Creighton, NE, United States
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Sands A.T.,Lexicon Pharmaceuticals Inc. | Zambrowicz B.P.,Lexicon Pharmaceuticals Inc. | Rosenstock J.,Dallas Diabetes and Endocrine Center | Lapuerta P.,Lexicon Pharmaceuticals Inc. | And 8 more authors.
Diabetes Care | Year: 2015

OBJECTIVE: To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS: In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002),for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes. © 2015 by the American Diabetes Association.


PubMed | Lexicon Pharmaceuticals Inc., Atlanta Diabetes Associates, University of Colorado at Denver, Creighton Diabetes Center and 4 more.
Type: Journal Article | Journal: Diabetes care | Year: 2015

To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes.We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment.In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group.As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.


PubMed | University of Minnesota, Childrens Hospital Los Angeles, Immune Tolerance Network, Indiana University and 15 more.
Type: Clinical Trial, Phase II | Journal: The lancet. Diabetes & endocrinology | Year: 2014

Type 1 diabetes results from autoimmune targeting of the pancreatic cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual cells in patients newly diagnosed with type 1 diabetes.The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458.Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred.Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve -cell function in patients with new-onset type 1 diabetes.


Tella S.H.,Creighton Diabetes Center | Tella S.H.,Creighton University | Rendell M.S.,Creighton Diabetes Center
Expert Opinion on Drug Safety | Year: 2015

Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i.Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents.Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question. © 2015 Informa UK, Ltd.


Rendell M.,Creighton Diabetes Center | Drincic A.,University of Nebraska Medical Center | Andukuri R.,Creighton Diabetes Center
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: Alogliptin is a highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). It is one of several agents of this class now available for treatment of type 2 diabetes. Areas covered: This review is based upon a PubMed search and personal experience with alogliptin. The pharmacokinetics and pharmacodynamics of alogliptin are reviewed. The glucose-lowering effect of this agent is discussed as monotherapy and in combination with metformin, sulfonylurea, piogilitazone and insulin. The potential adverse effects of alogliptin are summarized. Alogliptin is compared with the other available DPP-4 inhibitors. Expert opinion: Alogliptin is an additional choice in the group of DPP-4 inhibitors. As a group, these agents have a relatively modest glucose-lowering effect, inferior to that of metformin, sulfonylureas, and insulin. They do not have the benefit of weight loss offered by the glucagon-like polypeptide (GLP)-1 agonists. The primary use of DPP-4 inhibitors is in combination with other hypoglycemic agents, mainly metformin. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. A greater use of alogliptin and other DPP-4 inhibitors will occur if long-term studies show reduced cardiac events or long-term retention of insulin secretory capacity. The Examine Trial, a large study of alogliptin in coronary disease patients, is now underway and could provide important supportive data. © 2012 Informa UK, Ltd.


SB-509 is a zinc finger DNA-binding protein transcription factor (ZFP-TF) activator that upregulates the expression of vascular endothelial growth factor A (VEGF-A). VEGF-A plays an important role in both angiogenesis and neurological development. Independent research studies show that VEGF-A has direct neurotrophic activity on axonal outgrowth in in vitro culture conditions. The dual angiogenic and regenerative effects of VEGF-A on nerves suggest a potential therapeutic effect in neuropathic disorders. SB-509 stimulates endogenous VEGF-A expression, of all natural isoforms in their proper ratios. In the streptozotocin-induced diabetes model of neuropathy, SB-509 prevented the typical reduction in motor and sensory nerve conduction velocities. This favorable result led to human trials in diabetic neuropathy. A phase I trial showing trends for meaningful clinical improvement in SB-509-treated subjects led to a phase II trial. In the phase II trial, SB-509-treated subjects showed an increase of 55% in intraepidermal nerve fiber density (IENFD) compared to a decrease of 16% in placebo-treated subjects. Although there was no overall difference in clinical outcome measures between SB-509- and placebotreated subjects, subjects who started out with low IENFD showed clinical improvements correlating with increases in nerve fiber density. Additional clinical studies are in progress in diabetic neuropathy and amyotrophic lateral sclerosis (ALS). These studies have shown that plasmid-mediated delivery of the engineered zinc finger transcription factor is safe and may be a therapeutic option in a variety of diseases.


