AIM:To evaluate the long-term effectiveness and safety of a remote, medically supervised ketogenic nutrition therapy intervention for Veterans with type 2 diabetes (T2D). MATERIALS AND METHODS:This retrospective observational analysis examined de-identified medical records of Veterans with T2D who engaged in a remote continuous care intervention. Outcomes were HbA1c, weight, diabetes medication use and cardiometabolic markers (lipids, liver enzymes, kidney function) among those who remained enrolled for 2 or 3 years. Separately, we assessed weight, glucose and medication changes at programme departure among Veterans who discontinued before 2 years. Outcomes were analysed across subgroups. Linear mixed-effects models and paired t-tests evaluated changes over time. RESULTS:Among 640 enrolled Veterans (mean age: 59 years, BMI: 35 kg/m2, HbA1c: 8.4%), 310 (49%) remained engaged at 2 years and 197 (33%) at 3 years. At both time points, HbA1c was reduced by approximately 0.8%, alongside decreases in diabetes medication use. Weight decreased by approximately 9% at both 2 and 3 years. Overall, reductions in HbA1c and weight were seen across subgroups. Veterans who discontinued before 2 years experienced metabolic improvements, with greater benefits among those enrolled at least 6 months. CONCLUSIONS:For US Veterans, long-term participation in a remote ketogenic nutrition therapy intervention was associated with sustained improvements in glycaemic control, weight, medication use and select cardiometabolic markers. A 0.8% HbA1c reduction is associated with meaningful reductions in diabetes-related complications, highlighting the potential clinical relevance of these findings.

AIMS:Ketogenic diets are used by individuals with obesity and type 2 diabetes for improved glycaemic control, reduced appetite and weight loss. However, the risks associated with higher ketone levels, including diabetic ketoacidosis (DKA), in individuals with and without diabetes are not well-documented. MATERIALS AND METHODS:We analysed real world data from a single-centre telemedicine clinic specializing in a very low carbohydrate ketogenic diet (VLCKD) as a lifestyle intervention. Illnesses associated with ketosis (IAK) were defined as beta-hydroxybutyrate (BHB) levels ≥3 mmol/L when patients sought in-person care. We estimated the IAK and DKA incidence rate in individuals with and without type 2 diabetes. RESULTS:In 72 751 patient-years of follow-up, 86 people had IAK (incidence rate 1.18 per 1000 person-years). In 22 347 patient-years of follow-up of people without diabetes, the incidence rate of IAK was 0.04 per 1000 person-years with no DKA cases. In 50 404 patient-years of follow-up in people with type 2 diabetes (PWD), the incidence rates of IAK and of DKA were 1.69 and 1.01 per 1000 person-years, respectively. In 12 763 person-years of follow-up of PWD using SGLT2-inhibitors, the DKA incidence was 2.90 per 1000 patient-years. CONCLUSIONS:Very low carbohydrate ketogenic diets are generally safe with low rates of IAK, including DKA, in people with and without type 2 diabetes. The higher incidence of DKA in PWD on VLCKD who are also on SGLT2-inhibitors may be manageable through at-home monitoring of BHB levels.

