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About one in four Veterans lives with type 2 diabetes (T2D) , and nationwide, only 50% of Veterans meet the ADA glycemic target of A1c Disclosure A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Lifestyle interventions for type 2 diabetes (T2D) typically have poor retention, and drop out is often assumed to indicate treatment failure. A partnership between the Veterans Health Administration and Virta Health allows Veterans with T2D to enroll in Virta's clinic, which provides carbohydrate restricted nutrition therapy via continuous remote care. We sought to assess change in clinical outcomes upon clinic departure using medical record data. Percent change in clinical outcomes on a per patient basis from enrollment to time of departure were assessed with one sample t tests. Among 677 enrolled Veterans, 270 (40.0%) departed the clinic within 2 years (283±184 days in treatment; enrollment: age 58±9y, 13% female, 235±47 lb, 179±86 mg/dl glucose, 2.3±0.9 T2D medications) . Weight was significantly reduced at time of departure in all groups initiating nutrition therapy (p0.05) despite lower mean glucose which occurred concurrent with medication deprescription in most groups (p Disclosure B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Background: We previously reported 1- and 2-year effectiveness of a VLCI via CRC. Here we assess the long term effectiveness of the treatment via achievement of A1c ≤6.5%, Research Design and Methods: Patients with T2D who initially enrolled in a 2-year non-randomized, controlled clinical trial and received a VLCI via CRC were offered 3 additional years of prospective follow-up. Of the 200 patients completing 2 years, 169 (84.5%) consented to extend; 122 (72.2%) were retained at 5 years. Among those who extended, McNemar's test was used to assess the change in percent of patients meeting glycemic targets from baseline to 5 years among completers and on an intent-to-treat basis. Results: At 5 years, the percent of completing patients meeting glycemic goals improved across all defined targets (Table 1) . Of completing patients, 20% achieved diabetes remission, while 32.5% achieved an A1c Conclusions: One fifth of completing patients achieved the international consensus criteria for diabetes remission at 5 years, which is unique among lifestyle interventions. The proportion of people at A1c goal increased, suggesting the VLCI delivered via CRC may be an effective, long-term strategy to improve population health. Disclosure B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp. S.Phinney: Employee; Virta Health Corp.

Objective: We previously reported long term effectiveness of a very low carbohydrate intervention including nutritional ketosis (VLCI) delivered via continuous remote care (CRC) for improving weight and glycemia at 2 years in people with type 2 diabetes (T2D) . We assessed 5-year changes to determine if the intervention is sustainable, durable, and effective over a longer period of time. Research Design and Methods: Patients with T2D who were initially enrolled in a 2 year non-randomized, controlled clinical trial received a CRC emphasizing a VLCI. These patients were offered to continue for an additional 3 years of prospective follow-up. Of the 200 patients completing 2 years, 169 (84.5%) patients consented to the extension and 122 (72.2%) were retained at 5 years. Among those who extended, baseline versus 5 year differences in weight and glycemic outcomes were assessed using linear mixed effects models in an intent-to-treat analysis. P-values were adjusted using Holm-Bonferroni correction. Results: At five years, there were persistent improvements in weight from 116.4 to 107.6 kg (-8.8 kg, 95%CI [-11.0, -6.6]) , fasting insulin from 25.8 to 24.5 mIU/L (-7.9 mIU/L, 95%CI [-10.0, -5.8]) , and HOMA-IR from 9.1 to 6.6 (-2.5, 95%CI [-3.5, -1.5]) (all adjusted p-values Conclusions: Over 5 years follow-up, the VLCI with CRC showed excellent retention, sustained clinically significant weight loss, and stable glycemic control with reduced dependency on antidiabetes medications. Disclosure S.J.Athinarayanan: Employee; Virta Health Corp. S.Phinney: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp.

Type 2 diabetes (T2D) affects about one in four Veterans, a rate nearly three times the general population, and diabetes medications and supplies constitute about one quarter of these Veterans’ pharmacy spend. The Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via a continuous remote care model to Veterans in a pilot program. Five-month outcomes demonstrated significant reductions in HbA1c, BMI, diabetes medications and cost, and outpatient visits, but long term sustainability in this population is unknown. This retrospective, real-world, longitudinal analysis assessed the 1- and 2-year effects of the treatment on glycemia, diabetes medications, and body weight using medical record data. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . With initiation of nutritional intervention, glycemia fell necessitating medication titration and elimination to prevent hypoglycemia. The number of diabetes medications prescribed to each person significantly decreased from 2.4±0.9 to 1.3±0.9 and 1.6±0.8 at one and two years, respectively (ps Disclosure A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Type 2 Diabetes (T2D) affects one in four Veterans and often occurs with dyslipidemia, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD) . In a pilot program, the Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via continuous remote care to Veterans to reverse T2D by reducing glucose and dependence on medication, as demonstrated in prior research. This retrospective analysis assessed the 1- and 2-year effects on lipids and renal and hepatic markers in a real-world sample of Veterans with T2D using medical record data. Changes in metabolic markers from enrollment to 1- and 2-years (E, 1y, 2y) were assessed with paired t-tests with Holm-Bonferroni correction for multiple comparisons. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . HDL-C (E: 42±16, 1y: 46±12, 2y: 44±11 mg/dl; ps Disclosure M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Objective: To address the long-term effectiveness of VLCI for T2D, we report changes in lipids, inflammatory, hepatic, and renal markers at 5y. Research Design and Methods: Of the 200 subjects with T2D reaching 2-years in a non-randomized, controlled trial of CRC emphasizing VLCI, 169 (84.5%) consented to 3-year extension and 122 (61%) completed 5y. Metabolic changes from baseline (BL) to 5y were assessed with linear mixed effect models as an intent-to-treat analysis (n=169) . Holm-Bonferroni adjusted p-values are Results: At 5y, there were significant changes in HDLc from 43.0 mg/dl to 50.6 mg/dl (+17.7%) , apoA-I from 146.9 mg/dl to 153.5 mg/dl (+4.5%) , and no changes in Total Cholesterol, LDLc, apoB. There were marginal improvements in non-HDLc from 139.2 mg/dl to 128.9 mg/dl (-7.4%, unadjusted p-value Conclusions: People with T2D following VLCI for 5y show improvements in diabetic dyslipidemia and inflammation. Notably, there is no change in LDLc. There is no significant deterioration in liver and renal labs, although regression from CKD3 to 2 is possible with a VLCI and warrants further investigation. Disclosure C.G.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Phinney: Employee; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp.

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 …

Type 2 diabetes (T2D) and obesity are risk factors for severe COVID-19 infection and death. A medically supervised ketogenic diet (MSKD) can quickly reduce weight and glycemia, so we assessed the incidence of reported COVID-19, its severity, and factors associated with hospitalization in our geographically diverse, US-based, ambulatory population following initiation of a MSKD for T2D. Data were obtained from medical records and from surveys sent to T2D patients who self-reported COVID-19 diagnosis; 47.8% (294/614) responses and one known COVID-related death yielded a sample of 295 (50% male, 54±9 years, across 41 US states). We observed low reported rates of hospitalization (10.9%), ventilation (2.0%), and death (0.3%) relative to national reports. Weight and BMI did not differ by hospitalization status (Table 1), yet greater percent weight loss following initiation of MSKD was associated with reduced hospitalization after accounting for age, baseline weight, and days on MSKD (OR = 1.08, P = 0.03). Nutritional therapies, such as MSKD, that elicit rapid, significant weight loss may favorably impact hospitalization for and COVID-19 severity in patients with T2D. Disclosure B. M. Volk: Employee; Self; Virta Health Corp., Virta Health Corp. C. G. P. Roberts: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. M. Vantieghem: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. A. L. Mckenzie: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. P. George: Advisory Panel; Self; Altavant, United Therapeutics, Consultant; Self; United Therapeutics, Research Support; Self; Janssen Pharmaceuticals, Inc., Speaker’s Bureau; Self; Bayer U. S., Janssen Pharmaceuticals, Inc. S. J. Athinarayanan: Employee; Self; Virta Health Corp. R. N. Adams: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. S. Phinney: Stock/Shareholder; Self; Beyond Obesity LLC, Virta Health Corp. R. E. Ratner: Employee; Self; Virta Health Corp.

Very low carbohydrate diets (VLCD) can reduce weight and often target nutritional ketosis (NK). This analysis assessed the relationship between NK (mean blood beta-hydroxybutyrate, BHB) and weight loss during the first 90 days in 6283 patients treated via a continuous remote care model. Daily medical record weight and fingerstick BHB data obtained from patients with BMI ≥ 25 kg/m2 and type 2 diabetes or prediabetes counseled to target NK for 90 days were included. Linear regression and receiver operating characteristic curve analyses were performed. Clinically significant weight loss (≥5%, CSWL) was achieved by 63.0% (3958/6283) of patients (6.6±4.7% body weight loss at 90 days). Mean BHB over 90 days was a significant predictor of weight change (F=982, R2=0.135, P 1 mM higher likelihood of achieving CSWL within 90 days of initiating a VLCD. A therapeutic target for BHB may be > 0.5-0.7 mM, and likelihood of CSWL increases with higher mean BHB. Future analyses should explore means by which the relationship can be further refined and the impact of longer therapy duration. Disclosure A. L. Mckenzie: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. S. J. Athinarayanan: Employee; Self; Virta Health Corp. R. N. Adams: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. B. M. Volk: Employee; Self; Virta Health Corp., Virta Health Corp. S. Phinney: Stock/Shareholder; Self; Beyond Obesity LLC, Virta Health Corp. R. E. Ratner: Employee; Self; Virta Health Corp.

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. Certain groups are more vulnerable to COVID-19, notably older people and those with underlying medical conditions. Because diabetes is one of the conditions associated with high risk, the diabetes community urgently needs to know more about COVID-19 and its effects on people with diabetes. Between the first appearance of this illness in December 2019 and the time of writing this commentary, several detailed clinical descriptions have been published. Among 44,672 patients in China with infection confirmed by nucleic acid testing up to mid-February (5), most (87%) were between 30 and 79 years old. A large majority (81%) were considered to have mild illness, but in 14% it was judged to be severe and in 5% critical. Of all confirmed cases, 2.3% of patients died. Higher mortality rates were found among those ≥80 years old (14.8%), in those with preexisting cardiovascular …

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

Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear.To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped.Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P.005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC.1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

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.

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.

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 objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal.Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained.Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P.0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P.001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P.0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P.0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes.In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

© 2014 by the American Diabetes Association. The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with theAmerican Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade andmineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7)multidisciplinary approaches andmedical homemodels for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that willmeaningfully improve life for people with DKD.

OBJECTIVE GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODS Patients taking basal insulin (with or without oral agents) with HbA1c 7–10.5% (53–91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of RESULTS At week 26, HbA1c decreased from baseline by −0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and −0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, −0.16% (95% CI −0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (−0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). CONCLUSIONS Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk.

OBJECTIVE Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status. RESEARCH DESIGN AND METHODS A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years. RESULTS Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group. CONCLUSIONS Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.

AimsTo assess efficacy and safety of lixisenatide once-daily versus placebo in Type 2 diabetes mellitus (T2DM) patients inadequately controlled on sulfonylurea (SU)±metformin.MethodsIn this randomized, double-blind, two-arm, parallel-group, multicenter study, patients received lixisenatide 20μg once-daily or placebo for 24 weeks in a stepwise dose increase on top of SUs±metformin. Primary outcome was change in HbA1c from baseline to Week 24.ResultsLixisenatide provided a significant reduction in HbA1c at Week 24 versus placebo (LS mean: −0.85% vs. −0.10%; p

OBJECTIVE Epidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed. We aimed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial. RESEARCH DESIGN AND METHODS The ORIGIN trial is an international, long-term, randomized two-by-two factorial study comparing insulin glargine with standard care and n-3 fatty acids with placebo (double blind) in people with dysglycemia at high risk for cardiovascular events. The primary outcome measure (cancer substudy) was the occurrence of any new or recurrent adjudicated cancer. Cancer mortality and cancer subtypes were also analyzed. RESULTS Among 12,537 people (mean age 63.5 years, SD 7.8; 4,388 females), 953 developed a cancer event during the median follow-up of 6.2 years. In the glargine and standard care groups, the incidence of cancers was 1.32 and 1.32 per 100 person-years, respectively (P = 0.97), and in the n-3 fatty acid and placebo groups, it was 1.28 and 1.36 per 100 person-years, respectively (P = 0.39). No difference in the effect of either intervention was noted within predefined subgroups (P for all interactions ≥0.17). Cancer-related mortality and cancer-specific outcomes also did not differ between groups. Postrandomization HbA1c levels, glucose-lowering therapies (including metformin), and BMI did not affect cancer outcomes. CONCLUSIONS Insulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes, including cancer-specific mortality. Exposure to glucose-lowering therapies, including metformin, and HbA1c level during the study did not alter cancer risk.

