Hertzel Gerstein - Academia.edu (original) (raw)

Papers by Hertzel Gerstein

Diabetes Care, Feb 1, 2009

OBJECTIVE-Diabetes is associated with cognitive decline and dementia. However, the relationship b... more OBJECTIVE-Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS-The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. RESULTS-A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI Ϫ1.22 to Ϫ2.28; P Ͻ 0.0001), a 0.20-point lower MMSE score (Ϫ0.11 to Ϫ0.28; P Ͻ 0.0001), a 0.11-point lower memory score (Ϫ0.02 to Ϫ0.19, P ϭ 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31-0.19, P ϭ 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance. CONCLUSIONS-Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.

Diabetologia, Aug 30, 2021

Improvement of glucose levels into the normal range can occur in some people living with diabetes... more Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks vs benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed 'remission' as the most appropriate descriptive term, and HbA 1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission. This Consensus Report is jointly published in The Journal of Clinical Endocrinology & Metabolism, published by Oxford University Press on behalf of the Endocrine Society; Diabetologia, published by Springer-Verlag, GmbH, on behalf of the European Association for the Study of Diabetes; Diabetic Medicine, published by Wiley on behalf of Diabetes UK; and Diabetes Care, published by the American Diabetes Association. A consensus report of a particular topic contains a comprehensive examination and is authored by an expert panel and represents the panel's collective analysis, evaluation and opinion. The article was reviewed for EASD by its Committee on Clinical Affairs.

The Journal of Clinical Endocrinology and Metabolism, Feb 4, 2021

Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardio... more Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed. Objective: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years). Methods: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes). Results: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics

Cardiovascular Diabetology, 2021

Background The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 dia... more Background The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. Methods Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on ...

European Heart Journal, 2020

Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases intro... more Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of no...

New England Journal of Medicine, 2021

BACKGROUND Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar t... more BACKGROUND Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain. METHODS In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m 2 of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes). RESULTS A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo. CONCLUSIONS In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.

Diabetes Care, 2021

Improvement of glucose levels into the normal range can occur in some people living with diabetes... more Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed “remission” as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy a...

Cardiovascular Diabetology, 2020

Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) doub... more Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular de...

Diabetes Care, 2020

BACKGROUND Long-term glycemic control reduces retinopathy risk, but transient worsening can occur... more BACKGROUND Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes. PURPOSE To examine the associations between retinopathy, HbA1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs. DATA SOURCES Systematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. STUDY SELECTION Published trial reports were used as the primary data sources. DATA EXTRACTION HbA1c, SBP, and weight data throughout follow-up by treatment group were extracted. DATA SYNTHESIS Random-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studi...

Diabetes Care, 2020

OBJECTIVE The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) re... more OBJECTIVE The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models. RESULTS As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75–0.94, P = 0.003)—an effect driven by individuals without cardiovascular diseas...

Age and Ageing, 2019

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, ... more New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration...

The Lancet Diabetes & Endocrinology, 2019

Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk ... more Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Elsevier Editorial System(tm) for The Lancet Diabetes & Endocrinology Manuscript Draft Manuscript Number: THELANCETDE-D-19-00502R2 Title: Cardiovascular, mortality and renal outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes-a systematic review and meta-analysis of randomised trials Article Type: Article (Original Research)

Journal of Diabetes Research, 2018

Introduction. We investigated the association of diabetic retinopathy and neuropathy with increas... more Introduction. We investigated the association of diabetic retinopathy and neuropathy with increased risk of recurrent cardiovascular (CV) events in 6068 patients with type 2 diabetes mellitus (T2DM) and recent acute coronary syndrome (ACS) enrolled in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA). Methods. History of retinopathy and neuropathy as well as duration of T2DM were self-reported at screening. Proportional hazards regression models were used to assess relationships between retinopathy, neuropathy, and recurrent CV events. Results. At screening, retinopathy and neuropathy were reported in 10.7% and 17.5% of patients, respectively, while 5.7% reported both. When adjusted for randomized treatment only, both retinopathy and neuropathy were associated with a primary composite outcome (CV death, nonfatal MI, stroke, or hospitalization for unstable angina) (retinopathy: HR 1.44, 95% CI 1.19–1.75; neuropathy: HR 1.33, 95% CI 1.12–1.57), CV composite (CV death, ...

