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Since the start of the coronavirus disease 2019 (COVID-19) pandemic, patients with diabetes were rapidly recognized as a high-risk population for severe disease. Indeed, a high prevalence of diabetes among patients with COVID-19 who required hospitalization has been consistently reported, reaching 33.8% in 5,700 people hospitalized for COVID-19 in the New York City area (1). In addition, diabetes was associated with more than a doubled risk of intensive care unit (ICU) admission and more than a tripled risk of death (2). However, precise data regarding the type of diabetes are scarce. We report here the clinical characteristics and early prognosis of patients with type 1 diabetes (T1D) hospitalized for COVID-19 in the nationwide multicenter observational CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study (3). The aim of the CORONADO study was to describe the phenotypic characteristics and prognosis of patients with diabetes admitted with COVID-19 between 10 March and 10 April 2020 in 68 French hospitals. The protocol (ClinicalTrials.gov reg. no. NCT04324736) obtained all regulatory approvals as recently described (3). Inclusion criteria were 1 ) hospitalization for biologically and/or clinically/radiologically attested COVID-19 and 2 ) personal history of diabetes or newly diagnosed diabetes on admission. The composite primary end point combined tracheal intubation for mechanical ventilation and/or death on day 7 (D7). Secondary outcomes included death, tracheal intubation, and discharge on D7. Classification of diabetes was recorded in the electronic case report form as noted in the medical file by the physician in charge of the patient. In the present subanalysis, patients in whom diabetes was diagnosed on admission were excluded since the etiological diagnosis had not been formally established. All cases noted as T1D were carefully reviewed by local investigators and the steering committee …

More than 10% of adults undergoing colonoscopy have type 2 diabetes (T2D) (1). The use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has increased due to their glycemic control and benefits of lowering cardiovascular morbidity and mortality as well as reducing diabetic nephropathy (2,3). Diabetic ketoacidosis (DKA) is a rare complication associated with SGLT2i. Precipitating factors include fasting, dietary modifications, intercurrent illnesses, surgical stress, insulin insufficiency, and inappropriate management of SGLT2i in the periprocedural period. SGLT2i-induced ketoacidosis can present either with elevated blood glucose levels (BGL) or with near-normal BGL (

OBJECTIVE Preanalytical processing of blood samples can affect plasma glucose measurement because ongoing glycolysis by cells prior to centrifugation can lower its concentration. In June 2017, ACT Pathology changed the processing of oral glucose tolerance test (OGTT) blood samples for pregnant women from a delayed to an early centrifugation protocol. The effect of this change on the rate of gestational diabetes mellitus (GDM) diagnosis was determined. RESEARCH DESIGN AND METHODS All pregnant women in the Australian Capital Territory (ACT) are recommended for GDM testing with a 75-g OGTT using the World Health Organization diagnostic criteria. From January 2015 to May 2017, OGTT samples were collected into sodium fluoride (NaF) tubes and kept at room temperature until completion of the test (delayed centrifugation). From June 2017 to October 2018, OGTT samples in NaF tubes were centrifuged within 10 min (early centrifugation). RESULTS A total of 7,509 women were tested with the delayed centrifugation protocol and 4,808 with the early centrifugation protocol. The mean glucose concentrations for the fasting, 1-h, and 2-h OGTT samples were, respectively, 0.24 mmol/L (5.4%), 0.34 mmol/L (4.9%), and 0.16 mmol/L (2.3%) higher using the early centrifugation protocol (P < 0.0001 for all), increasing the GDM diagnosis rate from 11.6% (n = 869/7,509) to 20.6% (n = 1,007/4,887). CONCLUSIONS The findings of this study highlight the critical importance of the preanalytical processing protocol of OGTT blood samples used for diagnosing GDM. Delay in centrifuging of blood collected into NaF tubes will result in substantially lower rates of diagnosis than if blood is centrifuged early.

Reductions in blood glucose levels in people with diabetes are often achieved at the expense of increased hypoglycemia. A novel approach is to automatically deliver microdose glucagon when automation of insulin delivery alone is not sufficient to prevent hypoglycemia. The approach requires a bihormonal device and a stable form of glucagon or glucagon analog. The iLet bionic pancreas (Beta Bionics, Inc.) is a purpose-built, fully integrated device that receives a signal from a continuous glucose monitor (CGM) and contains autonomous, lifelong learning, mathematical dosing algorithms, which are initialized only with the patient’s body weight (1). We evaluated the function and safety of the iLet in both its insulin-only configuration and its bihormonal configuration delivering dasiglucagon, a chemically stable glucagon analog (Zealand Pharma), in a home-use study in adults with type 1 diabetes (T1D). This open-label, random-order, crossover, home-use trial (clinical trial reg. no. NCT03840278, ClinicalTrials.gov) was the first human study to test the bihormonal iLet configuration and the first multiday use of dasiglucagon in people with T1D (2). Ten participants used the insulin-only iLet for 7 days with insulin lispro (Eli Lilly) or aspart (Novo Nordisk), the bihormonal iLet for 7 days with dasiglucagon (4 mg/mL) and insulin lispro or aspart, or both, using the same glucose target (110 mg/dL), in random order. There were no restrictions on diet or exercise. The primary outcomes were prespecified iLet operational thresholds. The key secondary outcome was the median time with CGM glucose

The impact of the coronavirus disease 2019 (COVID-19) pandemic on amputation incidence in whole populations with diabetes is unknown. Previous reports are restricted to small cohorts from single specialist centers showing varying outcomes, including greater ulcer severity on presentation (1) and increased amputations (2). We aimed to carry out a population-based assessment of lower-limb major amputation, minor amputation, and revascularization procedure numbers and incidences during the first wave of the COVID-19 pandemic in England, covering the period March to June 2020, compared with equivalent time periods in 2017–2019. We also examined data 4 months following the first wave to assess if delayed presentations resulted in a rebound leading to higher than usual amputation incidence. The Secondary Uses Service data set contains data on inpatient care for all admissions to hospitals in England and was used to identify all major and minor lower-limb amputation and revascularization procedures in people with diabetes in England between 1 January 2017 and 31 October 2020, using all discharges from the hospital up to 31 December 2020. If more than one procedure was performed, all were counted for their respective analyses. For each year, the total number of people with diabetes aged 18 years and over was obtained from the National Diabetes Audit. Age, sex, ethnicity, and deprivation were identified as potential confounding factors. Due to geographical variations …

