Adjunctive Treatment For Type Research Articles

1865-LB: Exploring Incretin-Based Therapies as Adjunctive Treatment for Type 1 Diabetes—Real-World Insights and Future Directions

1865-LB: Exploring Incretin-Based Therapies as Adjunctive Treatment for Type 1 Diabetes—Real-World Insights and Future Directions

Glucagon-like peptide-1 receptor agonists as adjunctive treatment for type 1 diabetes: Renewed opportunities through tailored approaches?

Exogenous insulin has been the mainstay treatment for individuals living with type 1 diabetes (T1D). Although there has been tremendous growth in both pharmacological and technological advancements, insulin monotherapy has proven to be insufficient for maintaining optimal glycaemic targets for most adults with T1D. At present, there is still no breakthrough for the treatment of T1D. Adjunctive pharmacotherapies might therefore complement insulin management to achieve better glycaemic control, while possibly offering additional benefits. Recent interest in re-purposing glucagon-like peptide-1 receptor agonists (GLP-1RAs), a leading antihyperglycaemic medication class approved for type 2 diabetes, has prompted the field to seek extended potential for the T1D population. The adjunctive use of GLP-1RAs has been at the forefront of T1D research, albeit with some conflicting trial findings to date. However, the potential of GLP-1 agonism for T1D may have been underestimated, possibly from missed opportunities or categorized effects. Moreover, some GLP-1RAs have demonstrated extra-pancreatic potential with emerging multi-organ protection involving the heart, kidneys, liver and brain in varied cohorts, which may bode well for the growing T1D profile of comorbid complications. This narrative review aims to summarize and critically appraise the current evidence-based literature from large-scale randomized controlled trials and closed-loop system pilot studies that examined GLP-1RAs as adjunctive therapy for T1D. Furthermore, we outline uncharted opportunities with GLP-1 agonism using versatile approaches in selected T1D populations that may inspire and re-direct future research in this field.

The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases.

Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes, however, there is still a lack of understanding about the drug therapy. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used in the treatment of type 2 diabetes and potential applications may include the treatment of obesity as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin. Growing evidence suggests that GLP-1 RA has the potential to treat neurodegenerative diseases, particularly in diabetes-related Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here, we review the molecular mechanisms of the neuroprotective effects of GLP-1 RA in diabetes-related degenerative diseases, including AD and PD, and their potential effects.

Effects of the Ketogenic Diet on Glycemic Control in Diabetic Patients: Meta-Analysis of Clinical Trials.

IntroductionThe ketogenic diet is a diet that relies on reducing carbohydrate intake to a minimum while increasing fat intake. This induces a state of ketosis where it is hypothesized to favor fat metabolism for energy instead of carbohydrates. The diet is used to treat pediatric patients with seizures to control their symptoms. Today, it is used by many to help in weight loss. Extensive research is being conducted on the benefits of the diet, as it gains popularity among patients with diabetes and obesity, to evaluate its effects on glycemic control.MethodsThis review looks at the published literature and summarizes the interventional trials that use the ketogenic diet for glycemic control. Emphasis was on pooling the results of selected variables such as weight, glycemic control, and lipid profile. The meta-analysis was conducted by a trained statistician using the Cochrane software review manager (Revman version 5.4; Cochrane, London, UK). Results were reviewed by an independent reviewer adhering to the Cochrane Collaboration's guidelines.ResultsThe findings of this review show a significant effect of the ketogenic diet as compared to controls in terms of weight reduction, glycemic control, and improved lipid profile. A noticeable improvement was seen in glycated hemoglobin (HbA1c) and in high-density lipoprotein (HDL), favoring the ketogenic diet as compared to control.ConclusionThis review concludes that the ketogenic diet is superior to controls in terms of glycemic control and lipid profile improvements, and the results are significant enough to recommend it as an adjunctive treatment for type two diabetes.

SGLT inhibition: a possible adjunctive treatment for type 1 diabetes.

To identify and evaluate the recent trials of sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2, respectively) inhibitor use in patients with type 1 diabetes (T1D). SGLT-2 inhibitors have been approved by the Food and Drug Administration (FDA) and are effectively used in the treatment of type 2 diabetes (T2D). However, many studies (phase I-III) have validated their effects beyond improving glycemic control and have shown potential adjunctive use in adult patients with T1D treated with insulin therapy alone. A review of the literature showed that there is a potential adjunctive role for the SGLT inhibitors with insulin in T1D for improving glycemic control. The inTandem3 (A phase III study to evaluate the safety of sotagliflozin in patients with type 1 diabetes who have inadequate glycemic control with insulin therapy alone) and the DEPICT-1 (Dapagliflozin evaluation in patients with inadequately controlled type 1 diabetes) trials demonstrated significant benefits in adult patients with T1D. The SGLT inhibitors may become the first oral medication to be approved for adjunctive use in T1D. The risk of diabetic ketoacidosis still remains a concern, but considering additional benefits beyond glucose control, with proper counseling and education, these medications may allow a larger number of patients to achieve target glucose control without weight gain or increased risk of hypoglycemia.