Diabetes care, Jun 1, 2018

The American journal of medicine, Jan 22, 2017

Early stages of chronic kidney disease are associated with an increased cardiovascular risk in pa... more Early stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type two diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared to standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) and/or moderate chronic kidney disease (Stage 3). Τwo co-primary composite cardiovascular outcomes were assessed. The first was the composite endpoint of non-fatal MI, non-fatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were pre-...

Diabetes Care, 2016

OBJECTIVES This study investigated whether the beneficial effects of intensive glycemic control a... more OBJECTIVES This study investigated whether the beneficial effects of intensive glycemic control and fenofibrate treatment of dyslipidemia in reducing retinopathy progression demonstrated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study persisted beyond the clinical trial. RESEARCH DESIGN AND METHODS The ACCORD Study (2003–2009) randomized participants with type 2 diabetes to intensive or standard treatment for glycemia (A1C level at <6.0% [42 mmol/mol] vs. 7.0–7.9% [53–63 mmol/mol]), systolic blood pressure (<120 vs. 140 mmHg), and dyslipidemia (fenofibrate [160 mg] plus simvastatin or placebo plus simvastatin). ACCORD Eye Study participants, who had baseline and year 4 eye examinations and fundus photographs, were reexamined in the ACCORD Follow-On (ACCORDION) Eye Study (2010–2014) 4 years after the ACCORD trial closeout. The outcome measure was diabetic retinopathy progression of three or more steps on the Early Treatment Diabetic Retinopathy Study...

New England Journal of Medicine, 2015

BACKGROUND Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes,... more BACKGROUND Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P = 0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.

Alzheimer's & Dementia, 2014

the development of cognitive decline in the prevention of AD, this information may provide insigh... more the development of cognitive decline in the prevention of AD, this information may provide insight into the early development of disease. This study examines the role of apoE4 in ten-year cognitive change using a simple test of episodic memory. Methods: Participants were 162 women (aged 64-77 years) from the longitudinal prospective Women's Healthy Ageing Project (WHAP). The California Verbal Learning Test (CVLT) was used as a measure of episodic memory and administered in 2002 and 2012. Delayed recall of the CVLT word list was measured 25-30 minutes after the initial learning phase. Blood samples were collected for genetic analysis to determine the inheritance of the apoE4 allele. Age and education were included in the analysis as possible predictors of CVLT performance. Results: Of the 162 participants in the sample, 52 were found to possess the apoE4 allele. Participants lacking the apoE4 allele showed greater increase in CVLT delayed recall scores over 10 years (mean difference ¼ 2.96) than those with the apoE4 allele (mean difference ¼ 1.46), taking age and education into account, which was statistically significant (p<0.05). Conclusions: Inheritance of the apoE4 allele predicted differences in episodic memory change over ten years in our epidemiologically-sourced cohort. This result suggests that the influence of apoE4 can be observed before the onset of disease in healthy individuals. This study highlights the need for further work to determine a full cognitive profile for healthy individuals with a positive apoE4 status.

Diabetes Care, 2013

OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We d... more OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We determined whether comparable glycemic control could be achieved by self-titration versus physician titration of a once-daily bolus insulin dose in patients with type 2 diabetes who are unable to achieve optimal glycemia control with a basal insulin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes, an HbA1c level >7% (53 mmol/mol), and either nocturnal hypoglycemia episodes or an insufficient basal insulin glargine level (with or without oral agents) to achieve a fasting plasma glucose level ≤6 mmol/L (108 mg/dL) were studied. Participants all had bolus insulin glulisine added at breakfast and were allocated to either algorithm-guided patient self-titration or physician titration. The primary outcome was an HbA1c level ≤7% (53 mmol/mol) without severe hypoglycemia. RESULTS After a mean (SD) follow-up of 159.4 days (36.2 days), 28.4% of participants in the self-titration arm v...