The coronavirus disease 2019 (COVID-19) pandemic has created challenges for the provision of care for patients with diabetes. Increased physical distancing may worsen the preexisting disease burden and lead to progressively worse outcomes as a result of inadequate outpatient follow-up (1). In such an environment, the telehealth model may offer a valuable solution. However, there may be disparities in access to the internet, especially among individuals suffering from chronic medical conditions and minority patients, which may affect the implementation of the telehealth model. We aimed to assess 1 ) the disparities in internet access among those with hypertension or diabetes versus those without, 2 ) the disparities in internet access among Blacks and Hispanics compared with Whites, and 3 ) the extent of such disparities across the U.S. states. We used data from the 2016 to 2017 Behavioral Risk Factor Surveillance System (BRFSS), a nationwide telephone-based questionnaire administered by the Centers for Disease Control and Prevention among a random sample of U.S. adults regarding health-related behaviors, chronic health conditions, and the use of preventive services, to identify patients ≥18 years who reported having hypertension or diabetes (2). Participants were considered to have used the internet if they answered “Yes” to the question, “Have you used the internet in the past 30 days?” We analyzed these cross-sectional data using survey weights for BRFSS to account for the survey design. We used logistic regression models to study the association between hypertension, diabetes, race, and internet use …

New therapeutics for cardiovascular disease (CVD) prevention in diabetes are costly, highlighting the need for better risk stratification so that interventions may be targeted to those at the highest risk. High-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) are measures of subclinical cardiac damage associated with cardiovascular risk in the general population (1,2). The troponins appear differentially associated with diabetes (3). We assessed whether hs-cTnI or hs-cTnT could improve cardiovascular and mortality risk stratification in adults with diabetes and whether elevated concentrations of either troponin (≥90th percentile) were associated with mortality risk similar to those having a history of clinical CVD. We included 1,704 adults (ages 54–75 years) with diabetes (47.5% of whom were male, 33.8% Black, and 24.4% with CVD) in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 4 (1996–1998). Diabetes status was defined based on self-reported physician diagnosis, medication use, or blood glucose (fasting ≥126 mg/dL; nonfasting ≥200 mg/dL). hs-cTnI was measured in stored plasma using the ARCHITECT STAT High Sensitive Troponin-I assay (Abbott Diagnostics, Chicago, IL). hs-cTnT was measured in stored plasma using the Elecsys Troponin T assay (Roche Diagnostics, Indianapolis, IN). To compare hs-cTnI and hs-cTnT, we used percentile categories among those without CVD

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce cardiovascular (CV) events among patients with type 2 diabetes and high CV risk. Because consensus professional society recommendations endorse metformin as the first-line medication for type 2 diabetes, the CV efficacy of GLP-1RAs has primarily been studied with background metformin therapy (1). However, the European Society of Cardiology now recommends GLP-1RAs as a first-line type 2 diabetes treatment for patients at high CV risk (2). These discordant recommendations raise the question of how background metformin might influence the CV benefits of GLP-1RAs. Using data from the LEADER trial, we sought to answer this question by exploring possible heterogeneity in the CV efficacy of liraglutide related to baseline metformin treatment (3). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (NCT01179048, ClinicalTrials.gov) has been described elsewhere (3). Patients with type 2 diabetes and high CV risk underwent double-blind randomization to daily liraglutide versus placebo in addition to existing care. Each patient contributed data from randomization until censoring. The primary outcome was time from randomization to first occurrence of a composite of CV death, myocardial infarction, or stroke. Prespecified secondary outcomes included an expanded composite (primary plus coronary revascularization or hospitalization for unstable angina or heart failure), the composite components, and all-cause death. All outcomes were centrally adjudicated. Metformin treatment was identified at the baseline trial visit and each visit thereafter. Within each baseline metformin treatment subgroup, effect estimates for liraglutide versus placebo (hazard ratio [HR], 95% CI) were derived using Cox proportional hazards regression models; multivariable adjustment for baseline demographic and clinical factors was performed. Inverse probability for treatment weighting (IPTW) was used to account for imbalances in covariates between baseline metformin treatment subgroups (4). For multivariable analyses with IPTW, heterogeneity in the association between baseline metformin …

Cardiac mitochondrial alterations are suspected to play a key role in the development of diabetes-related heart failure as reported in some animal and few human studies in type 2 diabetes (1). It is yet unclear whether these alterations are induced by diabetes-related metabolic changes or develop secondary to other factors underlying heart failure including micro- and macrovascular disease. We hypothesized that 1 ) exposure to type 2 diabetes provokes myocardial mitochondrial impairment prior to apparent left ventricular heart failure in humans and 2 ) these mitochondrial alterations are accompanied by increased oxidative stress, edema, and intracellular inflammation. The cohort of this cross-sectional clinical study (study number 5263R; ClinicalTrials.gov NCT03386864) comprised adult heart transplant recipients undergoing routine transcatheter ventricular endomyocardial biopsies (EMB) post-transplantation, who received heart transplants of donors without type 2 diabetes. Thus, time between transplantation and EMB (2.9 ± 2.4 years) corresponded to the exposure of the hearts to type 2 diabetes. The first post-transplantation visit was included; exclusion criteria comprised allograft rejection (>0R according to International Society for Heart and Lung Transplantation criteria) and coronary artery disease (assessed via coronary angiography). Participants underwent oral glucose tolerance tests to assess glucose tolerance and insulin sensitivity (oral glucose insulin sensitivity [OGIS]). Cardiac magnetic resonance imaging was conducted at 1.5T to determine ventricular volumes and function, left ventricular T2 relaxation time, global left ventricular longitudinal strain (GLS), and diastolic strain rate. EMBs were attained for assessment of allograft rejection, mRNA expression of nuclear factor κ-light-chain-enhancer of activated B cells p105 subunit (NF-κB1), Toll-like receptor 9 (TLR9), and mitochondrially encoded cytochrome c oxidase I (CO1) and mitochondrial function using high-resolution respirometry in permeabilized …

Young-onset type 2 diabetes has a more aggressive clinical course than type 2 diabetes that occurs at an older age (1). Accruing evidence suggests that young adults with type 2 diabetes have complication rates exceeding those of individuals of similar age with type 1 diabetes (1–3). However, prior studies have focused on select populations and the generalizability of their findings is not clear. To address this gap in the literature, we analyzed recent national data to characterize the prevalence of complications among U.S. adults with young-onset type 1 and type 2 diabetes. We pooled data from the 2016 and 2017 National Health Interview Survey (NHIS). The NHIS is the only representative U.S. study that collects self-reported information on types of diabetes. Participants reported whether they had ever been diagnosed with diabetes other than during pregnancy. Those with diagnosed diabetes reported the type of diabetes (type 1, type 2, other), age of diagnosis, and use of antidiabetes medication. Following past research, we defined young-onset type 2 diabetes as being diagnosed before age 40 (1). We defined young-onset type 1 diabetes using this same cut point for comparability. We classified …

Glucose abnormalities exist in the prediabetic state well before a diagnosis of diabetes is made, and continuous glucose monitoring (CGM) is a sensitive method to detect these early abnormalities. Although insufficient data exist to support CGM for diagnosing diabetes, glucose patterns on CGM can provide insight into disease pathophysiology. Our group has used CGM to study early dysglycemia in several populations of youth at risk for diabetes—specifically, type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis–related diabetes (CFRD). We hypothesized that, in youth at risk for different types of diabetes matched by HbA1c, average sensor glucose would be no different, but specific CGM measures might differ among groups. For this analysis, we combined data from three groups of youth: 1 ) antibody-positive (Ab+) children from DAISY (Diabetes Autoimmunity Study in the Young) (1), 2 ) youth with cystic fibrosis (CF) from the Glycemic Monitoring in Cystic Fibrosis Study (NCT02211235, ClinicalTrials.gov), and 3 ) overweight/obese youth with BMI ≥85th percentile at risk for T2D (2). Inclusion criteria were ages 10–18 years and HbA1c

Racial/ethnic inequity exists in all aspects of health care and does not exclude the field of advanced diabetes technology. Despite the recent increase in technological therapeutic options for diabetes management and mounting evidence of positive effects on glycemic outcomes, emerging reports have highlighted that insulin pump and continuous glucose monitor use remain significantly lower in Black and Hispanic compared with White populations (1,2). Critical needs remain to bridge gaps in technology use. An important issue that we in the scientific and research communities can modify is the inclusion of minorities in clinical trials of diabetes devices. The population prevalence estimates of type 1 diabetes in the U.S. were as follows: non-Hispanic White, 72%; Hispanic, 15.7%; non-Hispanic Black, 9.3%; and Asian, 2.4% (3). Adequate racial/ethnic representation in parallel with the prevalence of type 1 diabetes is needed not only to evaluate widespread efficacy and acceptability of diabetes technology but also to create better dissemination and marketing plans that increase use among underrepresented groups. To evaluate the current state, we investigated racial/ethnic enrollment of participants in published clinical trials of type 1 diabetes technology to estimate whether trial enrollment had adequate representation of racial/ethnic minority groups. We used Medline, Embase, and Cochrane Central databases to systematically search for randomized controlled trials (RCTs) of currently U.S. Food and Drug Administration (FDA)-approved hybrid closed-loop and continuous glucose monitoring devices in the U.S. We included only U.S. studies, as …

Nontraumatic lower-extremity amputations (NLEAs) are a disabling and costly complication of uncontrolled diabetes (1). Factors influencing NLEAs include glycemic control, vascular disease, foot ulcer, and diabetes prevention practices (2,3). Texas has high rates of underinsured individuals, high prevalence of diabetes, a growing Hispanic population, and high rates of NLEAs (4). We examine trends of lower-extremity amputation rates among adults with diabetes in Dallas County between 2015 and 2019. Using data from the Dallas-Fort Worth Hospital Council Educational and Research Foundation (DFWHC) and the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System (BRFSS), we calculated age-adjusted rates for major, minor, and overall NLEAs between 1 October 2015 and 30 September 2019. We followed the methodology used by Geiss et al. (3) and calculated age-adjusted NLEA rates per 1,000 adults with diabetes, using four adult age categories, with denominator data (numbers of adults with diabetes) estimated using BRFSS Dallas County diabetes prevalence data. Because of the transition of the ICD-9 to ICD-10 coding system on 1 October 2015, the 2015 quarter 4 data were annualized to account for quarters 1–3 that were coded using the prior ICD-9 system and therefore not used. The 2019 data were annualized to …

Rapid implementation of remote continuous glucose monitoring (CGM) is occurring across hospitals during the coronavirus disease 2019 (COVID-19) pandemic. Despite limited experience, the U.S. Food and Drug Administration is not objecting to the inpatient use of CGM to limit the exposure of health care workers to severe acute respiratory syndrome coronavirus 2 and to reduce the waste of personal protective equipment (1). Recent efforts in non–intensive care unit (ICU) patients suggest that CGM devices are accurate in the inpatient setting and can help monitor patients remotely (2,3). In addition, two recent small trials enrolling non-ICU patients confirm the feasibility of using remote real-time CGM in the hospital (4,5). The accuracy of sensors, however, may be affected during various conditions that have not been well studied (i.e., MRI, surgery, shock requiring vasopressor therapy, hypoxia) (1). To mitigate potential CGM inaccuracy, a hybrid approach using real-time CGM with periodic point-of-care (POC) validation has been suggested (1). We report here on the likely loss of sensor signal during cardiac surgery and potential loss of accuracy in the operating room (OR). We also report on the accuracy of sensors that recovered immediately after surgery during critical illness. We evaluated the performance of sensors in adults without diabetes undergoing scheduled or urgent coronary artery bypass surgery (CABG). We excluded …

Over the last two decades, the large majority of clinical guidelines on the treatment of hyperglycemia in subjects with type 2 diabetes have suggested metformin as the first-line glucose-lowering treatment alongside lifestyle changes to reach personalized glycemic targets. Recently, the European Society of Cardiology recommended using glucagon-like peptide 1 receptor agonists (GLP-1RA) or sodium–glucose cotransporter 2 inhibitors (SGLT-2i) as first-line glucose-lowering therapy in subjects with type 2 diabetes at high or very high risk of cardiovascular disease, ahead of metformin treatment, to reduce cardiovascular events (1). Following the European Society of Cardiology guidelines, several analyses have investigated whether the cardiovascular effects of GLP-1RA or SGLT-2i would differ in relation to the use of metformin. Some of these studies reported a “statistically significant” difference (i.e., interaction) in the cardiovascular effects of SGLT-2is, whereby subjects with metformin have a lower cardiovascular protection from SGLT-2i, leading to several hypotheses about the possible pharmacological mechanisms. Interpreting interaction results, however, may be difficult, as they suffer from well-known drawbacks, including limited statistical power (2). For overcoming this problem and identifying who may be most likely to benefit from a specific treatment, trial-specific interactions may be combined with a meta-analytical approach (3). In this study, we systematically investigated the differences in the treatment effect of incretins (GLP-1RA and dipeptidyl peptidase 4 inhibitors [DPP-4i]) and SGLT-2i on cardiovascular outcomes according to metformin use. We included DPP-4i given their overlapping pharmacodynamics with GLP-1RAs and the previous evidence of interactions with metformin (4). On 5 October 2020, we searched for randomized controlled trials (RCTs) in adults with type 2 diabetes reporting incretin or SGLT-2i treatment effect for the primary cardiovascular outcome (major adverse cardiovascular event [MACE]) stratified by baseline metformin use; details of the search, included trials, and risk of bias are available on request. We …

Diabetic retinopathy (DR) is a common complication of diabetes and may lead to blindness through vision-threatening complications, such as diabetic macular edema and proliferative DR (PDR). Several studies have established that certain systemic factors have associations with incidence and progression of DR, namely, glycemic control, arterial hypertension, high cholesterol and hyperlipidemia obesity, inflammatory markers, sleep-disordered breathing, and exercise (1,2). In addition to systemic factors, there are ocular factors that should be considered, since they may identify the eyes at risk (2). We here report a 5-year prospective longitudinal observational cohort study that investigates the risk of both systemic and ocular factors that may play a role in the development of diabetic macular edema and PDR, the vision-threatening complications of DR. This observational cohort study included eyes/patients with mild nonproliferative PDR, Early Treatment Diabetic Retinopathy Study (ETDRS) classification grades 20 and 35 (3), who were followed for a period of 5 years or until the time of development of center-involved macular edema (CIME), clinically significant macular edema (CSME), or PDR. A total of 212 patients were included: men and women with diagnosed adult-onset type 2 diabetes, aged 42–82 years, with a maximum baseline HbA1c value of 10% (86 mmol/mol). Exclusion criteria included any laser treatment or intravitreal injections or any other comorbidity that could affect the retina. …

Severe hypoglycemia in patients with diabetes is an adverse drug event that is associated with poor outcomes, such as cardiovascular events, falls, high rehospitalization rates, and increased mortality (1,2). Several strategies, including adjustment of glucose-lowering therapy and glycemic targets, have been recommended in patients with severe hypoglycemia (1,3). However, it is not clear how changes in diabetes management are maintained after severe hypoglycemia among patients with type 2 diabetes. We conducted a retrospective analysis of data from the OptumLabs Data Warehouse, a de-identified administrative claims database of over 200 million individuals enrolled in commercial and Medicare Advantage plans across the U.S. (4). Data were accessed in adherence with the Health Insurance Portability and Accountability Act of 1996, and the Yale School of Medicine Human Investigations Committee deemed the study exempt from institutional review board review. We included commercially insured or Medicare Advantage beneficiaries who were aged 18 years or older, had pharmacologically treated type 2 diabetes, and had a severe hypoglycemic event. Severe hypoglycemia was identified as the first event during an observation window of 1 July 2013 through 30 June 2014, based on primary/principal diagnosis codes for hypoglycemia from an emergency department visit, observation stay, or hospital …

Immune checkpoint inhibitors (ICIs), including cytotoxic T cell–associated protein-4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors, have greatly improved the clinical outcomes of cancer patients (1). However, immune-related adverse effects involving various organs, including endocrine organs, can occur during ICI therapy (2). Cases of diabetes associated with ICI therapy have also been reported, which can be life-threatening (3–5). However, the incidence and characteristics of ICI-associated diabetes mellitus (ICI-DM) remain unclear. Therefore, we conducted a retrospective study with data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), a pharmacovigilance database, to investigate this issue (6). We used the FAERS to identify all reported cases of new-onset diabetes that were associated with ICIs approved by the FDA (i.e., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab) between 1 January 2015 and 31 December 2019. Patients with new-onset type 1 diabetes, fulminant type 1 diabetes, diabetic ketoacidosis (DKA), or diabetic ketosis secondary to ICI therapy were considered to have ICI-DM. Those with DKA or diabetic ketosis secondary to type 2 diabetes or diabetes without detailed subtypes were excluded. We then used the χ …

A recent retrospective cohort study found that new use of dipeptidyl peptidase 4 inhibitors (DPP4i) of 1.6 years was associated with an increased risk of inflammatory bowel disease (IBD) compared with other antidiabetes medications (hazard ratio 1.75 (95% CI 1.22, 2.49) (1). We previously demonstrated a weak association in an analysis of 86 prevalent and incident cases of IBD among DPP4i users using the U.S. Food and Drug Administration's Adverse Event Reporting System (2). In contrast, a cohort study suggested DPP4i initiation reduces risk of autoimmune diseases including IBD (3). Because the link between DPP4i and IBD remains uncertain, we performed a meta-analysis of randomized controlled trials (RCTs) to evaluate this potential association among patients with type 2 diabetes (T2D). This meta-analysis is registered with the international prospective register of systematic reviews (PROSPERO) (no. CRD42018095206). We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 28 April 2018 to identify DPP4i trials in T2D patients that explicitly reported IBD events. The large-scale cardiovascular trial for linagliptin (CARMELINA trial [4]) was published 7 months after our search; we therefore included this study. Two reviewers independently performed study selection, data extraction, and quality assessment. The primary outcome …

Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is an autoimmune digestive system disease (1). A recent cohort study using the U.K. Clinical Practice Research Datalink (CPRD) involving 7,231 dipeptidyl peptidase 4 inhibitor (DPP4i) users with 49 IBD cases indicated that new use of DPP4is over a median duration of 1.6 years was associated with IBD risk in patients with type 2 diabetes compared with other noninsulin antihyperglycemic drugs (hazard ratio 1.75, 95% CI 1.22, 2.49) (2). Current evidence regarding the effect of DPP4is on IBD risk is very limited. We thus performed a disproportionality analysis using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, which contains all adverse events spontaneously reported to the Food and Drug Administration since 2004 (3). We downloaded the FAERS data files from 2004 1st quarter to 2017 3rd quarter, used generic and trade names to identify DPP4is (sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin) and comparator drugs, and identified outcomes using Medical Dictionary for Regulatory Activities terms. The primary outcome was IBD (both CD and UC), and secondary outcomes were CD and UC, separately. The safety signal of DPP4is and IBD was assessed by reporting odds ratio (ROR) using two-by-two contingency tables (4). A signal was defined as an ROR of ≥2. The data were analyzed by SAS 9.4 …

Material need insecurity—limited or uncertain ability to access or pay for basic needs such as food, housing, or energy (1)—is reported by 18.9% of older adults with chronic health conditions (2). The association between material need insecurity and health is likely bidirectional (1,3). The sacrifices and trade-offs made to meet material needs lead to exacerbation of chronic conditions, and poor health creates circumstances that precipitate insecurity (3). Material need insecure (MNI) individuals receiving treatment for diabetes tend to be no less likely than material need secure (MNS) individuals to receive recommended health care services (4). However, upstream challenges leading to insecurities (such as unstable employment, family, and housing situations) likely undermine patients’ ability to manage health conditions for reasons that extend beyond access to medical services (1). This problem is especially relevant in Latino patients who face higher rates of material deprivation and worse diabetes outcomes than non-Latino individuals, even after accounting for access to care (5). As efforts to screen for and respond to material need insecurity in clinical settings expand, it is important for providers to consider correlates of insecurity that extend beyond a patient’s lack of resources. The current study uses secondary analysis of cross-sectional observational data from low-income Latino …

Effective management of diabetes during the coronavirus disease 2019 (COVID-19) pandemic is critical given that hyperglycemia is both a risk factor for infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been associated with poorer outcomes for those infected (1). Unfortunately, inadequate diabetes self-management due to medication nonadherence is prevalent among patients with diabetes and is a major contributor to poor diabetes outcomes (2,3). Research suggests that mail order pharmacy (MOP) use can improve medication adherence (3). However, there is little data on how the COVID-19 pandemic is related to MOP use. Regrettably, racial/ethnic minority patients with diabetes have poorer medication adherence than White patients, and research shows marked disparities among racial/ethnic minorities in SARS-CoV-2 infection rates and outcomes, but little is known about racial/ethnic differences in MOP use during the COVID-19 pandemic (3,4). The objectives of our study were to 1 ) assess the association between the COVID-19 pandemic shelter-in-place order and MOP use and 2 ) examine these associations by patient race/ethnicity. We conducted a retrospective cohort study using a cohort from a randomized encouragement trial conducted in 2017–2018 at Kaiser Permanente Northern California (KPNC), the Encouraging Mail Order Pharmacy Use to Improve Outcomes and Reduce Disparities …

Clinical research focuses on the relationship between one or more independent variables and some dependent variable or outcome chosen to reflect some underlying process. For categorical variables, the research may either be focused on a specific end point such as myocardial infarction (MI) or on an underlying construct such as vascular disease (with MI as just one exemplar). In the latter instance, a composite index such as major adverse cardiovascular event (MACE), defined as either a nonfatal stroke, nonfatal MI, or cardiovascular death, may be used. Composite categorical outcomes such as MACE optimize power by ensuring a high event rate, and the results they yield are generalizable to diseases that are consistent with the underlying construct. It is therefore surprising that there is no widely used method to combine continuous variables into composite continuous outcomes. Nevertheless, there is a clear need for such a methodology when the underlying construct cannot be easily captured by one measurement. Glucose control is an example of a construct that can be assessed in many ways, including fasting or postprandial plasma glucose, HbA1c, fructosamine, or “time in target.” A composite of two or more of these could provide a better reflection of glucose control than any one alone. Whereas sophisticated statistical techniques such as structural equation modeling (1) can be used to model some underlying construct or latent variable from two or more measurements, a simpler way of combining them into an index that reflects the underlying construct could provide a powerful tool for both researchers and clinicians. Such an approach is described below. When the same measurements are made using the …

In people with chronically severe hyperglycemia, a paradoxical deterioration of microvascular complications may occur if glycemic control is improved very rapidly. This “early worsening” is well documented for retinopathy (1) and painful neuropathy (2), but not nephropathy. We describe three men and one woman (ages 38–61 years) who presented with marked hyperglycemia. Type 2 diabetes had not previously been recognized in three cases, but the presence of retinopathy and signs of neuropathy indicated diabetes of at least 5 years’ duration. In the fourth case, diabetes had been diagnosed 6 years earlier, but the subject had declined treatment. In case 1, diabetes was recognized coincident with Hodgkin lymphoma, which was successfully treated with nonnephrotoxic chemotherapy. In case 2, diabetes was recognized at presentation with sepsis and acute kidney injury that rapidly improved with volume repletion and antibiotic treatment. None were smokers, had cardiovascular disease, or had a family history of renal disease. At presentation mean values were as follows: BMI 25.0 kg/m2, A1C 118 mmol/mol (12.9%), and estimated glomerular filtration rate (eGFR) 70 mL/min/1.73 m2. One subject was treated with insulin from diagnosis; one took insulin for 3 months, then transferred to oral hypoglycemic agents; and two were treated only with …

The coronavirus disease 2019 (COVID-19) epidemic reached Europe at the beginning of the year 2020. It posed an enormous toll on people and the economy and had a significant impact on health care systems. Health care delivery had to be modified in order to fulfill the increased demands due to the epidemic and to prevent infection spread. The first case in Slovenia (2,095,861 inhabitants) was confirmed on 4 March 2020. The COVID-19 epidemic was officially declared on 12 March. All preventative medical activities, including those of foot clinics (foot screening and perfusion pressure measurement) were suspended by a decree of the government and fully resumed only after 15 May 2020. The outpatient foot clinic at University Medical Centre Ljubljana has been running daily without limitations since then (with two full-time and one part-time nurse and one doctor, a consultant diabetologist), in spite of the strong second wave that began in mid-August. During the lockdown period, the clinic remained open for all foot ulcer patients without signs or symptoms of COVID-19 who have not been in contact with COVID-19 patients. Strict measures to limit …

Psychological stress is a known general health risk potentially increasing the risk of type 1 diabetes. Consistent with this hypothesis, there were reports of a higher incidence of type 1 diabetes after other stressful catastrophic events, e.g., the Chernobyl incident in 1986 or the Los Angeles earthquake in 1994 (1,2). Over the past few months, coronavirus disease 2019 (COVID-19) and subsequent social distancing have affected biological, psychological, economic, and social aspects of life. Social distancing during the lockdown could be perceived as a stressful situation for children and adolescents, who could not attend kindergarten or school and were unable to pursue hobbies like sports or meeting friends. Perceived stress caused by feelings of isolation may have increased the risk of type 1 diabetes (3). Since type 1 diabetes is also associated with viral infections (4), explaining, for example, the higher type 1 diabetes incidence during winter months, COVID-19 infection may have caused an increase of type 1 diabetes manifestations by affecting immune regulation or by directly damaging pancreatic β-cells (5 …

Patients taking metformin adhere to their prescribed regimen, on average, about 65% of the time (1,2). Given metformin’s central role in type 2 diabetes management, optimizing adherence is important. Common causes of nonadherence include cost and side effects. Metformin is inexpensive but causes gastrointestinal side effects in up to 25% of patients (2). Extended-release (ER) formulations reduce side effects but may cost more, and they have not been clearly shown to improve adherence in routine practice (3). As a result, although it is common practice to change from immediate release (IR) formulations to ER once patients develop side effects, there is not a consensus on whether ER formulations should routinely be used when metformin is first prescribed (3). We undertook a retrospective cohort study of how cost and initial choice of formulation affect adherence and persistence to metformin. The study used merged de-identified claims data from commercial insurance carriers in the U.S. from 1 January 2012 to 31 December 2016 (4). A cohort was identified of patients age 18 years or older who filled an initial 30-day prescription for …

Type 2 diabetes (T2D) has been associated with hepatitis C virus (HCV) infection as an independent risk factor. The increased insulin resistance induced by the HCV core protein or the treatment with interferon-based therapy (IBT) may have a role (1). It is generally agreed that IBT for patients with chronic hepatitis C (CHC) may trigger short-term insulin resistance. However, the long-term risk of developing T2D for CHC patients with IBT remains unclear. Studies suggested that if viral clearance is achieved after IBT, the risk of T2D might be reduced by two-thirds in CHC patients (2,3). An Italian study argued that a lower insulin resistance at baseline may be the reason for reduced risk of T2D (4). We therefore conducted a retrospective cohort study, using insurance claims data of Taiwan, to examine 1 ) whether CHC patients are at an elevated risk of developing T2D and 2 ) whether CHC patients receiving IBT are at a reduced risk of T2D, not only through viral clearance but also through possible alterations of glucose metabolism. The health insurance of Taiwan is a universal insurance system with 99% of all 23 million residents covered. We used a subset of claims data of 1 million beneficiaries randomly selected from all residents to …

Bariatric surgery induces weight loss and restores glucose metabolism in patients with obesity and type 2 diabetes (T2D) (1). In patients with autoimmune diabetes that eventually results in β-cell failure, the glycemic effects of bariatric surgery are limited (2). Adult patients with latent autoimmune diabetes in adults (LADA) have a slower decline in β-cell function and lower requirement for insulin therapy than patients with classical young-onset type 1 diabetes (T1D) (3). They are often misdiagnosed as having T2D and might have unrealistic expectations of diabetes remission after bariatric surgery with additional risk for development of postoperative diabetic ketoacidosis (DKA) (4). The safety and efficacy of bariatric surgery in patients with obesity and LADA have not been characterized. We retrospectively analyzed medical records of patients with obesity and LADA who underwent bariatric surgery at the Cleveland Clinic Health System in the U.S. LADA status was defined as adult-onset diabetes with presence of GAD antibodies. We compared pre- and postsurgery BMI, glycemic control (HbA1c), daily insulin dose, and blood pressure and lipid profile using a paired Student t test, with a P value of 0.05 considered significant. Between October 2006 and March 2018, nine female patients underwent laparoscopic bariatric surgery (five Roux-en-Y gastric bypass and four sleeve gastrectomy) and one male patient underwent sleeve gastrectomy. The median age at …

Pathogen burden has been linked to the occurrence of selected noncommunicable health events, particularly coronary heart disease (1). In addition to an inflammatory hypothesis, pathogen burden may contribute to features of immune senescence, such as the accumulation of differentiated cytotoxic T cells that are associated with impaired glucose homeostasis (2). This raises the possibility of a link between early life infection and diabetes, although longitudinal studies are scarce. Existing data on acquired infections and diabetes risk have been inconsistent, which may be ascribed to methodological weaknesses such as small sample sizes ( n < 150) in studies largely on patient groups rather than the general population and a scarcity of prospective cohort studies. In the only prospective evidence of which we are aware, childhood illness of sufficient severity to warrant hospitalization was associated with markers of metabolic health, including fasting glucose (3). In the present analysis we use data from a national birth cohort of the general population in which exposure to infection was assessed in childhood before the onset of diabetes that was ascertained some 35 years later. We used data from the 1970 …

One in three Medicare beneficiaries have diabetes, and 3.1 million require insulin (1). As insulin prices rise (2), one in four people on insulin report reducing use due to cost (3). Insulin price and affordability concerns the 7 in 10 Medicare beneficiaries with Part D drug coverage, which requires significant deductibles and copayments and places no maximum on out-of-pocket costs (4,5). In particular, Medicare Part D has a coverage gap (doughnut hole) whereby beneficiaries pay a percentage of a drug’s price until reaching catastrophic coverage (4). To lower financial burden, the Affordable Care Act incrementally reduced patients’ cost-sharing during the gap from 100% to 25% of drug price (2010 to 2019) (4). Concurrently, manufacturers had to provide greater price discounts during the gap, reaching a 70% discount by 2019 (4). Although patients now pay a lower percentage of a drug’s price, these savings can be counterbalanced by simultaneous price increases. Patients’ cost-sharing during the gap also uses a drug’s full list price and excludes manufacturer rebates that insulate plans from rising prices (2). We examined how patients’ out-of-pocket costs for insulin would have dropped from 2014 to 2019 due to Part D policy changes and whether higher …

Cardiac stress testing in patients with diabetes mellitus (DM) is a topic of much debate (1,2). The clinical heterogeneity and varied interpretation of atypical symptoms in this population may lead to significant variation in cardiac stress testing with downstream implications in health care expenditure. We evaluated facility-level variation in cardiac stress test use among patients with DM across the Veterans Affairs (VA) health care system. We identified patients with DM aged ≥18 years with a primary care clinic visit during VA fiscal year 2014 at one of the 130 VA facilities and associated clinics. Patient demographics and medical history were identified using clinical data sources and ICD-9-CM codes. We calculated diagnostic cost group relative risk score (DCG-RRS), a validated surrogate for overall illness burden. Facility-level cardiac stress test use was defined as the number of stress tests performed per facility per 100 patients with DM in the preceding 365 days. Stress testing modalities evaluated included exercise treadmill test, stress echocardiography, and SPECT/PET MPI (myocardial perfusion imaging [single photon emission computed tomography or positron emission tomography]). Facilities with

The significant increase in the complexity of diabetes care over the last two decades is associated with a high economic burden (1), with almost one-quarter of adults with diabetes burdened with significant out of pocket expenses (OOPEs) (2). Little is known about the OOPEs for families of adolescents and young adults with type 1 diabetes. We therefore report the diabetes-related OOPEs for these families from the SEARCH for Diabetes in Youth (SEARCH) study and their association with demographic, socioeconomic, clinical, and health care characteristics. A detailed description of the SEARCH study methods has previously been published (3). Participants had a baseline visit shortly after diabetes diagnosis and one or more follow-up visits; this report includes data from a follow-up visit between November 2011 and July 2015, at which time participants’ diabetes duration was >5 years. Participants ≥18 years old or a parent/guardian of participants

Background: Previous studies demonstrate that aggregation of Asian ethnic subgroups masks variation in the prevalence of diabetes (DM) across these groups. Population data also suggest that Asian ethnic differences exist in the prevalence of diagnosed polycystic ovary syndrome (PCOS), but few studies have compared the risk of PCOS and DM in the same Asian subgroups, accounting for differences in BMI. We previously found that the prevalence of PCOS based on ≥1 diagnosis ranged from 1.6–1.9% in White, Hispanic, and Black women and 1.2%, 1.7%, and 3.5% for Chinese, Filipina, and South Asian women age 21–44 years. In this study, we further examined and compared the risk of clinical PCOS and clinical DM by weight status in these Asian subgroups. METHODS: Using data from women receiving care in a large integrated healthcare system, we conducted a cross-sectional, retrospective study of 19,848 Chinese, 23,890 Filipina, and 19,905 South Asian women aged 21–44 years who had ≥1 clinic visit in 2016. Ethnicity was based on data from the electronic health record (EHR), and those identified in the EHR as Asian with unspecified ethnicity were assigned as Chinese, Filipina, and South Asian based on algorithms that included primary language and surname. BMI was calculated from non-gestational height and weight and classified as healthy, overweight (23 to

Bariatric surgery is considered an effective (1,2) and relatively safe (3) option for the treatment of obesity and its comorbidities, including type 1 and type 2 diabetes. Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes, which mainly occurs in patients with type 1 diabetes but can present in patients with type 2 diabetes under stressful conditions (4,5). The characteristics of early postoperative DKA following bariatric surgery are largely unknown. The objective of this study is to determine the incidence and clinical circumstances underlying DKA after bariatric surgery. From January 2005 to December 2015, a total of 12 patients who developed DKA within 90 days following bariatric surgery at an academic center were identified in a database approved by an institutional review board. All patients met the American Diabetes Association criteria for the diagnosis of DKA (4,5). Two endocrinologists independently verified the diagnosis of DKA in the included patients. Baseline characteristics, intraoperative data, and postoperative outcomes were assessed. Of the 12 patients who developed …

Studies including ours indicate that systemic inhibition of dipeptidyl peptidase 4 (DPP4), an ubiquitously expressed peptidase, by pharmaceutical inhibitors improved atherosclerosis (1,2). However, the role of immune cell–derived DPP4 is not well defined in atherosclerosis. Our previous work demonstrated that DPP4 expression on monocytes/macrophages was increased in obesity and associated with the degree of insulin resistance (3). To test if the obesity-related increase of monocyte DPP4 plays a role in vascular disease, we investigated the relationship of monocyte DPP4 expression with human aortic atherosclerosis, obesity, and lipid metabolism. A total of 14 control volunteers and 27 atherosclerotic patients without diagnosed heart, lung, or liver diseases and without prescription drugs (except ACE inhibitors and angiotensin receptor blockers) were selected from Aliskiren Effect on Aortic Plaque Progression (ALPINE), a phase 4 clinical trial (clinical trial reg. no. NCT01417104, clinicaltrials.gov). Presence of aortic atherosclerotic plaque (Fig. 1 A ) was confirmed by high-resolution three-dimensional MRI. Figure 1 A : High-resolution three-dimensional dark-blood MRI was used to confirm the aortic atherosclerotic plaque in patients with atherosclerotic disease. Arrows indicate the thickening of the aortic wall. Scale bars, 10 mm. B and C : DPP4 expression on circulating immune cells. Peripheral blood mononuclear cells were isolated from healthy volunteers, and CD11b+ monocyte and CD3+ T cells were gated for …

We hypothesized that persons with type 1 diabetes with higher serum levels of carboxymethyl lysine (CML) and soluble receptor for advanced glycation end products (sRAGE) are at a higher risk of developing incident diabetic nephropathy (DN). We examined this hypothesis using data from up to four follow-up examinations over a 22-year period in persons with type 1 diabetes participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). We also examined the relationship of CML and sRAGE to mortality. Descriptions of the cohort, participation statistics, and reasons for nonparticipation have appeared elsewhere (1). Of 1,210 persons with type 1 diabetes receiving care in an 11-county area of south central Wisconsin in 1979–1980, 996 were examined in 1980–1982. The individuals were 3–79 years of age with type 1 diabetes duration of 1–59 years. These persons participated in up to six follow-up examinations in 1984–1986 ( n = 903), 1990–1992 ( n = 816), 1994–1996 ( n = 667), 2000–2001 ( n = 567), 2005–2007 ( n = 520), and 2012–2014 ( n = 414). The tenets of the Declaration of Helsinki were followed, and institutional review board approval was obtained from the University of Wisconsin–Madison. Written informed consent was obtained. Starting with the third examination in 1990–1992 and continuing with follow-up examinations, serum was collected, processed, and frozen at −80°C. Serum sRAGE and CML levels were measured …

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes caused by a mutation in a single gene. The frequency of mutation carriers for HNF4A-MODY has been reported to be 1.2% (1). Our group has previously published on the successful use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy in three consecutive generations of a family with an HNF1A-MODY (2). Although GLP-1 RA therapy has been studied in patients with HNF1A-MODY (3), it has not been studied in patients with HNF4A-MODY. In this father-son cohort, we demonstrate successful use of GLP-1 RA therapy in two patients with c.790:1 bp deletion of G; codon:264 mutations of HNF4A. The son first presented with neonatal hypoglycemia, then later developed diabetes and …

We previously developed and validated a hypoglycemia risk stratification tool (1) and made available the computer source code for implementation (online-only supplemental eTable 2 [1]). This tool classifies 12-month risk of hypoglycemia-related utilization (HRU) of emergency department (ED) or in-patient services among type 2 diabetes (T2D) patients as high (>5%), intermediate (1–5%), or low (

Recently, the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) suggested that semaglutide may increase the risk for diabetic retinopathy (DR) adverse events (AEs) compared with placebo. Other trials of glucagon-like peptide 1 receptor agonists (GLP-1RA) showed a numerically higher incidence of DR AEs for liraglutide but not exenatide. However, these trials did not systematically assess DR. Our population-based cohort study of older U.S. adults suggested that GLP-1RA use for approximately 1 year does not increase DR risk (1). As current evidence on GLP-1RA–associated DR risk is still limited, we conducted a disproportionality analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to examine the association between GLP-1RA and DR events. We used generic and brand names to identify GLP-1RA (exenatide, liraglutide, albiglutide, and dulaglutide) and comparator drugs in the FAERS database and Medical Dictionary for Regulatory Activities (MedDRA v21.0) preferred terms to identify DR cases (diabetic retinopathy, retinopathy, macular edema, retinopathy proliferative, retinopathy hemorrhagic, blindness, vitreous hemorrhage) from 28 April 2005 (approval date for the first GLP-1RA, exenatide) to 30 September 2017. We performed a disproportionality analysis using the reporting odds ratio (ROR) to assess whether there is a signal for a potentially increased risk of DR among GLP-1RA users. The ROR is calculated by …

Cardiovascular disease (CVD) accounts for ≥75% of hospitalizations and >50% of all deaths among patients with diabetes (1,2). Guideline-directed therapies for patients with diabetes aged 50 years and older with an additional cardiovascular risk factor such as hypertension include cardioprotective medications (antiplatelet therapy, statins, and antihypertensives shown to reduce cardiovascular events) and lifestyle counseling for healthy behaviors (weight loss/diet, exercise, and smoking cessation) (1,3). However, data are limited on trends in usage of pharmacotherapies and lifestyle counseling for patients with diabetes at increased CVD risk. Therefore, we used nationally representative data to investigate trends in medication use and lifestyle counseling among U.S. outpatients aged 50 years and over with diabetes and hypertension. All visits to office-based physicians and hospital-based clinics by adults (aged 50 years and older with hypertension; N = 14,096 visits) from 2006 to 2015 in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were included. Data include patient symptoms, comorbidities, and demographics; physician diagnoses; medications ordered or provided; and medical services provided. Diabetes and hypertension were identified using ICD-9-Clinical Modification diagnosis codes. Physician decision making and treatment were evaluated using 1 ) Multum Lexicon drug codes/categories and generic codes for antiplatelet agents (aspirin and clopidogrel), …

Impaired fasting glucose, also termed prediabetes, is increasingly prevalent and is associated with adverse cardiovascular risk (1). The cardiovascular risks attributed to prediabetes may be driven primarily by the conversion from prediabetes to overt diabetes (2). Given limited data on outcomes among nonconverters in the community, the extent to which some individuals with prediabetes never go on to develop diabetes and yet still experience adverse cardiovascular risk remains unclear. We therefore investigated the frequency of cardiovascular versus noncardiovascular deaths in people who developed early- and late-onset prediabetes without ever progressing to diabetes. We used data from the Framingham Heart Study collected on the Offspring Cohort participants aged 18–77 years at the time of initial fasting plasma glucose (FPG) assessment (1983–1987) who had serial FPG testing over subsequent examinations with continuous surveillance for outcomes including cause-specific mortality (3). As applied in prior epidemiological investigations (4), we used a case-control design focusing on the cause-specific outcome of cardiovascular death to minimize the competing risk issues that would be encountered in time-to-event analyses. To focus on outcomes associated with a given chronic glycemic state maintained over the entire lifetime, we restricted our analyses to only those participants for whom data were available over the life course and until death. We included participants who attended …