Simplici-T1—First Clinical Trial to Test Activation of Glucokinase as an Adjunctive Treatment for Type 1 Diabetes

TTP399 is an oral liver selective Glucokinase Activator (GKA). Because it exhibits an insulin-independent mechanism of action, it may be suitable as an adjunctive treatment for type 1 diabetes (T1DM). In clinical trials in type 2 diabetes (T2DM), TTP399 has shown significant reduction in postprandial glucose, increased percentage time in range and decreased percentage time in hypo or hyperglycemia. Moreover, TTP399 significantly reduced HbA1c without significant hypoglycemia, dyslipidemia, or ketoacidosis. The Simplici-T1 trial (NCT03335371) is an adaptive three-part (sentinel, learning phase and confirming phase) Phase 1b/2 Proof of Concept study designed to explore the effect of TTP399 as adjunctive therapy for the treatment of T1DM. The aims of the study are to: (1) evaluate the safety of TTP399 and (2) evaluate whether TTP399 can replace or reduce mealtime insulin bolus and improve A1c in patients with T1DM. The sentinel phase, an open label, dose escalation study in 5 adults with T1DM on insulin pump therapy and continuous glucose monitoring (CGM), showed that TTP399 was well tolerated. No incidents of severe hypoglycemia or diabetic ketoacidosis were observed. When compared to baseline, trends toward improved glycemic control while reducing insulin dose (Table) were observed with TTP399 treatment, supporting continuing to the randomized, placebo controlled phase of the study. Disclosure J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. C. Valcarce: Employee; Self; VTV Therapeutics. J.L. Freeman: Employee; Self; VTV Therapeutics. Stock/Shareholder; Self; VTV Therapeutics. Stock/Shareholder; Spouse/Partner; VTV Therapeutics. I. Dunn: Employee; Self; VTV Therapeutics. C. Dvergsten: Employee; Self; VTV Therapeutics. M. Kirkman: Research Support; Self; Bayer AG, Theracos, Inc.. Consultant; Self; National Institutes of Health. Research Support; Self; National Institutes of Health, Centers for Disease Control and Prevention. A. Kass: None. J. Diner: None. K.A. Bergamo: None.

Diabetic Ketoacidosis In Patients With Type 2 Diabetes Recently Commenced On SGLT-2 Inhibitors: An Ongoing Concern

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly used as an adjunctive treatment for type 2 diabetes. We report the occurrence of diabetic ketoacidosis (DKA) in 3 patients with type 2 diabetes recently commenced on SGLT-2 inhibitors. Clinical presentation, laboratory data, and treatment outcomes of all 3 cases are described. All 3 patients had documented history of longstanding type 2 diabetes. The presentation in all patients was that of hyperglycaemia, acidosis, and ketosis occurring within 4 weeks of commencing SGLT-2 inhibitors. The risk factors for developing DKA were infection, myocardial infarction, and alcohol excess. DKA resolved within 24 hours of initiating intravenous fluids and insulin in all cases. This case series illustrates the importance of careful patient selection, education, and monitoring when starting this group of antidiabetic medications. DKA = diabetic ketoacidosis SGLT-2 = sodium-glucose cotransporter 2 T2D = type 2 diabetes.

Safety of exenatide once weekly for 52weeks in Japanese patients with type 2 diabetes mellitus.

An initial 26-week, randomized, open-label study compared the efficacy and safety of exenatide 10mcg twice daily with exenatide 2mg once weekly in Asian patients with type 2 diabetes who experienced inadequate glycemic control with oral antidiabetes medications. The aim of this study was to evaluate the safety of exenatide once weekly in Japanese patients, a subset of the initial patient population, who continued into this extension study for an additional 26weeks of therapy on exenatide once weekly, followed by 10weeks without exenatide once weekly. Japanese patients initially assigned to exenatide twice daily (n=62) switched to exenatide once weekly for the extended 26weeks, and patients initially assigned to exenatide once weekly (n=74) continued on this regimen for the remainder of the study (total treatment of 52weeks). A total of 68% of patients reported one or more treatment-emergent adverse events during the extension period; the most common of these were nasopharyngitis (14%) and vomiting (6%). No major hypoglycemic episodes were reported. Improvements in glycated hemoglobin, fasting plasma glucose and postprandial glucose were maintained over 52weeks of treatment. At week52, bodyweight remained reduced from baseline. Exenatide once weekly added to oral antidiabetes medication was well tolerated in Japanese patients with type 2 diabetes, and was associated with glycemic control and weight loss through to 52weeks, supporting the use of exenatide once weekly as an adjunctive treatment for type 2 diabetes in this patient population. The initial 26-week portion of this trial was registered with ClinicalTrials.gov (no. NCT00917267).

