Philip Raskin

Background: IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods: We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results: There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4 ⁺ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion: Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4 ⁺ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes. Trial Registration: ClinicalTrials.gov NCT02293837. Funding: NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

INTRODUCTION AND AIMS: Obesity increases the risk for chronic kidney disease (CKD) and its progression to end-stage renal disease. In animal models of obesity, the anti-inflammatory effects of bardoxolone methyl (BARD) have been shown to reduce fat accumulation by decreasing fatty acid synthesis and improving metabolism. Treatment with BARD in a multinational, randomized, double-blind, placebo-controlled phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) as well as decreases in body weight. We performed post-hoc analyses to further characterize decreases in weight with BARD.

Background: This article reviews the clinical efficacy, safety, and patient outcomes literature on the first once weekly treatment for type 2 diabetes mellitus (T2DM), exenatide extended-release (ER). Methods: Relevant literature on exenatide ER and T2DM was identified through PubMed database searches from inception until April 2014. Results: Exenatide ER is the first medication for the treatment of T2DM dosed on a weekly schedule. Exenatide ER is a glucagon-like peptide-1 (GLP-1) receptor agonist, the third to be approved in the US, and is associated with a low risk of hypoglycemia, may result in weight loss, and has proven to be a safe and effective treatment for T2DM. Exenatide ER reduces A_1c levels by decreasing fasting and postprandial hyperglycemia. The most common adverse events are gastrointestinal in nature, which are lesser in frequency than those observed with short-acting exenatide. Exenatide ER has been shown to be more effective than exenatide twice daily and slightly less efficacious than liraglutide. Exenatide ER is useful as monotherapy and in combination with other oral antidiabetic drugs. Conclusion: Once weekly treatment options for diabetes such as exenatide ER have the potential to offer substantial convenience for patients who have high medication burden and poor medication adherence.

Summary: Results from randomized controlled trials have demonstrated that the risk of microvascular complications can be reduced by intensive glycaemic control in patients with type 2 diabetes mellitus (T2DM). However, only about half of patients with diagnosed diabetes achieve recommended glycaemic goals. New therapies with complementary mechanisms of action that are independent of insulin secretion or action may provide additional therapeutic options to enable patients to achieve glycaemic control. The kidney plays an important role in glucose homeostasis, primarily by the reabsorption of filtered glucose. The sodium–glucose cotransporter 2 (SGLT2), located in the proximal convoluted tubule, is responsible for the majority of glucose reabsorption by the kidney. SGLT2 inhibitors offer a novel approach to treat T2DM and reduce hyperglycaemia by increasing urinary excretion of glucose. Dapagliflozin, an SGLT2 inhibitor recently approved in Europe for the treatment of T2DM, improves glycaemic control in patients with T2DM when used as monotherapy or when added to other diabetes medications, such as metformin, sulfonylureas, pioglitazone, and insulin. As a class, SGLT2 inhibitors are well tolerated and have a low propensity to cause hypoglycaemia. An increase in signs, symptoms, and other events suggestive of genital and, in some studies, urinary tract infections has been reported with SGLT2 inhibitors. Results from ongoing and future clinical trials will help define the role for this new class of investigational compounds, with its unique mechanism of action, as a treatment option for reducing hyperglycaemia in patients with T2DM. Copyright © 2013 John Wiley & Sons, Ltd.

Diabetes is a common comorbidity among hospitalized patients and has been linked to increased length of stay, morbidity, and mortality. In addition, multiple pathophysiological factors contribute to incident hyperglycemia in a sizable proportion of inpatients without previously diagnosed diabetes. Insulin is the mainstay of therapy for inpatient management of diabetes and hyperglycemia. In this article, we discuss initial treatment planning and insulin initiation for established and treatment-naïve patients with diabetes who are being treated with human and analog-based insulin therapy. As a publicly funded and cost-conscious hospital, we rely on human insulin for first-line therapy and generally find good results, reserving more costly insulin analogs for patients with type 1 diabetes. We also describe a novel continuous insulin-infusion protocol, the Parkland glucose insulin infusion protocol, which controls severe hyperglycemia safely and effectively in hospitalized patients who are unable to tolerate oral nutrition or are in other complicated clinical situations. We outline transitions from intravenous to subcutaneous insulin and other planning and diabetes education necessary to facilitate discharge. Lastly, we discuss steps for the development and implementation of a continuous intravenous insulin-infusion protocol at the institutional level.

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy.

P>Aims: To review the efficacy and safety of liraglutide from the phase 3 trials, focusing primarily on glycaemic control. Key findings: Liraglutide was shown to reduce glycated haemoglobin (HbA(1c)) levels by up to 1.5% from baseline, significantly more than the comparators sitagliptin (-0.9%), glimepiride (-0.5%), rosiglitazone (-0.4%), insulin glargine (-1.1%) and exenatide (-0.8%). Both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were shown to be significantly reduced from baseline [up to -2.4 mmol/l (-43.2 mg/dl) and -2.7 mmol/l (-48.6 mg/dl) for FPG and PPG in the liraglutide 1.8 mg group, respectively]. Changes in HbA(1c), FPG and PPG levels were sustained for the duration of the studies (up to 52 weeks). The glycaemic control offered by liraglutide was not associated with an increased rate of minor hypoglycaemic events compared with comparator treatments, with rates significantly lower than those of glimepiride and exenatide. Major hypoglycaemic events were rare and only occurred in combination with a sulfonylurea. Nausea was the most frequent adverse event, but subsided within the first few weeks. Conclusions: Liraglutide has been shown to offer effective glycaemic control for patients with type 2 diabetes and is appropriate for use across the conventional continuum of care. Despite the sustained reductions in HbA(1c), FPG and PPG levels achieved with liraglutide, rates of minor hypoglycaemia were generally low, although the risk increased when combined with a sulfonylurea. Liraglutide is therefore a promising new option for the treatment of type 2 diabetes.

The safety and efficacy of exenatide once weekly is evaluated over 52 weeks in the DURATION-1 trial in patients with type 2 diabetes. This long-acting glucagon-like peptide 1 receptor agonist given as a once weekly subcutaneous injection was found to produce better glycemic control as compared to twice daily exenatide and had a good safety profile over the trial period. Its use can help to reduce the complexity of drug regimen in patients with type 2 diabetes while maintaining a good safety and efficacy profile.

Aim: To assess the efficacy and safety of a new repaglinide/metformin fixed‐dose combination (FDC) tablet administered either twice a day (BID) or three times a day (TID) for the management of type 2 diabetes. Methods: This was a 26‐week, multicentre, open‐label parallel trial in which subjects poorly controlled with mono‐ or dual‐oral antidiabetic therapy were randomized 1 : 1 : 1 to instead receive repaglinide/metformin FDC either BID or TID or a rosiglitazone/metformin FDC BID. Two primary hypotheses were tested in a hierarchical manner: (i) treatment with the repaglinide/metformin FDC BID is non‐inferior to that of the rosiglitazone/metformin FDC BID as measured by changes in haemoglobin A1c (HbA1c) (results presented in companion paper) and (ii) repaglinide/metformin BID is non‐inferior to repaglinide/metformin TID (as measured by changes in HbA1c). Additional efficacy and safety end‐points were also assessed. Results: A total of 561 subjects were randomized; 383 completed the study. Repaglinide/metformin FDC BID was non‐inferior to repaglinide/metformin FDC TID with respect to HbA1c. Additionally, changes in mean fasting plasma glucose values from baseline to end of study were not significantly different between the BID and the TID dose groups. There were no major hypoglycaemic episodes reported in either group during the trial, and overall adverse event profiles were similar. Conclusion: The efficacy of twice‐daily dosing of a repaglinide/metformin FDC tablet was non‐inferior to that of three‐times‐daily dosing.