and TP2 combined. Total daily insulin dose, weight change, and incidence and rates of hypoglycemia were not statistically significantly different between treatments. One case of severe hypoglycemia and 1 of diabetic ketoacidosis was observed with insulin aspart. One case of severe infusion site abscess was noted with insulin lispro. Overall, both insulin lispro and insulin aspart were well tolerated with similar AEs reported. CONCLUSION: Insulin lispro and insulin aspart performed similarly after 16 weeks of treatment, with noninferiority for HbA1c and no significant difference in parameters measured. These findings indicate that insulin lispro and insulin aspart can both be used safely and effectively in patients with T2D using CSII.

AUTONOMY: the first randomized trial comparing two patient-driven approaches to initiate and titrate prandial insulin lispro in type 2 diabetes.

OBJECTIVE: To compare two self-titration algorithms for initiating and escalating prandial insulin lispro in patients with type 2 diabetes inadequately controlled on basal insulin. RESEARCH DESIGN AND METHODS: The trial was designed as two independent, multinational, parallel, open-label studies (A and B), identical in design, to provide substantial evidence of efficacy and safety in endocrine and generalist settings. Subjects were 18-85 years old (study A: N = 528; study B: N = 578), on basal insulin plus oral antidiabetic drugs for ≥3 months, and had an HbA1c 7.0% to ≤12.0% (>53.0 to ≤107.7 mmol/mol). Once optimized on insulin glargine, subjects were randomized to one of two self-titration algorithm groups adjusting lispro either every day (Q1D) or every 3 days (Q3D) for 24 weeks. The primary outcome was the change in HbA1c from baseline. The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old. RESULTS: Baseline HbA1c was similar (study A: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.453; study B: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.162). Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D -0.96% [-10.49 mmol/mol], Q1D -1.00% [-10.93 mmol/mol], Q3D-Q1D 0.04% [0.44 mmol/mol] [95% CI -0.15 to 0.22 (-1.64 to 2.40)]; study B: Q3D -0.92% [-10.06 mmol/mol], Q1D -0.98% [-10.71 mmol/mol], Q3D-Q1D 0.06% [0.66 mmol/mol] [95% CI -0.12 to 0.24 (-1.31 to 2.62)]). The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. In general, no clinically relevant differences were found between the two algorithms in subjects ≥65 years old in either study. CONCLUSIONS: Prandial insulin lispro can effectively and safely be initiated, by either of two self-titrated algorithms, in a variety of practice settings.

The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.

Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes.

OBJECTIVE: To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo). RESULTS: Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001). CONCLUSIONS: Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.

14-day in vitro chemical stability of insulin lispro in the MiniMed Paradigm pump.

BACKGROUND: Insulin lispro was subjected to a simulated in-use study in the Medtronic MiniMed Paradigm(®) pump system (Medtronic, Northridge, CA) under stressed conditions over 14 days. METHODS: Basal and bolus insulin doses were delivered under conditions of elevated temperature (37°C) and continuous shaking over 14 days. The simulation included a study arm with infusion set changes every 3 days and an arm with no infusion set changes over the entire study period. Analyses were performed on samples pumped through the infusion system and on samples retained in the pump reservoir. RESULTS: Results met U.S. Pharmacopeia criteria for insulin lispro potency through the entire testing period. No precipitation was observed on visual inspection, and no occlusion alarms were noted. CONCLUSIONS: Insulin lispro demonstrated appropriate physicochemical stability for up to 14 days in the MiniMed Paradigm pump system.

Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.

BACKGROUND: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1(c) (HbA1(c)) targets. OBJECTIVE: To test whether twice-daily exenatide injections reduce HbA1(c) levels more than placebo in people receiving insulin glargine. DESIGN: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1(c) level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) SETTING: 59 centers in 5 countries. PATIENTS: Adults with type 2 diabetes and an HbA1(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). INTERVENTION: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks. MEASUREMENTS: The primary outcome was change in HbA1(c) level. Secondary outcomes included the percentage of participants with HbA1(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. RESULTS: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. LIMITATIONS: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. CONCLUSION: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. PRIMARY FUNDING SOURCE: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.

Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican-American patients with Type 2 diabetes: a double tracer OGTT study.

OBJECTIVES: By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes. METHODS: In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4-h) double tracer oral glucose tolerance test (OGTT) (1-(14)C-glucose orally and 3-(3)H-glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. beta-cell function was assessed as the incremental ratio of insulin to glucose (DeltaI/DeltaG) during the OGTT. RESULTS: Pioglitazone decreased fasting plasma glucose concentration (10.5 +/- 0.7 to 7.8 +/- 0.6 mM, P < 0.0003) and HbA1c (9.7 +/- 0.7 to 7.5 +/- 0.5%, P < 0.003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20.0 +/- 1.1 to 17.3 +/- 0.8 micromol/kg(ffm) min, P < 0.005) and HepIR (from 8194 declined by 49% to 3989, P < 0.002). During the OGTT, total glucose Ra during the 0- to 120-min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0- to 240-min time period, pioglitazone caused only a modest increase in MCR (P < 0.07) but markedly increased DeltaI/DeltaG (P = 0.003). The decrease in 2h-postprandial hyperglycaemia correlated closely with the increase in DeltaI/DeltaG (r = -0.76, P = 0.004) and tissue clearance (r = -0.74, P = 0.006) and with the decrease in HepIR (r = 0.62, P = 0.006). CONCLUSIONS: In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving beta-cell function.

Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes.

OBJECTIVE: To determine the effect of a lifestyle modification program plus exenatide versus lifestyle modification program plus placebo on weight loss in overweight or obese participants with type 2 diabetes treated with metformin and/or sulfonylurea. METHODS: In this 24-week, multicenter, randomized, double-blind, placebo-controlled study, 194 patients participated in a lifestyle modification program, consisting of goals of 600 kcal/day deficit and physical activity of at least 2.5 hours/week. Participants were randomized to 5 microg exenatide twice daily injection + lifestyle modification program (n = 96) or placebo + lifestyle modification program (n = 98), and after 4 weeks increased their exenatide dose to 10 microg twice daily or volume equivalent of placebo. RESULTS: Baseline characteristics: (mean +/- standard deviation) age, 54.8 +/- 9.5 years; weight, 95.5 +/- 16.0 kg; hemoglobin A(1c), 7.6 +/- 0.8%. At 24 weeks (least squares mean +/- standard error), treatments showed similar decreases in caloric intake (-378 +/- 58 vs -295 +/- 58 kcal/day, exenatide + lifestyle modification program vs placebo + lifestyle modification program, P = .27) and increases in exercise-derived energy expenditure. Exenatide + lifestyle modification program showed greater change in weight (-6.16 +/- 0.54 kg vs -3.97 +/- 0.52 kg, P = .003), hemoglobin A(1c) (-1.21 +/- 0.09% vs -0.73 +/- 0.09%, P <.0001), systolic (-9.44 +/- 1.40 vs -1.97 +/- 1.40 mm Hg, P <.001) and diastolic blood pressure (-2.22 +/- 1.00 vs 0.47 +/- 0.99 mm Hg, P = .04). Nausea was reported more for exenatide + lifestyle modification program than placebo + lifestyle modification program (44.8% vs 19.4%, respectively, P <.001), with no difference in withdrawal rates due to adverse events (4.2% vs 5.1%, respectively, P = 1.0) or rates of hypoglycemia. CONCLUSIONS: When combined with lifestyle modification, exenatide treatment led to significant weight loss, improved glycemic control, and decreased blood pressure compared with lifestyle modification alone in overweight or obese participants with type 2 diabetes on metformin and/or sulfonylurea treatment.

Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin.

OBJECTIVE: Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin. RESEARCH DESIGN AND METHODS: In this 20-week, randomized, open-label, multicenter study, participants (mean age, 56 +/- 10 years; weight, 93 +/- 16 kg; A1C, 7.8 +/- 0.7%) continued their metformin regimen and received either EXE 10 microg b.i.d. (n = 45), ROSI 4 mg b.i.d. (n = 45), or EXE 10 microg b.i.d. + ROSI 4 mg b.i.d. (n = 47). Seventy-three participants underwent clamp procedures to quantitate insulin secretion and insulin sensitivity. RESULTS A1C declined in all groups (P < 0.05), but decreased most with EXE+ROSI (EXE+ROSI, -1.3 +/- 0.1%; ROSI, -1.0 +/- 0.1%, EXE, -0.9 +/- 0.1%; EXE+ROSI vs. EXE or ROSI, P < 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE, -2.8 +/- 0.5 kg; EXE+ROSI, -1.2 +/- 0.5 kg; ROSI, + 1.5 +/- 0.5 kg; P < 0.05 between and within all groups). At week 20, 1st and 2nd phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P < 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014). CONCLUSIONS: Therapy with EXE+ROSI offset the weight gain observed with ROSI and elicited an additive effect on glycemic control with significant improvements in beta-cell function and insulin sensitivity.

Effects of exenatide versus insulin analogues on weight change in subjects with type 2 diabetes: a pooled post-hoc analysis.

BACKGROUND AND OBJECTIVE: In two previously reported multi-center, randomized, open-label, comparator (insulin) controlled trials in patients with type 2 diabetes sub-optimally controlled with metformin and a sulfonylurea, treatment with exenatide and insulin analogue therapy produced similar reductions in glycosylated hemoglobin A(1c) (A1C). However, treatment with exenatide was associated with a reduction in body weight while insulin analogue therapy was associated with weight gain. This analysis further characterizes the relative impact of commonly employed insulin analogues versus exenatide on weight change over a 6-month period. RESEARCH DESIGN AND METHODS: In this pooled post-hoc analysis of two trials, 1047 subjects with diabetes were compared regarding the relative impact of an adjunctive treatment - an insulin analogue (glargine or biphasic insulin aspart) or exenatide (5 mug twice daily for 4 weeks, 10 mug thereafter) - on body weight. RESULTS: While exenatide treatment provided similarly effective glycemic control compared with insulin analogue therapy, it was also associated with weight reduction in the majority of subjects (73.3%, averaging 3 kg decrease by endpoint), with approximately 22% achieving > or =5% weight loss, and 3.2% of subjects achieving > or =10% weight loss. In contrast, by the end of the study most insulin-treated subjects (75.9%) had gained weight (mean 3 kg). Only 2% of insulin-treated subjects achieved > or =5% weight loss, and 0.2% of subjects achieved > or =10% weight loss. CONCLUSIONS: These findings support the use of exenatide as a treatment option in insulin-naïve subjects with type 2 diabetes and who are overweight and sub-optimally controlled by metformin and sulfonylurea. However, these results should be interpreted with caution given the exploratory nature of this post-hoc analysis.