Carnitine and type 2 diabetes

Studies in humans and animals demonstrate that "lipid over supply" causes or worsens insulin resistance via multiple mechanisms involving the accumulation of intracellular lipids in multiple tissues. In particular, the accumulation of fatty acyl CoA derivatives/metabolites in muscle inhibits both insulin signaling and glucose oxidation. Therefore agents that ameliorate the accumulation of fatty acyl CoA derivatives and/or their metabolites would be beneficial in the treatment or prevention of insulin resistance and T2D. Hyperinsulemic/euglycemic clamp studies in humans and carnitine supplementation studies in rodents provide "proof-of-concept" that carnitine is effective at improving insulin-stimulated glucose utilization and in reversing abnormalities of fuel metabolism associated with T2D. Carefully controlled clinical trials are warranted to determine the efficacy dietary carnitine supplementation as an adjunctive treatment for type 2 diabetes.

Exenatide pharmacokinetics in healthy Chinese subjects

Exenatide is an adjunctive treatment for Type 2 diabetes. This was the first study to evaluate the pharmacokinetics, safety and tolerability of therapeutic doses (5 microg and 10 microg) of exenatide after single and multiple subcutaneous injections in healthy adult Chinese subjects. 24 healthy volunteers were randomized to receive either 5 microg or 10 microg of exenatide by subcutaneous injection. Subjects received a single injection of exenatide on Day 1, twice daily on Days 2 and 3, and once on Day 4. Serial blood samples were drawn for pharmacokinetic assessment at pre-dose and up to 12 h post dose on Day 1 and Day 4. Adverse events, vital signs, 12-lead ECG, body weight and clinical laboratory evaluations were assessed. Exenatide, 5 microg and 10 microg, was rapidly absorbed with a median tmax of 1 h after single and multiple doses. Exenatide Cmax and AUCtau,ss were (geometric mean (90% CI)) 145 (119 - 176) pg/ml and 370 (297 - 460) pg x h/ml, respectively, after multiple dosing with 5 microg. The Cmax and AUCtau,ss were 311 (271 - 357) pg/ml and 878 (785 - 983) pg x h/ml, respectively, for 10 microg. Mean half-life (t1/2, range 0.99 - 1.25 h), apparent volume of distribution (Vz/F, 19.2 - 22.3 l), and apparent clearance (CL/F, range 11.4 - 13.5 l/h) remained consistent between single and multiple doses and across the two dose levels. Both the accumulation ratios and linearity index approached 1.0. The most common adverse events were gastrointestinal in nature and mild in severity. The frequency of adverse events increased with dose, such that 8% of subjects who received 5 microg and 42% of subjects who received 10 microg experienced adverse events. Exenatide was rapidly absorbed, with similar pharmacokinetic properties following single and multiple doses. Exenatide exposure after multiple doses approximately doubled from 5 microg to 10 microg.

Estimating the Long-Term Cost-Effectiveness of Exenatide in the United States: An Adjunctive Treatment for Type 2 Diabetes Mellitus

Objectives This analysis provides an early estimate of the cost-effectiveness of adjunctive exenatide in treating type 2 diabetes mellitus in the United States. Data from pivotal phase III 30-week clinical trials and 52 weeks of their subsequent open-label extension studies (i.e., 82 weeks total) were used to project the effects of 30 years of adjunctive exenatide treatment. Methods This analysis utilized a published and validated Markov model incorporating Monte Carlo simulation with tracker variables to estimate the clinical and cost outcomes of adding exenatide to a background of metformin and/or sulfonylurea treatment, with the effects of 30 years of adjunctive exenatide treatment (projected from data from 82 weeks of exenatide treatment) compared with no additional treatment beyond metformin and/or a sulfonylurea. Sensitivity analyses were performed on key clinical assumptions, discount rates, and shorter time horizons. Results The base-case scenario (30 years of exenatide) yielded an incremental cost-effectiveness ratio (ICER) of $35,571. We found that shortening the time horizons and removing the lipid effects of exenatide had the greatest negative impact on ICERs when performing sensitivity analysis. Conclusions Our analysis demonstrated that exenatide used for 20 or 30 years compared with no additional treatment beyond metformin and/or a sulfonylurea is cost-effective in the adjunctive treatment of type 2 diabetes with an ICER less than $50,000 per life-year gained. Sensitivity analyses suggest that, in addition to sustained reduction in HbA 1c, the added clinical effects of improved lipid values, systolic blood pressure, and reduced body mass index all positively contributed to the cost-effectiveness of exenatide.

Exenatide effects on statin pharmacokinetics and lipid response

Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.

Chromium as adjunctive treatment for type 2 diabetes.

To review the chemistry, pharmacology, efficacy, and safety of trivalent chromium in the treatment of type 2 diabetes and hyperlipidemia. The English literature was searched from 1966 through May 2002 using MEDLINE, International Pharmaceutical Abstracts, and EMBASE. The key words included chromium, glucose, lipids, and diabetes. Pertinent references from review articles and studies were used as additional sources. Trivalent chromium is an essential nutrient and has a key role in lipid and glucose metabolism. Supplementation with chromium does not appear to reduce glucose levels in euglycemia. It may, however, have some efficacy in reducing glucose levels in hyperglycemia. The effects of chromium on lipid levels are variable. Chromium in doses <1000 microg/d appears to be safe for short-term administration. Kidney function and dermatologic changes need to be monitored. Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed.