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Bernard Zinman - Top 30 Publications

Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events.

Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME.

Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)(1) and is a predictor of cardiovascular death.(2) Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49-0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50-0.85) versus placebo when given in addition to standard of care.(3) We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial.

Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial.

Circulating B-type Natriuretic Peptide in Women with and without Recent Gestational Diabetes:The Impact of Current Glucose Intolerance.

Circulating B-type natriuretic peptide, as measured by the N-terminal fragment of its prohormone (NT-proBNP), is inversely associated with incident type 2 diabetes (T2DM) but positively related to future cardiovascular disease (CVD). Recognizing that gestational diabetes (GDM) identifies women at future risk for both T2DM and CVD, we sought to determine whether gestational glucose tolerance relates to NT-proBNP in the years after delivery.

Response to Comment on Lachin et al. Association of Glycemic Variability in Type 1 Diabetes With Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial. Diabetes Care 2017;40:777-783.

Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial.

Empagliflozin reduced the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with type 2 diabetes (T2D) and established CV disease (CVD) in the EMPA-REG OUTCOME® trial. We investigated whether the benefit of empagliflozin was observed across the spectrum of HF risk.

Diabetes Research and Care Through the Ages.

As has been well established, the Diabetes Care journal's most visible signature event is the Diabetes Care Symposium held each year during the American Diabetes Association's Scientific Sessions. Held this past year on 10 June 2017 in San Diego, California, at the 77th Scientific Sessions, this event has become one of the most attended sessions during the Scientific Sessions. Each year, in order to continue to have the symposium generate interest, we revise the format and content of this event. For this past year, our 6th annual symposium, I felt it was time to provide a comprehensive overview of our efforts in diabetes care to determine, first and foremost, how we arrived at our current state of management. I also felt the narrative needed to include the current status of management, especially with a focus toward cardiovascular disease, and finally, we wanted to ask what the future holds. Toward this goal, I asked four of the most noted experts in the world to provide their opinion on this topic. The symposium started with a very thoughtful presentation by Dr. Jay Skyler entitled "A Look Back as to How We Got Here." That was followed by two lectures on current concepts by Dr. Bernard Zinman entitled "Current Treatment Paradigms Today-How Well Are We Doing?" and by Dr. Matthew Riddle entitled "Evolving Concepts and Future Directions for Cardiovascular Outcomes Trials." The final lecture for the symposium was delivered by Dr. Ele Ferrannini and was entitled "What Does the Future Hold?" As always, a well-attended and well-received symposium is now the norm for our signature event and our efforts were rewarded by the enthusiasm of the attendees. This narrative summarizes the lectures held at the symposium.-William T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association.

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.

Bladder cancer in the EMPA-REG OUTCOME trial.

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.

The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

Empagliflozin and Clinical Outcomes in Patients with Type 2 Diabetes, Established Cardiovascular Disease and Chronic Kidney Disease.

Background -Empagliflozin, a sodium glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME(®) trial. Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease. Methods -Patients with type 2 diabetes, established cardiovascular disease and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m(2) at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL/min/1.73m(2) and/or urine albumin-creatinine ratio [UACR] >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45 to <60, 60 to <90, ≥90 mL/min/1.73m2) and baseline UACR (>300, 30 to ≤300, <30 mg/g). Results -Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes for >10 years, 58% were receiving insulin and 84% were taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR] 0.71 [95% CI 0.52, 0.98]), the risk of all-cause mortality by 24% (HR 0.76 [95% CI 0.59, 0.99]), the risk of hospitalization for heart failure by 39% (HR 0.61 [95% CI 0.42, 0.87]) and the risk of all-cause hospitalization by 19% (HR 0.81 [95% CI 0.72, 0.92]). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and of UACR at baseline and across the two doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL/min/1.73m(2) was consistent with the overall trial population. Conclusions -Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease. Clinical Trial Registration -URL: https://clinicaltrials.gov/. Unique identifier: NCT01131676.

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.

Response by Zinman et al to Letter Regarding Article, "Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk".

Antihyperglycemic agents and cardiovascular outcomes: recent insights.

To summarize cardiovascular outcome trials (CVOTs) with antihyperglycemic agents conducted since 2008 US Food and Drug Administration guidance.

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.

In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status.

Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia.

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.

Novel Diabetes Drugs and the Cardiovascular Specialist.

Recently, treatment with 2 newer classes of type 2 diabetes drugs were found to reduce events in patients with diabetes and cardiovascular (CV) disease, a group common in cardiology clinics. The sodium-glucose cotransporter 2 inhibitor, empagliflozin, markedly and rapidly reduced CV death and heart failure hospitalization, likely with hemodynamic/metabolic-driven mechanisms of action. More recently, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide also reduced CV death and/or major adverse CV events, but did so more slowly and did not influence heart failure risks, suggesting alternative mechanisms of benefit. We will discuss drug therapy for diabetes relative to CV risk, briefly summarize key findings of CV benefit from recent trials, discuss potential mechanisms for benefits of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 agonists, and suggest how such drugs might be embraced by CV specialists to reduce CV events and mortality in their patients.