Lead Author's Financial Disclosures S.J.A. is an employee of Virta Health and offered stock options from Virta Health. Study Funding None. Background/Synopsis LDL-C estimated using the Friedewald equation (LDL-CF) is limited in type 2 diabetes (T2D) due to hypertriglyceridemia (HTG). In our recent study of 262 patients with T2D, a low carbohydrate intervention with nutritional ketosis significantly improved atherogenic dyslipidemia (ALP) in participants with T2D, where a majority of the participants transitioned from a predominantly small, dense LDL phenotype (phenotype B) to a large, buoyant LDL phenotype (phenotype A). However, the improvement in ALP was associated with an increase in LDL-CF. Objective/Purpose This study assessed differences between LDL-CF versus other recently adopted LDL-C equations to estimate the effect of our intervention on LDL-C, and assess the performance of these equations across a broad range of HTG. Methods LDL-C were recalculated using Martin-Hopkins (LDL-CMH) and the new proposed NIH 2 (LDL-CN2) equations. The effect size of the intervention on LDL-C change from baseline to 2 years was assessed using each LDL-C equation with repeated measure ANOVA. Since LDL-CN2 is recommended for use with triglycerides (TG) up to 800mg/dL, we calculated LDL-C with this equation using two cut-offs: TG≤400mg/dL and TG≤800mg/dL. We then assessed the differences between LDL-CMH, LDL-CN2 and LDL-CF at each time point among those with TG≤400mg/dL using a linear mixed effect model (LMM) and covariates that were initially used for the assessment of LDL-CF (Table 1). Results There was an increase in LDL-C in all three LDL-C equations, with medium effect sizes in both LDL-CF (ηp2=0.08, +13.5% from 100.9mg/dL) and LDL-CN2 (ηp2 =0.07 for TG≤400mg/dL, +11.6% from 104.8mg/dL or ηp2 =0.06 for TG≤800mg/dL, +10.7% from 104.6mg/dL) and a small effect with LDL-CMH (ηp2=0.04, +9.2% from 106.5mg/dL). At baseline, LDL-CMH estimated significantly greater LDL-C than the other two equations, especially in individuals with HTG and phenotype B (Table 1). At 1 and 2 years when the proportion of individuals with ALP and HTG significantly decreased in the intervention, there were no significant differences in the estimated LDL-C between the equations. Conclusions In patients with T2D where HTG is a common lipid abnormality, LDL-CMH may be the most appropriate equation to use in assessing change in LDL-C. For patients with greater than 400mg/dL of TG, LDL-CN2 can be alternatively considered. Future studies should compare these equations with direct LDL-C measurements in patients with T2D. S.J.A. is an employee of Virta Health and offered stock options from Virta Health. None.

In this issue of Diabetes Care , Dr. Mayer Davidson proposes that prescription of metformin for patients with prediabetes is inappropriate (1). We respectfully disagree. Hyperglycemia is a continuous risk factor for adverse health outcomes. Both the degree and duration of hyperglycemia are associated with the development and progression of diabetic microvascular and macrovascular complications (2), and early aggressive management of hyperglycemia in both type 1 and type 2 diabetes confers lifelong health benefits (3,4). We believe that Dr. Davidson’s approach to watchful waiting, “to follow [high-risk individuals] closely and immediately introduce metformin when their glycemia meets the criteria for diabetes…,” is inadequate. Numerous studies have demonstrated that there is a delay of 3–8 years between the onset and the diagnosis of type 2 diabetes (5), and at the time of diagnosis as many as 8–16% of patients have diabetic retinopathy, 17–22% have microalbuminuria, and 14–48% have peripheral polyneuropathy (6,7). A recent epidemiologic analysis of new-onset diabetes in the U.K. demonstrated a statistically significant increased risk of microvascular complications at diagnosis among individuals identified previously with prediabetes compared with those with previous normal glucose tolerance (adjusted odds ratio of 1.76 for retinopathy and 1.14 for nephropathy) (8). Therefore, there is no reason to withhold metformin, a safe, effective, and cost-saving treatment to delay or prevent the development of type 2 diabetes, from individuals at high risk. That said, a number of caveats apply. First, the Diabetes Prevention Program (DPP) and indeed most of the other major diabetes prevention trials studied individuals at extremely …

In this issue of Diabetes Care , Dr. Mayer Davidson proposes that prescription of metformin for patients with prediabetes is inappropriate (1). We respectfully disagree. Hyperglycemia is a continuous risk factor for adverse health outcomes. Both the degree and duration of hyperglycemia are associated with the development and progression of diabetic microvascular and macrovascular complications (2), and early aggressive management of hyperglycemia in both type 1 and type 2 diabetes confers lifelong health benefits (3,4). We believe that Dr. Davidson’s approach to watchful waiting, “to follow [high-risk individuals] closely and immediately introduce metformin when their glycemia meets the criteria for diabetes…,” is inadequate. Numerous studies have demonstrated that there is a delay of 3–8 years between the onset and the diagnosis of type 2 diabetes (5), and at the time of diagnosis as many as 8–16% of patients have diabetic retinopathy, 17–22% have microalbuminuria, and 14–48% have peripheral polyneuropathy (6,7). A recent epidemiologic analysis of new-onset diabetes in the U.K. demonstrated a statistically significant increased risk of microvascular complications at diagnosis among individuals identified previously with prediabetes compared with those with previous normal glucose tolerance (adjusted odds ratio of 1.76 for retinopathy and 1.14 for nephropathy) (8). Therefore, there is no reason to withhold metformin, a safe, effective, and cost-saving treatment to delay or prevent the development of type 2 diabetes, from individuals at high risk. That said, a number of caveats apply.\n\nFirst, the Diabetes Prevention Program (DPP) and indeed most of the other major diabetes prevention trials studied individuals at extremely …

Epidemic infections have frightened and harmed people for millennia.Plague (1) and typhus (2), bacterial infections associated with poor sanitation and high mortality, have devastated populations.Both still reappear intermittently, but they are generally contained with better sanitation and control of rodent and insect vectors along with antibiotics.In contrast, viral epidemics persist.A unique strain of influenza caused a global epidemic (pandemic) in 1918 resulting in millions of deaths (3).Among recent outbreaks of viral infections, several have been caused by coronaviruses (4).One of these, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now causing a pandemic illness termed coronavirus disease 2019 (COVID-19) that poses unique challenges.This novel coronavirus is readily transmitted from person-to-person, even by those who are infected but without symptoms.In susceptible people it causes severe illness and often death from pulmonary and systemic injuries.At present, we have neither a preventive vaccine nor well-studied pharmacotherapy, although work to develop these is vigorously underway.

OBJECTIVE To determine if the International Hypoglycaemia Study Group (IHSG) level 2 low glucose definition can identify clinically relevant hypoglycemia in clinical trials and offer value as an end point for future trials. RESEARCH DESIGN AND METHODS A post hoc analysis was performed of the SWITCH (SWITCH 1: n = 501, type 1 diabetes; SWITCH 2: n = 721, type 2 diabetes) and DEVOTE (n = 7,637, type 2 diabetes) trials utilizing the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec or insulin glargine 100 units/mL. In the main analysis, the following definitions were compared: 1) American Diabetes Association (ADA) 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); and 2) IHSG level 2 (PG confirmed <3.0 mmol/L, independent of symptoms). RESULTS In SWITCH 2, the estimated rate ratios of hypoglycemic events indicated increasing differences between treatments with decreasing PG levels until 3.0 mmol/L, following which no additional treatment differences were observed. Similar results were observed for the SWITCH 1 trial. In SWITCH 2, the IHSG level 2 definition produced a rate ratio that was lower than the ADA 2005 definition. CONCLUSIONS The IHSG level 2 definition was validated in a series of clinical trials, demonstrating its ability to discriminate between basal insulins. This definition is therefore recommended to be uniformly adopted by regulatory bodies and used in future clinical trials.

Intensive insulin management is currently the only option for effective treatment of type 1 diabetes. Recent data from the T1D Exchange (T1DX) registry (1), which comprises leading U.S. diabetes treatment centers, show that despite the widespread availability of insulin analogs and increasing use of insulin pumps and continuous glucose monitoring systems, only about 20% of adult patients achieve the A1C target of <7% (53 mmol/mol) recommended by the American Diabetes Association (2). It is reasonable to assume that glycemic control of patients receiving care outside of major centers might be even worse. The T1DX registry has also shown that nearly 5% of adult participants experienced one or more episodes of diabetic ketoacidosis (DKA) within the past 12 months (3), and the Centers for Disease Control and Prevention recently reported a 6.3% annual increase in hospitalization rates for DKA from 2009 to 2014, with highest rates in persons aged <45 years (4). Moreover, the majority of patients are either overweight or obese, potentially increasing their risk of cardiovascular disease (1). There is clearly an unmet need for noninsulin adjunctive therapies that improve glycemic control without increasing the risk of hypoglycemia or contributing to weight gain, and it is noteworthy that among nearly 50,000 pediatric and adult participants in the T1DX registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria, two large consortia of diabetes centers, adjuvant medications are being used off-label by 5.4% of participants in T1DX and 1.6% in DPV (5). Sodium–glucose cotransporter 2 (SGLT2) inhibitors block the SGLT2 transporter in the proximal renal tubule resulting in glucosuria and natriuresis and are approved and indicated for type 2 diabetes. Dual SGLT1+2 inhibitors have the additional effect of inhibiting SGLT1 in the gastrointestinal tract, thereby delaying intestinal absorption of glucose and galactose. Owing to …

Despite needs for new therapies and improvements in existing approaches in cardiovascular, pulmonary, endocrine, and renal disease, investment in these areas is lagging relative to other specialties. This article summarizes a meeting of key stakeholders of U.S. Food and Drug Administration (FDA) officials, representatives from academia, national organizations, and patients and caregivers. The purpose was to identify and discuss high-priority issues, establish areas of common interest, and explore opportunities for collaboration. During the meeting (September 2016), the construct of a “multimorbidity continuum” emerged, in which chronic diseases are understood as their effects on the whole rather than individual organ systems. Cross-disciplinary priorities included: 1) the need to generate greater high-quality evidence at lower cost; 2) the imperative to develop and implement patient-centered approaches to clinical investigations; 3) the importance of trial participation in under-represented populations, particularly with comorbid conditions, and 4) the need for progress in tobacco regulation. Representatives from each therapeutic area reported on their consensus priorities, and FDA representatives discussed the agency’s role in facilitating broader approaches to therapeutic development and evaluation of disease as linked across organ systems rather than in isolation, and emphasized the importance of patient engagement, collaboration and communication across stakeholders.

IN BRIEF Metformin, an established therapy for the treatment of type 2 diabetes, has demonstrated safety and effectiveness in the prevention or delay of type 2 diabetes in people at high risk. The Diabetes Prevention Program randomized clinical trial demonstrated that intensive lifestyle intervention and metformin therapy reduced progression to diabetes by 58 and 31%, respectively, compared to placebo in people at risk of type 2 diabetes. Although lifestyle intervention was beneficial in all groups, metformin had a selectively greater effect in those who were more obese, had a higher fasting glucose, had a history of gestational diabetes, or were younger. Long-term effects included an 18% diabetes reduction with metformin compared to placebo over 15 years, a reduction in microvascular complications among those who did not progress to diabetes (without difference among treatment arms), and suggestion by coronary calcium assessment of a possible impact on atherosclerosis in men. Although long-term follow-up to assess later-stage outcomes is underway, current efforts to address gaps in evidence and translation remain of significant public health interest.

Hypoglycemia is the limiting factor in controlling glucose levels in Diabetes. Rather than being a side effect, hypoglycemia is the mechanism of action for insulin therapy, with a very narrow therapeutic window. Until recently, regulatory bodies listed hypoglycemia only as an adverse effect of therapy; however, one insulin preparation is now recognized and labelled as reducing the risk of severe hypoglycemia. This paper describes internationally agreed upon definitions for hypoglycemia and proposed regulatory approaches for recognition and labeling of diabetes therapies to facilitate personalized care.

The prevalence of diabetes continues to escalate (1,2) with profound impact on complications and mortality (3–5). Evidence-based guidelines (6–9) and performance measures have been developed (10–12). However, there is currently no sustainable nationwide mechanism by which to 1 ) systematically evaluate and track the quality of care in primary and specialty settings or 2 ) evaluate the real-world treatment strategies and their effects on health outcomes. Over the past two decades, quality-oriented registries in cardiovascular disease have pioneered mechanisms of quality assessment, benchmarking, and feedback to individual providers and institutions, and there is evidence that such initiatives can translate into improved quality of care and patient outcomes (13–17). In an effort to extend these efforts to diabetes and cardiometabolic care, the Diabetes Collaborative Registry (DCR) was formed in 2014 by the American College of Cardiology, the American Diabetes Association, the American College of Physicians, the American Association of Clinical Endocrinologists, and the Joslin Diabetes Center. The DCR is a real-world, quality-oriented registry covering the spectrum from primary to specialty outpatient care in the U.S., thereby permitting evaluations of multidisciplinary diabetes care across the spectrum of the disease process (from diagnosis to complications) and the relationship between treatment patterns and health outcomes. Despite evidence-based guidelines for treating patients with diabetes (1,7,9,18,19), a divide exists between the recommendations and their practical application (20). The DCR seeks to fill this void through collecting data on a national level, allowing for regular feedback and benchmarking that we envision will result in rapid-cycle quality improvement efforts. Through measuring adherence to clinical guidelines, quantifying local performance, and reporting these …

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.

The Cardiometabolic Think Tank was convened on June 20, 2014, in Washington, DC, as a “call to action” activity focused on defining new patient care models and approaches to address contemporary issues of cardiometabolic risk and disease. Individual experts representing >20 professional organizations participated in this roundtable discussion. The Think Tank consensus was that the metabolic syndrome (MetS) is a complex pathophysiological state comprised of a cluster of clinically measured and typically unmeasured risk factors, is progressive in its course, and is associated with serious and extensive comorbidity, but tends to be clinically under-recognized. The ideal patient care model for MetS must accurately identify those at risk before MetS develops and must recognize subtypes and stages of MetS to more effectively direct prevention and therapies. This new MetS care model introduces both affirmed and emerging concepts that will require consensus development, validation, and optimization in the future.

The Cardiometabolic Think Tank was convened on June 20, 2014, in Washington, DC, as a "call to action" activity focused on defining new patient care models and approaches to address contemporary issues of cardiometabolic risk and disease. Individual experts representing >20 professional organizations participated in this roundtable discussion. The Think Tank consensus was that the metabolic syndrome (MetS) is a complex pathophysiological state comprised of a cluster of clinically measured and typically unmeasured risk factors, is progressive in its course, and is associated with serious and extensive comorbidity, but tends to be clinically under-recognized. The ideal patient care model for MetS must accurately identify those at risk before MetS develops and must recognize subtypes and stages of MetS to more effectively direct prevention and therapies. This new MetS care model introduces both affirmed and emerging concepts that will require consensus development, validation, and optimization in the future.

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.

From 27–29 October 2014, more than 100 people gathered in Chicago, IL, to participate in a research symposium titled “Diabetes and the Microbiome,” jointly sponsored by the American Diabetes Association and JDRF. The conference brought together international scholars and trainees from multiple disciplines, including microbiology, bioinformatics, endocrinology, metabolism, and immunology, to share the current understanding of host-microbe interactions and their influences on diabetes and metabolism. Notably, this gathering was the first to assemble specialists with distinct expertise in type 1 diabetes, type 2 diabetes, immunology, and microbiology with the goal of discussing and defining potential pathophysiologies linking the microbiome and diabetes. In addition to reviewing existing evidence in the field, speakers presented their own original research to provide a comprehensive view of the current understanding of the topics under discussion. Presentations and discussions throughout the conference reflected a number of important concepts. The microbiota in any host represent a complex ecosystem with a high degree of interindividual variability. Different microbial communities, comprising bacteria, archaea, viruses, and fungi, occupy separate niches in and on the human body. Individually and collectively, these microbes provide benefits to the host—including nutrient harvest from food and protection against pathogens. They are dynamically regulated by both host genes and the environment, and they critically influence both physiology and lifelong health. The objective of the symposium was to discuss the relationship between the host and the microbiome—the combination of microbiota and their biomolecular environment and ecology—specifically with regard to metabolic and immunological systems and to define the critical research needed to understand and potentially target the microbiome in the prevention and treatment of diabetes. In this report, we present meeting highlights in the following areas: 1) relationships between diabetes and the microbiome, 2) bioinformatic tools, resources, and study design considerations, 3) microbial programming of the immune system, 4) the microbiome and energy balance, 5) interventions, and 6) limitations, unanswered questions, and resource and policy needs.