Rendell M.,Creighton Diabetes Center
Expert Opinion on Drug Safety | Year: 2013

Introduction: The evaluation of agents to treat elevated blood glucose is straightforward and is accomplished with short duration studies, but it is more difficult to demonstrate safety of these agents over long periods of clinical use. Numerous large studies have raised questions as to the cardiovascular risks of certain drugs such as the thiazolidinediones and even challenged the wisdom of aggressive attempts to normalize plasma glucose. As a result of this uncertainty, the FDA issued new Guidance to Industry to assess cardiovascular risk. This new approach has markedly increased the burden to achieve approval of new diabetes drugs. Areas covered: The author has reviewed the recent history of drug approvals for diabetes drugs, using MEDLINE searches and freedom of information requests to the FDA. The thiazolidinedione saga illustrates that certain risks do not clearly manifest in the relatively short duration studies needed to evaluate control of blood sugar levels. Furthermore, the UKPDS and DCCT-EDIC studies show us that the lowering of plasma glucose has a beneficial effect which can only be reliably assessed over a very long time period. Expert opinion: The present day approval process is flawed in the conception that regulatory agencies can guarantee absolute safety. It is important to acknowledge that the risk-benefit relationship for new agents can only be determined by ongoing long-term clinical experience and prolonged longitudinal controlled studies. The increased costs of thorough safety evaluations must be defrayed by early initial approval and marketing of new therapeutic agents. Patent lifetimes and marketing exclusivity should be prolonged until results of long-term studies are finalized. © 2013 Informa UK, Ltd.


Rendell M.,Creighton Diabetes Center | Akturk H.K.,Creighton Diabetes Center | Tella S.H.,Creighton Diabetes Center
Expert Opinion on Drug Safety | Year: 2013

Introduction: In 2009, several epidemiological studies suggested a higher frequency of malignancy in insulin glargine-treated patients. A number of follow-up epidemiological population studies as well as two randomized, controlled clinical studies, one a 5000-patient retinopathy study and the other a 12,000-patient cardiovascular outcomes trial (ORIGIN), found no higher frequency of malignancy in glargine-treated patients. Areas covered: We reviewed the existing literature as well as U.S. FDA records to investigate the association of cancer, diabetes, and insulin. There is a 20-40% higher incidence of malignancy in type 2 diabetes patients. Certain cancers are more common, including hepatocellular and pancreatic carcinoma, colorectal cancer, renal cancer, and breast and endometrial cancer, and non-Hodgkin's lymphoma. There are numerous inter-related factors which may promote both diabetes and malignancy, including dietary patterns, obesity, insulin resistance, and alcoholism. Patients who receive insulin treatment are typically older and "sicker" than those who receive oral agents. Expert opinion: It is very difficult to prove causal associations between diabetes and cancer due to the host of confounding factors. The hypothesis that hyperinsulinemia and IGF-1 receptor activation promote cancer is strong, but confounded by the association of hyperinsulinemia with obesity, which separately promotes malignancy. Although statistical techniques to adjust for confounding variables can improve epidemiological comparisons, the lesson of the glargine cancer controversy is that controlled clinical trials are the only means to definitely prove hypotheses. © 2013 Informa UK, Ltd.


PubMed | Creighton Diabetes Center
Type: Journal Article | Journal: Journal of diabetes science and technology | Year: 2016

Point-of-care (POC) testing of HbA1c is used as a time-efficient tool to improve treatment and management planning for diabetes in the clinic setting. HbA1c values are the basis for monitoring ongoing response to treatment and to make adjustments to diabetes therapy. Yet, there is ongoing controversy as to the accuracy of POC assays. Diabetes is a lifelong disease, so comparability of results over a long period of time is needed to follow the response to treatment.We compared the Afinion automated boronate affinity assay and the DCA Vantage immunoassay-based POC techniques to the Tosoh G8 and Bio-Rad Variant II ion-exchange high-performance liquid chromatography (HPLC) central laboratory methods in a study lasting 3 years. College of American Pathology Survey results and American Proficiency testing were utilized to assess the external validity of the POC techniques.Despite high correlations among the 4 techniques, there were significant and variable differences obtained over time. The Biorad values varied from 0.1 to 0.4% higher than the Afinion values. The DCA results were usually higher than the Afinion values, but fell below the Afinion results in the last 6 months of our study. Both POC techniques gave systematically lower values than the Tosoh measurements, and both the POC and the central laboratory measurements showed variable differences from the National Glycohemoglobin Standardization Program values over the duration of this study.All who rely on POC methods as well as on central laboratory measurement of HbA1c must understand the potential limitations of these assays. The assessment of diabetes blood sugar control should proceed from the evaluation of HbA1c combined with review of plasma glucose and of self-monitored blood glucose values.


PubMed | Creighton Diabetes Center
Type: Journal Article | Journal: Expert opinion on drug safety | Year: 2014

Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i.This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents.DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.

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