Bernard Zinman's research while affiliated with Mount Sinai Hospital, Toronto and other places
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Publications (678)
Aims/hypothesis:
Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first...
In early type 2 diabetes, the strategy of “induction” with short-term intensive insulin therapy followed by “maintenance” with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials....
Background:
Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences...
Aim:
To identify baseline determinants of diabetes remission in response to short-term insulin-based therapy.
Methods:
In this study, adult patients with type 2 diabetes (T2D) of less than 7 years duration were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice-daily lispro, or (c) glargine + twice-daily exenatid...
The cumulative effect of postpartum weight retention from each pregnancy in a woman’s life may contribute to her risk of ultimately developing cardiovascular (CV) disease and type 2 diabetes. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the traject...
Short-term treatment with insulin can induce remission of type 2 diabetes (T2DM) in some patients but not others. We thus sought to identify baseline predictors of diabetes remission in response to short-term insulin-based therapy. In this study, adult patients with T2DM of <7 years duration were randomized to 8-weeks treatment with (i) insulin gla...
Introduction
Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.
Research design and methods
We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The...
Objectives:
REDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of RE...
Objective
Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to eva...
Rationale & objective:
It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the CREDENCE study.
Study design:
Secondary analysis of a randomized controlled...
Background:
Metformin is increasingly being used during pregnancy, with potentially adverse long-term effects on children. We aimed to examine adiposity in children of women with type 2 diabetes from the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial, with and without in-utero exposure to metformin, up to 24 months of age.
Meth...
Objective:
To compare postpartum glucose tolerance between women treated for gestational diabetes mellitus (GDM) and those not treated.
Research design and methods:
Metabolic testing was performed at 3 and 12 months postpartum in 599 women comprising the following gestational glucose tolerance groups: 1) normal glucose challenge test (GCT) and o...
OBJECTIVE
Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years’ duration of type 1 diabetes. We aimed to determine a simple, risk factor–based screening schedule that optimizes early detection and testing frequency.
RESEARCH DESIGN AND METHODS
Urinary albumin excretion measurements from 1,343 particip...
Aims
Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-...
Combining a glucagon-like peptide-1 receptor agonist (GLP1-RA) with basal insulin is an emerging option when initiating injectable therapy in longstanding type 2 diabetes (T2DM). Recognizing that short-term insulin therapy can improve beta-cell function and induce glycemic remission in early T2DM, we hypothesized that adding the short-acting GLP1-R...
OBJECTIVE
Estimated time in range (eTIR) obtained from DCCT glucose profiles (pre- and postprandial and bedtime) was recently reported to be associated with microvascular outcomes and was recommended as a clinical trial outcome, but without consideration of HbA1c.
RESEARCH DESIGN AND METHODS
The associations of eTIR with diabetic retinopathy and m...
Background
The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardio...
Objective:
In the MiTy (Metformin in Women With Type 2 Diabetes in Pregnancy) randomized trial of metformin versus placebo added to insulin, we found numerous benefits with metformin but identified an increased proportion of infants who were small for gestational age (SGA). We aimed to determine the predictors of SGA in order to individualize care...
Background: In the MiTy trial [pregnant T2D randomized to metformin vs. placebo], infants exposed to metformin in-utero had a lower risk of large-for-gestational-age (LGA) but were at higher risk of small-for-gestational-age (SGA) . To date, there are limited data on the effect of in-utero exposure to metformin on infant/child growth in T2D, accord...
Background: Offspring of mothers with T2D are at increased risk of obesity and diabetes. In the MiTy trial [pregnant T2D randomized to metformin vs. placebo], infants exposed to metformin were lighter, had lower fat-mass and risk of large-for-gestational-age, but at higher risk of small-for-gestational-age. There are questions on the long-term effe...
The PIONEER 8 (NCT03021187) trial demonstrated significant glucose-lowering efficacy of oral semaglutide vs. placebo (pbo) in patients (pts) with T2D inadequately controlled with insulin. Additionally, those assigned to oral semaglutide (7 or 14 mg daily) had a lower total daily insulin dose at end of treatment (week 52) relative to baseline, vs. t...