While predictive tools are being developed to identify those at highest risk for developing diabetes, little is known whether these assays affect clinical care.Thirty sites who used the PreDx(®) (Tethys BioScience, Emeryville, CA) abstracted clinical information from baseline clinic visits prior to a PreDx test and from the most recent visit at time of abstraction. All visits occurred between May 2008-April 2011 (median follow-up 198 days, IQR 124-334). The primary analysis was the influence of the PreDx test (5-year diabetes prediction) on subsequent care; descriptive statistics were used to summarize baseline and follow-up variables. Overall 913 patients with 2 abstracted visits were included. Relative to baseline, median SBP decreased 1.5 mmHg (p = 0.039), DBP decreased 2 mmHg (p 0.001), LDL-C decreased 4 mg/dL (p = 0.009), and HDL-C increased 2 mg/dL (p 0.001) at follow-up. Behavioral or lifestyle counseling was not significantly different from baseline to follow-up (71.2% vs. 68.1% (p = 0.077), but BMI was lower by 0.2 kg/m(2) at follow up (p = 0.013). At follow-up, more patients were prescribed metformin (13.7% vs. 9.7%, p 0.001). A higher PreDx score was significantly associated with metformin prescription (p = 0.0003), lifestyle counseling (p = 0.0099), and a lower BMI at follow-up (p = 0.007).The use of a prognostic test in patients perceived to be high risk for diabetes was associated with a modest but significant increase in the prescription of metformin and lifestyle interventions and a reduction in BMI.

Aims: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. Methods: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. Results: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3–2.3), 1.7 (1.2–2.3) and 2.0 (1.3–3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. Conclusions: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions

OBJECTIVE Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance. RESEARCH DESIGN AND METHODS We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years. RESULTS In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes. CONCLUSIONS In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes.In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TW(AM)) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TW(PM)) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA(1c) 7.0-10.0%; body-mass index ≤45 kg/m(2)) were randomly allocated (1:1) without stratification by a central interactive response system to IDeg 3TW or IGlar OD. Both groups continued taking metformin with or without dipeptidyl peptidase-4 inhibitors. Insulin was titrated to achieve a prebreakfast self-monitored blood glucose (SMBG) concentration of between 3.9 and less than 5.0 mmol/L. The primary outcome was non-inferiority of IDeg 3TW compared with IGlar OD, as assessed by change in HbA(1c) from baseline to 26 weeks (non-inferiority limit of 0.4%) by ANOVA in an intent-to-treat analysis (full analysis set). These trials are registered with ClinicalTrials.gov, numbers NCT01068678 and NCT01076647.We recruited 460 patients for the AM trial (IDeg 3TW(AM), n=230; IGlar OD, n=230) and 467 patients for the PM trial (IDeg 3TW(PM), n=233; IGlar OD, n=234). After 26 weeks, mean HbA decreased by 0.9% (IDeg 3TW(AM)) and 1.3% (IGlar OD) in the AM trial, and by 1.1% (IDeg 3TW(PM)) and 1.4% (IGlar OD) in the PM trial. Non-inferiority was not confirmed in either trial (estimated treatment difference [IDeg 3TW(AM)-IGlar OD] 0.34%, 95% CI 0.18-0.51; [IDeg 3TW(PM)-IGlar OD] 0.26%, 0.11-0.41). Across the two trials, rates of confirmed hypoglycaemia (SMBG3.1 mmol/L or severe [needing assistance]) ranged from 1.0 to 1.6 episodes per patient-year and were similar for IDeg 3TW(AM) and IGlar OD (estimated rate ratio [ERR] 1.04, 95% CI 0.69-1.55), but higher for IDeg 3TW(PM) than for IGlar OD (ERR 1.58, 1.03-2.43). The rate of nocturnal confirmed hypoglycaemia was higher for IDeg 3TW(AM) than for IGlar OD (ERR 2.12, 1.08-4.16); we noted no significant difference between IDeg 3TW(PM) and IGlar OD (ERR 0.60, 0.21-1.69).The inferior glycaemic control and increased risk of hypoglycaemia with IDeg 3TW compared with IGlar OD do not support a three-times-weekly dosing regimen.Novo Nordisk.

