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John B Buse - Top 30 Publications

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2).

The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes.

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality.

The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Background The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. Methods We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. Results In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. Conclusions Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes.

Background In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. Methods In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. Results A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). Conclusions Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).

Liraglutide and Renal Outcomes in Type 2 Diabetes.

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.

Hypertension Control in Adults With Diabetes Mellitus and Recurrent Cardiovascular Events: Global Results From the Trial Evaluating Cardiovascular Outcomes With Sitagliptin.

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function.

The War Is Not Yet Won.

Genetic variants in HSD17B3, SMAD3, and IPO11 impact circulating lipids in response to fenofibrate in individuals with type 2 diabetes.

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated T2D patients, we examined lipid changes in response to fenofibrate therapy using genome-wide association(GWA). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects(p<5x10(-6) ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects(q<0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression(q<0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that TGF-ß and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in T2D patients. This article is protected by copyright. All rights reserved.

Comparative safety of pioglitazone versus clinically meaningful treatment alternatives concerning the risk of bladder cancer in older US adults with type 2 diabetes.

To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl-peptidase-4 inhibitors [DPP-4s] or sulfonylureas.

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.

Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.

Glucose Self-monitoring in Non-Insulin-Treated Patients With Type 2 Diabetes in Primary Care Settings: A Randomized Trial.

The value of self-monitoring of blood glucose (SMBG) levels in patients with non-insulin-treated type 2 diabetes has been debated.

Three approaches to glucose monitoring in non-insulin treated diabetes: a pragmatic randomized clinical trial protocol.

For the nearly 75% of patients living with type 2 diabetes (T2DM) that do not use insulin, decisions regarding self-monitoring of blood glucose (SMBG) can be especially problematic. While in theory SMBG holds great promise for sparking favorable behavior change, it is a resource intensive activity without firmly established patient benefits. This study describes our study protocol to assess the impact of three different SMBG testing approaches on patient-centered outcomes in patients with non-insulin treated T2DM within a community-based, clinic setting.

Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial.

Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial.

Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: Results From the LEADER Randomized Trial.

To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5-5.0 years.

Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

EXSCEL is a randomized, double-blind, placebo-controlled trial examining the effect of exenatide once-weekly (EQW) versus placebo on time to the primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in patients with type 2 diabetes mellitus (DM) and a wide range of cardiovascular (CV) risk.

Differential Use of Screening Mammography in Older Women Initiating Metformin versus Sulfonylurea.

Differential use of screening mammography may lead to biased detection of breast cancer. This study aimed to compare receipt of screening mammography and the incidence of screen-detected breast cancer between metformin and sulfonylurea initiators.

Sodium-Glucose Cotransporter 2 Inhibitors and Diabetic Ketoacidosis: A Case Series From Three Academic Institutions.

Insulin-Responsive Glucagon Delivery for Prevention of Hypoglycemia.

Hypoglycemia, the state of abnormally low blood glucose level, is an acute complication of insulin and sulfonylurea therapy in diabetes management. Frequent insulin dosing and boluses during daily diabetes care leads to an increased risk of dangerously low glucose levels, which can cause behavioral and cognitive disturbance, seizure, coma, and even death. This study reports an insulin-responsive glucagon delivery method based on a microneedle (MN)-array patch for the prevention of hypoglycemia. The controlled release of glucagon is achieved in response to elevated insulin concentration by taking advantage of the specific interaction between insulin aptamer and target insulin. Integrating a painless MN-array patch, it is demonstrated that this insulin-triggered glucagon delivery device is able to prevent hypoglycemia following a high-dose insulin injection in a chemically induced type 1 diabetic mouse model.

Red Blood Cells for Glucose-Responsive Insulin Delivery.

Glucose-responsive delivery of insulin mimicking the function of pancreatic β-cells to achieve meticulous control of blood glucose (BG) would revolutionize diabetes care. Here the authors report the development of a new glucose-responsive insulin delivery system based on the potential interaction between the glucose derivative-modified insulin (Glc-Insulin) and glucose transporters on erythrocytes (or red blood cells, RBCs) membrane. After being conjugated with the glucosamine, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of BG level in vivo. The delivery vehicle can be further simplified utilizing injectable polymeric nanocarriers coated with RBC membrane and loaded with Glc-Insulin. The described work is the first demonstration of utilizing RBC membrane to achieve smart insulin delivery with fast responsiveness.

No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives.

To compare the cardiovascular (CV) risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors relative to sulphonylureas (SUs) and thiazolidinediones (TZDs).

Comparative Effect of Initiating Metformin Versus Sulfonylureas on Breast Cancer Risk in Older Women.

Several observational studies have reported that metformin may be associated with reduced risk of breast cancer; however, many of these studies were affected by time-related biases such as immortal time bias and time-window bias. This study aimed to examine the relative risk of breast cancer for older women initiating metformin versus sulfonylureas while avoiding such biases.

Response to Comment on Cefalu et al. Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care 2016;39:1186-1201.

Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery.

A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h.

H2O2-Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery.

A self-regulated "smart" insulin administration system would be highly desirable for diabetes management. Here, a glucose-responsive insulin delivery device, which integrates H2O2-responsive polymeric vesicles (PVs) with a transcutaneous microneedle-array patch was prepared to achieve a fast response, excellent biocompatibility, and painless administration. The PVs are self-assembled from block copolymer incorporated with polyethylene glycol (PEG) and phenylboronic ester (PBE)-conjugated polyserine (designated mPEG-b-P(Ser-PBE)) and loaded with glucose oxidase (GOx) and insulin. The polymeric vesicles function as both moieties of the glucose sensing element (GOx) and the insulin release actuator to provide basal insulin release as well as promote insulin release in response to hyperglycemic states. In the current study, insulin release responds quickly to elevated glucose and its kinetics can be modulated by adjusting the concentration of GOx loaded into the microneedles. In vivo testing indicates that a single patch can regulate glucose levels effectively with reduced risk of hypoglycemia.

Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes.

Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity.

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.

Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response.

Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10(-7) to p = 1.76 × 10(-5), by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available.

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum.

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

Pancreatic Safety of Sitagliptin in the TECOS Study.

We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).