Background:
Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk...
Aims
Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that SGLT2 inhibitor use by type 2 diabetes (T2D) patients was associated with a 49% lower risk of nephrolithiasis, compared to GLP-1 receptor agonists. We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using exis...
Aims
Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that SGLT2 inhibitor use by type 2 diabetes (T2D) patients was associated with a 49% lower risk of nephrolithiasis, compared to GLP-1 receptor agonists. We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using exis...
Objective:
The continuum of maternal glycemia in pregnancy shows continuous associations with both: 1) neonatal birth weight at delivery, and 2) subsequent adiposity later in childhood. While treating gestational diabetes mellitus (GDM) can lower birth weight and thereby disrupt the former association, it is unclear if such treatment reduces child...
Aims
Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial.
Methods
Patients (n=7,020...
Introduction:
People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes.
Methods:
We assessed expos...
Aim
- Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy.
Methods
- The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100mg daily or placebo. Neuropathy events were defined post-hoc as any rep...
Aims:
Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease (NAFLD)-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OU...
OBJECTIVE
Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the risk of lower-extremity complications is unknown. We examined whether former intensive versus conventional glycemic control among Diabetes Control and Complications Trial (DCCT) participants wit...
OBJECTIVE
Rapid loss of estimated glomerular filtration rate (eGFR) within its normal range has been proposed as a strong predictor of future kidney disease. We investigated this association of eGFR slope early in the course of type 1 diabetes with long-term incidence of kidney and cardiovascular complications.
RESEARCH DESIGN AND METHODS
The annu...
Background
Diabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressi...
Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes (T2D).
Methods: Pooled (N=12,637) and by-trial data from SUSTAIN 6 (N=3297) and LEADER (N=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persisten...
Aims:
In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or...
Aims:
Elevated uric acid (UA) levels are common in type 2 diabetes (T2D) and may lead to gouty arthritis. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) decrease UA levels and may reduce gout incidence. We aim to evaluate the effect of empagliflozin on UA levels, anti-gout medication and gout episodes in EMPA-REG OUTCOME (NCT01131676).
Mater...
The evolution of basal insulin therapy over the past 100 years since the discovery of insulin is a testimony to the biomedical bench‐to‐bedside process, wherein incremental advances in the basic sciences are progressively translated over time into a series of enhancements in clinical care, each building upon the success of its predecessors. The eme...
Aims:
Insulin use in type 2 diabetes, while often necessary, is associated with hypoglycemia and weight gain, requires training, and may add significant costs. We evaluated the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial.
Materials and methods:
In EMPA-REG OU...
Background
Recent studies have suggested that gestational diabetes (GDM) is a heterogeneous condition with distinct subtypes determined by whether the predominant metabolic abnormality is impaired insulin sensitivity or deficient insulin secretion. However, it is not known if the elevated future risk of pre-diabetes/diabetes associated with GDM var...
Objectives
Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.
Background
In the EMP...
[This corrects the article DOI: 10.1093/ckj/sfaa225.].
Background: Canagliflozin reduces the incidence of kidney and cardiovascular events in people with type 2 diabetes and chronic kidney disease (CKD). We assessed the effects of canagliflozin according to age and sex in a randomized, placebo-controlled trial.
Methods: The CREDENCE study randomized participants with type 2 diabetes and albuminuric CKD...
Aims
In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what tim...
Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal ou...
Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk, and progression, of diabetic kidney disease. We hypothesized that sodium-glucose cotransporter 2 inhibitors could similarly improve the microvascular complication of neuropathy.
Methods: The CREDENCE trial randomized participants with type 2 diabetes and albuminuria to canaglifl...
Aims/hypothesis:
Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes.
Methods:
The CAROLINA-COGNITION study was part of...
A Correction to this paper has been published: https://doi.org/10.1007/s00125-021-05445-z
Objective:
To determine the association of adipose tissue insulin resistance with longitudinal changes in biomarkers of adipose tissue function, circulating lipids, and dysglycemia.
Research design and methods:
Adults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort had up to four assessments o...