Aims To examine the ability of fasting plasma glucose (FPG) and/or 2-h glucose to confirm diabetes and to determine the proportion of participants with HbA1c ≥ 6.5%. Methods Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-h glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. Results 772 (24%) participants had elevated FPG or 2-h glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-h glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-h glucose, the larger number of 2-h glucose triggers resulted in 87% of confirmed cases triggering on 2-h glucose. Confirmation rates increased to 75% among persons with FPG ≥ 126 mg/dl and HbA1c ≥ 6.5%. Conclusions Only half of the persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-h glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG ≥ 126 mg/dl and HbA1c ≥ 6.5%, the confirmation rate was increased.

OBJECTIVE Taspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide. RESEARCH DESIGN AND METHODS Overweight adults with inadequately controlled type 2 diabetes on metformin ± a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 µg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA1c after 24 weeks. RESULTS Mean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c significantly more than exenatide (taspoglutide 10 mg: –1.24% [SE 0.09], difference –0.26, 95% CI –0.37 to –0.15, P < 0.0001; taspoglutide 20 mg: –1.31% [0.08], difference –0.33, –0.44 to –0.22, P < 0.0001; exenatide: –0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, –1.6 kg; taspoglutide 20 mg, –2.3 kg) as did exenatide (–2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA1c and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients. CONCLUSIONS Once-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions.

This study evaluated the relationship between skin intrinsic fluorescence (SIF) and long-term mean hemoglobin A1c (HbA1c) in individuals with type 1 diabetes.We undertook a cross-sectional analysis of 172 individuals with type 1 diabetes followed longitudinally with HbA1c data available over an average of 16.6 years. SIF was evaluated cross-sectionally using the SCOUT DS device (VeraLight Inc., Albuquerque, NM) and correlated with most recent HbA1c and long-term mean HbA1c. Potential determinants of this relationship, including age, gender, smoking status, duration of diabetes, and renal function, were also evaluated.Age-adjusted skin intrinsic fluorescence significantly correlated with long-term mean HbA1c (R=0.44, P0.0001). In contrast, there was no significant relationship between SIF and most recent HbA1c (R=0.14, P=0.075). The best-fit model describing the relationship between SIF and mean HbA1c controlled for factors of age, duration of disease, renal function, and site of study conduct. Controlling for these factors was also important in understanding the relationship between most recent HbA1c and SIF. Evaluating longer-term HbA1c data also strengthened the relationship between SIF and mean HbA1c. In the presence of renal dysfunction or damage, as indicated by an estimated glomerular filtration rate of60 mL/min/1.73 m2 or presence of gross proteinuria, there was no significant correlation between SIF and mean HbA1c.Noninvasive detection of SIF significantly correlates with long-term mean HbA1c, providing insight into long-term glycemic exposure. Age, duration of diabetes, and renal function are potential contributors to this relationship.

Objective— To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. Methods and Results— CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly ( P =0.01) lower with pioglitazone treatment (4.76×10 –3 mm/year; 95% CI: 2.39×10 –3 –7.14×10 –3 mm/year) compared with placebo (9.69×10 –3 mm/year; 95% CI: 7.24×10 –3 –12.15×10 –3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA 1c , fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo ( P Conclusion— Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

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.

Diabet. Med. 30, 46–55 (2013) Abstract Aims Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. Methods This long-term follow-up (median 10 years, interquartile range 9.0–10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. Results After 10 years’ follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (−2 to −3) and diastolic (−6 to −6.5 mmHg) blood pressure, and for LDL cholesterol (−0.51 to −0.6 mmol/l) and triglycerides (−0.23 to −0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. Conclusion Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.