Diabetes Care, Feb 1, 2009

OBJECTIVE-Diabetes is associated with cognitive decline and dementia. However, the relationship b... more OBJECTIVE-Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS-The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. RESULTS-A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI Ϫ1.22 to Ϫ2.28; P Ͻ 0.0001), a 0.20-point lower MMSE score (Ϫ0.11 to Ϫ0.28; P Ͻ 0.0001), a 0.11-point lower memory score (Ϫ0.02 to Ϫ0.19, P ϭ 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31-0.19, P ϭ 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance. CONCLUSIONS-Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.

Diabetologia, Aug 30, 2021

Improvement of glucose levels into the normal range can occur in some people living with diabetes... more Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks vs benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed 'remission' as the most appropriate descriptive term, and HbA 1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission. This Consensus Report is jointly published in The Journal of Clinical Endocrinology & Metabolism, published by Oxford University Press on behalf of the Endocrine Society; Diabetologia, published by Springer-Verlag, GmbH, on behalf of the European Association for the Study of Diabetes; Diabetic Medicine, published by Wiley on behalf of Diabetes UK; and Diabetes Care, published by the American Diabetes Association. A consensus report of a particular topic contains a comprehensive examination and is authored by an expert panel and represents the panel's collective analysis, evaluation and opinion. The article was reviewed for EASD by its Committee on Clinical Affairs.

The Journal of Clinical Endocrinology and Metabolism, Feb 4, 2021

Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardio... more Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed. Objective: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years). Methods: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes). Results: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics

Cardiovascular Diabetology, 2021

Background The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 dia... more Background The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. Methods Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on ...

European Heart Journal, 2020

Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases intro... more Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of no...

New England Journal of Medicine, 2021

BACKGROUND Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar t... more BACKGROUND Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain. METHODS In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m 2 of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes). RESULTS A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo. CONCLUSIONS In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.

Diabetes Care, 2021

Improvement of glucose levels into the normal range can occur in some people living with diabetes... more Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed “remission” as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy a...

Cardiovascular Diabetology, 2020

Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) doub... more Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular de...

Diabetes Care, 2020

BACKGROUND Long-term glycemic control reduces retinopathy risk, but transient worsening can occur... more BACKGROUND Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes. PURPOSE To examine the associations between retinopathy, HbA1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs. DATA SOURCES Systematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes. STUDY SELECTION Published trial reports were used as the primary data sources. DATA EXTRACTION HbA1c, SBP, and weight data throughout follow-up by treatment group were extracted. DATA SYNTHESIS Random-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studi...

Diabetes Care, 2020

OBJECTIVE The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) re... more OBJECTIVE The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models. RESULTS As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75–0.94, P = 0.003)—an effect driven by individuals without cardiovascular diseas...

Age and Ageing, 2019

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, ... more New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration...

The Lancet Diabetes & Endocrinology, 2019

Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk ... more Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Elsevier Editorial System(tm) for The Lancet Diabetes & Endocrinology Manuscript Draft Manuscript Number: THELANCETDE-D-19-00502R2 Title: Cardiovascular, mortality and renal outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes-a systematic review and meta-analysis of randomised trials Article Type: Article (Original Research)

Journal of Diabetes Research, 2018

Introduction. We investigated the association of diabetic retinopathy and neuropathy with increas... more Introduction. We investigated the association of diabetic retinopathy and neuropathy with increased risk of recurrent cardiovascular (CV) events in 6068 patients with type 2 diabetes mellitus (T2DM) and recent acute coronary syndrome (ACS) enrolled in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA). Methods. History of retinopathy and neuropathy as well as duration of T2DM were self-reported at screening. Proportional hazards regression models were used to assess relationships between retinopathy, neuropathy, and recurrent CV events. Results. At screening, retinopathy and neuropathy were reported in 10.7% and 17.5% of patients, respectively, while 5.7% reported both. When adjusted for randomized treatment only, both retinopathy and neuropathy were associated with a primary composite outcome (CV death, nonfatal MI, stroke, or hospitalization for unstable angina) (retinopathy: HR 1.44, 95% CI 1.19–1.75; neuropathy: HR 1.33, 95% CI 1.12–1.57), CV composite (CV death, ...

Diabetes care, Jun 1, 2018

The American journal of medicine, Jan 22, 2017

Early stages of chronic kidney disease are associated with an increased cardiovascular risk in pa... more Early stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type two diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared to standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) and/or moderate chronic kidney disease (Stage 3). Τwo co-primary composite cardiovascular outcomes were assessed. The first was the composite endpoint of non-fatal MI, non-fatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were pre-...

Diabetes Care, 2016

OBJECTIVES This study investigated whether the beneficial effects of intensive glycemic control a... more OBJECTIVES This study investigated whether the beneficial effects of intensive glycemic control and fenofibrate treatment of dyslipidemia in reducing retinopathy progression demonstrated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study persisted beyond the clinical trial. RESEARCH DESIGN AND METHODS The ACCORD Study (2003–2009) randomized participants with type 2 diabetes to intensive or standard treatment for glycemia (A1C level at <6.0% [42 mmol/mol] vs. 7.0–7.9% [53–63 mmol/mol]), systolic blood pressure (<120 vs. 140 mmHg), and dyslipidemia (fenofibrate [160 mg] plus simvastatin or placebo plus simvastatin). ACCORD Eye Study participants, who had baseline and year 4 eye examinations and fundus photographs, were reexamined in the ACCORD Follow-On (ACCORDION) Eye Study (2010–2014) 4 years after the ACCORD trial closeout. The outcome measure was diabetic retinopathy progression of three or more steps on the Early Treatment Diabetic Retinopathy Study...

New England Journal of Medicine, 2015

BACKGROUND Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes,... more BACKGROUND Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P = 0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.

Alzheimer's & Dementia, 2014

the development of cognitive decline in the prevention of AD, this information may provide insigh... more the development of cognitive decline in the prevention of AD, this information may provide insight into the early development of disease. This study examines the role of apoE4 in ten-year cognitive change using a simple test of episodic memory. Methods: Participants were 162 women (aged 64-77 years) from the longitudinal prospective Women's Healthy Ageing Project (WHAP). The California Verbal Learning Test (CVLT) was used as a measure of episodic memory and administered in 2002 and 2012. Delayed recall of the CVLT word list was measured 25-30 minutes after the initial learning phase. Blood samples were collected for genetic analysis to determine the inheritance of the apoE4 allele. Age and education were included in the analysis as possible predictors of CVLT performance. Results: Of the 162 participants in the sample, 52 were found to possess the apoE4 allele. Participants lacking the apoE4 allele showed greater increase in CVLT delayed recall scores over 10 years (mean difference ¼ 2.96) than those with the apoE4 allele (mean difference ¼ 1.46), taking age and education into account, which was statistically significant (p<0.05). Conclusions: Inheritance of the apoE4 allele predicted differences in episodic memory change over ten years in our epidemiologically-sourced cohort. This result suggests that the influence of apoE4 can be observed before the onset of disease in healthy individuals. This study highlights the need for further work to determine a full cognitive profile for healthy individuals with a positive apoE4 status.

Diabetes Care, 2013

OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We d... more OBJECTIVE Diabetes self-management is universally regarded as a foundation of diabetes care. We determined whether comparable glycemic control could be achieved by self-titration versus physician titration of a once-daily bolus insulin dose in patients with type 2 diabetes who are unable to achieve optimal glycemia control with a basal insulin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes, an HbA1c level >7% (53 mmol/mol), and either nocturnal hypoglycemia episodes or an insufficient basal insulin glargine level (with or without oral agents) to achieve a fasting plasma glucose level ≤6 mmol/L (108 mg/dL) were studied. Participants all had bolus insulin glulisine added at breakfast and were allocated to either algorithm-guided patient self-titration or physician titration. The primary outcome was an HbA1c level ≤7% (53 mmol/mol) without severe hypoglycemia. RESULTS After a mean (SD) follow-up of 159.4 days (36.2 days), 28.4% of participants in the self-titration arm v...