Aims:
When administered in early T2DM, short-term intensive insulin therapy (IIT) can improve reversible beta-cell dysfunction and induce remission of diabetes, but these effects are not permanent. To preserve beta-cell function, we have previously suggested that "induction" IIT should be followed by a "maintenance therapy", such as metformin. Her...
There has been a great deal of controversy regarding priority of discovery of insulin. Indeed, many scientists made important and, in some cases, seminal contributions to identifying the endocrine role of the pancreas and the potential for pancreatic extracts to have a glucose-lowering effect. The purpose of this article is to describe the early ex...
Aim:
To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians.
Methods:
In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evalua...
Background
Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis.
Aims and methods
We studied the relationship between HF diagnosis, use of LD, and outcomes in four patient subgroups with type-2 diabetes mellitus (T2DM) in EMPA-REG OUTCOME; [i) investiga...
The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery and therapeutic efficacy. Normal endogenous insulin secretion consists of a highly orchestrated physiologic loop wherein multiple metabolic signals trig...
Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease and is associated with significant mortality and morbidity. In the CREDENCE trial canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In this current analysis we sought to determine whether the effect of can...
Background
Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches.
Methods and Result...
Background and objectives
The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥30...
Aims:
Individuals with atherosclerotic cardiovascular disease (ASCVD) are at elevated risk of recurrent cardiovascular (CV)/heart failure (HF) events. Polyvascular disease (ASCVD involving ≥2 arterial beds) predicts CV events, but the relationship with HF events is unclear. We determined the relationship between polyvascular disease and risk of HF...
Background
Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP.
Methods
Cardiovascular and renal microvascular outcome study with LINA randomize...
Objectives
This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).
Background
Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.
Me...
Objective
It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME.
Methods
Participants with type 2 diabetes and high cardi...
Aim
To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk.
Methods
In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post...
Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, w...
Background
Patients with type 2 diabetes and atherosclerotic cardiovascular disease are at high clinical risk. We assessed the effect of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on total cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial.
Methods
The EMPA-REG OUTCOME trial was a randomised, double-b...
We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15...
Aim:
To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses.
Materials and methods:
People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to lin...
Background
Glucagon‐like peptide 1 receptor agonists (GLP‐1 RA) have previously shown improved measures of memory and reduced phospho‐tau burden in preclinical animal models relevant to progressive cognitive impairment (Hansen. J Alzheimers Dis .2015;46:877‐88; Hansen. Brain Res .2016;1634:158‐70). Liraglutide and semaglutide are structurally simil...
Background and objectives
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is...
Background
Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial.
Methods
A total of 7020 pati...
Introduction: In the REDUCE-IT trial, icosapent ethyl (IPE) was shown to reduce major adverse cardiac events (MACE) including cardiovascular (CV) death in patients with elevated triglycerides (TG) and atherosclerotic CV disease (ASCVD) and/or diabetes. There are limited data evaluating the external applicability of REDUCE-IT inclusion criteria in c...
Introduction: Type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD) often co-exist yielding increased risk of cardiovascular (CV) complications, including heart failure (HF). In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) reduced the risk of CV death and hospitalization for HF (HHF) in patients with T2D and CV disease (CVD). W...
Introduction: In EMPA-REG OUTCOME®, the sodium-glucose transporter inhibitor, empagliflozin (EMPA), reduced the risk of first cardiovascular (CV) events primarily CV mortality and hospitalization for heart failure in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease. In analyses including total events, EMPA...
Background: Many patients with type 2 diabetes (T2D) will, over time, require insulin therapy for glycemic control. Treatment-attendant adverse effects of insulin such as weight gain and hypoglycemia may be especially problematic in those with CVD. Delaying the need for insulin initiation may therefore be an important therapeutic goal, especially i...
Introduction: In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced the risk of major adverse cardiovascular (CV) events (MACE), CV mortality and hospitalization for heart failure (HHF) in analyses of first events in patients with type 2 diabetes (T2D) and atherosclerotic CV disease (ASCVD). We assessed the effect of EMPA on the total burden of CV even...