Aims The efficacy and safety of insulin degludec (degludec), a new-generation ultra-long-acting basal insulin, was compared with insulin glargine (glargine) in people with Type 1 diabetes mellitus in a 16-week, open-label, randomized trial. Health status, an important aspect of effective diabetes management, was also assessed. Methods Degludec (n = 59) or glargine (n = 59) were injected once daily, with insulin aspart at mealtimes. Health status assessment utilized the validated Short Form 36 Health Survey, version 2, which has two summary component scores for mental and physical well-being, each comprising four domains. Results At study end, HbA1c reductions were comparable between groups, but confirmed nocturnal hypoglycaemia was significantly less frequent with degludec [relative rate 0.42 (95% CI 0.25–0.69)], and overall hypoglycaemia numerically less frequent [relative rate 0.72 (95% CI 0.52–1.00)]. After 16 weeks, a significant improvement in Short Form 36 Health Survey mental component score of +3.01 (95% CI 0.32–5.70) was obtained for degludec against glargine, attributable to significant differences in the social functioning [+8.04 (95% CI 1.89–14.18)] and mental health domains [+2.46 (95% CI 0.10–4.82)]. For mental component score, Cohen’s effect size was 0.42, indicating a small-to-medium clinically meaningful difference. The physical component score [+0.66 (95% CI –2.30 to 3.62)] and remaining domains were not significantly different between degludec and glargine. Conclusions In the context of comparable overall glycaemic control with glargine, degludec improved mental well-being as measured using the mental component score of the Short Form 36 Health Survey. The improvements in overall mental component score and the underlying social functioning and mental health domains with degludec compared with glargine may relate to the observed reduction in hypoglycaemic events.

The burden of diabetes is enormous and escalating at an alarming rate (1–3). Nearly 26 million Americans have the disease, including over 10% of the total adult population and over 25% of the population aged 65 years and older. While most of those individuals have type 2 diabetes, nearly 1 million Americans have type 1 diabetes. An additional 79 million American adults have prediabetes, which, when added to those with diabetes, suggests that nearly half of the adult population currently has impaired glucose metabolism (1). If present trends continue, as many as one in three American adults will be diagnosed with diabetes by 2050; the majority of cases will include older adults and racial and ethnic minorities (4). The high prevalence of diabetes, especially among the aging population, comes at a considerable economic cost. In 2007, diabetes and prediabetes accounted for approximately $218 billion in direct medical costs and lost productivity in the U.S. (5). Health care expenditures for individuals with diabetes are 2.3 times greater than expenditures for those without diabetes, and diabetes complications account for a significant proportion of those costs (5). Diabetes significantly increases the risk of cardiovascular events and death, and is the leading cause of end-stage renal disease, blindness, and nontraumatic lower-limb amputations in the U.S. (1). Despite medical advances significantly decreasing the risk of complications and associated mortality, the trajectory of these declines has been blunted by the overall increase in the number of people afflicted with diabetes. Decades of intensive research have resulted in vastly improved understanding of the pathophysiology and impact of diabetes, as well as a host of new and improved therapies. The translation of this research into practice has led to reductions in chronic complications and mortality in people with diabetes (6). Yet, as the incidence and …

OBJECTIVE The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after randomization. We report the 10-year within-trial cost-effectiveness of the interventions. RESEARCH DESIGN AND METHODS Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. RESULTS Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,572) than metformin ($2,281) or placebo ($752). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($26,810 lifestyle vs. $27,384 metformin vs. $29,007 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($31,382 lifestyle vs. $29,665 metformin vs. $29,759 placebo). The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.89) than metformin (6.79) or placebo (6.74). When costs and outcomes were discounted at 3% and adjusted for survival, lifestyle cost $12,878 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo. CONCLUSIONS Over 10 years, from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent.

Aim: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. Methods: This was a multicenter, randomized, open-label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) ≥7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent-to-treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA1c, fasting plasma glucose and weight from study baseline to endpoint (week 52). Results: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA1c: 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of −0.87 kg (p = 0.243). Conclusion: Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated.

Gestational diabetes mellitus (GDM) is a pregnancy complication that is becoming more prevalent with recent population trends in obesity and advancing maternal age. A diagnosis of GDM not only increases risk for maternal and fetal complications during pregnancy, but also significantly increases a woman's risk of both type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in the postpartum. Even women with milder forms of abnormal glucose homeostasis during pregnancy, specifically gestational impaired glucose tolerance, are at increased risk, justifying the recent recommendation to tighten the diagnostic criteria for GDM, thus implicating many more women. Risk factors that increase risk for future CVD among women with a history of GDM include postpartum progression to T2DM; metabolic syndrome; obesity; hypertension; and altered levels of circulating inflammatory markers, specifically, adiponectin, C-reactive protein, and tumor necrosis factor-α. Medical therapies such as metformin that prevent progression to T2DM may prove to be our primary defense against earlier CVD among women with GDM.