Impact of the Glucagon Assay When Assessing the Effect of Chronic Liraglutide Therapy on Glucagon Secretion.

Glucagon-like peptide-1 agonists acutely lower serum glucagon. However, in the Liraglutide and β-Cell Repair (LIBRA) Trial, 48-week treatment with liraglutide yielded lower/unchanged fasting glucagon but, surprisingly, enhanced postchallenge glucagonemia [measured by R&D Systems (Minneapolis, MN) assay].

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.

Association of Glycemic Variability in Type 1 Diabetes With Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial.

The Diabetes Control and Complications Trial (DCCT) demonstrated the beneficial effects of intensive versus conventional therapy on the development and progression of microvascular complications of type 1 diabetes. These beneficial effects were almost completely explained by the difference between groups in the levels of HbA1c, which in turn were associated with the risk of these complications. We assessed the association of glucose variability within and between quarterly 7-point glucose profiles with the development and progression of retinopathy, nephropathy, and cardiovascular autonomic neuropathy during the DCCT.

Asymmetric dimethylarginine and arginine metabolites in women with and without a history of gestational diabetes.

Dysregulation of arginine metabolism, as evidenced by increased circulating levels of asymmetric dimethylarginine (ADMA), has been proposed as an early event in the natural history of cardiovascular disease. Since the diagnosis of gestational diabetes mellitus (GDM) identifies a patient population at increased future risk of cardiovascular disease later in life, we sought to characterize arginine metabolism in women with and without a history of recent GDM.

Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.

In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89-1.56; P=0.26). We further investigated cerebrovascular events.

Electrocardiographic Abnormalities and Cardiovascular Disease Risk in Type 1 Diabetes: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study.

We examined the association between the prevalence and incidence of electrocardiographic (ECG) abnormalities and the development of cardiovascular disease (CVD) in patients with type 1 diabetes, among whom these ECG abnormalities are common.

Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P  < .001), 24 weeks ( P  < .001), 36 weeks ( P  = .03) and 48 weeks ( P  = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.

Traditional foods and 25(OH)D concentrations in a subarctic First Nations community.

Sub-optimal vitamin D status is common worldwide and the condition may be associated with increased risk for various chronic diseases. In particular, low vitamin D status is highly prevalent in indigenous communities in Canada, although limited data are available on the determinants of serum 25-hydroxyvitamin D (25(OH)D) concentrations in this population. The relationship between traditional food consumption and vitamin D status has not been well documented.

Prior lactation reduces future diabetic risk through sustained postweaning effects on insulin sensitivity.

Breastfeeding for ≥12 mo is recommended for optimal infant nutrition but may hold maternal benefits as well. Indeed, lactation has been associated with lower long-term risk of diabetes in the mother, but the mechanism by which it imparts sustained postweaning effects on glucose tolerance remains unclear. In this context, we postulated that lactation could potentially induce postweaning beneficial effects on glucose tolerance by modifying the natural history of insulin sensitivity and/or pancreatic β-cell function over time. Thus, in this study, we evaluated the relationships between duration of lactation [≤3 mo (n = 70), 3-12 mo (n = 140), and ≥12 mo (n = 120)] and trajectories of insulin sensitivity/resistance, β-cell function, and glycemia over the first 3 yr postpartum in a cohort of 330 women comprising the full spectrum of glucose tolerance in pregnancy, who underwent serial metabolic characterization, including oral glucose tolerance tests, at 3 mo, 1 yr, and 3 yr postpartum. The prevalence of dysglycemia (pre-diabetes/diabetes) at 3 yr postpartum was lower in women who breastfed for ≥12 mo (12.5%) than in those who breastfed for ≤3 mo (21.4%) or for 3-12 mo (25.7%)(overall P = 0.028). On logistic regression analysis, lactation for ≥12 mo independently predicted a lower likelihood of prediabetes/diabetes at 3 yr postpartum (OR = 0.37, 95% CI 0.18-0.78, P = 0.009). Notably, lactation for ≥12 mo predicted lesser worsening of insulin sensitivity/resistance (P < 0.0001), fasting glucose (P < 0.0001), and 2-h glucose (P = 0.011) over 3 yr compared with lactation ≤3 mo but no differences in β-cell function (P ≥ 0.37). It has thus emerged that adherence to current breastfeeding recommendations reduces future diabetic risk through sustained postweaning effects on insulin sensitivity/resistance but not β-cell function.

Can the Combination of Incretin Agents and Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Reconcile the Yin and Yang of Glucagon?

Diabetes: Steno-2 - a small study with a big heart.