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Hypertensive disorders of pregnancy (HDP), including pre‐existing hypertension, gestational hypertension, and preeclampsia, further complicate already high‐risk pregnancies in women with diabetes mellitus (DM). Women with both pre‐existing and gestational diabetes are at increased risk for HDP, leading to higher maternal and fetal morbidity. Further, particularly in diabetic women and women with a history of gestational diabetes, HDP significantly increases the risk for future cardiovascular events. For clinicians, women with hypertension and diabetes during pregnancy pose a management challenge. Specifically, preconception management should stress strict control of glycemia, blood pressure, and prevention of diabetic complications, specifically nephropathy, which specifically increases the risk for preeclampsia. During gestation, clinicians must be aware of potential maternal and fetal complications associated with various anti‐hypertensive therapies, including known fetotoxicity of ACE inhibitors and ARBs when given in the 2nd or 3rd trimester, and the risks and benefits of expectant management versus delivery in cases of severe gestational hypertension or preeclampsia. Indeed, diabetic women must be followed closely prior to conception and throughout gestation to minimize the risk of HDP and its associated complications. J Clin Hypertens (Greenwich). 2011;13:275–284. © 2011 Wiley Periodicals, Inc.

Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

National health care policy is a relatively new concept in the U.S. with a rather tortured and painful past (1). President Theodore Roosevelt's initial efforts to establish national health insurance in 1912 failed. Twenty-three years later, his cousin Franklin Roosevelt incorporated Maternal and Child Health Grants into the original Social Security Act passed in 1935 in the midst of the New Deal. His successor, Harry Truman, attempted to extend medical care to the poor through grant authorization to the states, but met opposition from the American Medical Association, and both Senate and House versions of the bill foundered. Until recently, the Medicare and Medicaid programs signed into law by Lyndon Johnson in 1965 were the most significant legislation addressing health care delivery and financing in the U.S.—extending care to the elderly, the disabled, and the poor. Since then, many have tried to establish national coverage, but neither the Republicans nor the Democrats have had success. Richard Nixon's Comprehensive Health Insurance Plan in 1972 was very much like the Obama Plan presented in 2009, but was considered inadequate to meet the national needs by the Democratic opposition. The Clinton administration's attempt to introduce the Health Security Act was met with bipartisan opposition so fierce that the bill was never brought to the floor of either chamber for a vote. The Patient Protection and Affordable Care Act (PPACA) of 2010 is clearly the most sweeping revision of health care delivery and finance since the introduction of Medicare and Medicaid. The questions surrounding it are numerous, and its impact remains to be seen; however, it is worthwhile to examine why health reform is necessary. Independent of the source of payment, per capita health care expenditures in the U.S. rose over the last 30 years from approximately $1,000 to $7,000 (adjusted for inflation) (Fig. …

Aims: Most treatments for type 2 diabetes fail over time, necessitating combination therapy. We investigated the safety, tolerability and efficacy of liraglutide monotherapy compared with glimepiride monotherapy over 2 years. Methods: Participants were randomized to receive once-daily liraglutide 1.2 mg, liraglutide 1.8 mg or glimepiride 8 mg. Participants completing the 1-year randomized, double-blind, double-dummy period could continue open-label treatment for an additional year. Safety data were evaluated for the full population exposed to treatment, and efficacy data were evaluated for the full intention-to-treat (ITT) and 2-year completer populations. Outcome measures included change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and frequency of nausea and hypoglycaemia. Results: For patients completing 2 years of therapy, HbA1c reductions were −0.6% with glimepiride versus −0.9% with liraglutide 1.2 mg (difference: −0.37, 95% CI: −0.71 to −0.02; p = 0.0376) and −1.1% with liraglutide 1.8 mg (difference: −0.55, 95% CI: −0.88 to −0.21; p = 0.0016). In the ITT population, HbA1c reductions were −0.3% with glimepiride versus −0.6% with liraglutide 1.2 mg (difference: −0.31, 95% CI: −0.54 to −0.08; p = 0.0076) and −0.9% with liraglutide 1.8 mg (difference: −0.60, 95% CI: −0.83 to −0.38; p < 0.0001). For both ITT and completer populations, liraglutide was more effective in reducing HbA1c, FPG and weight. Over 2 years, rates of minor hypoglycaemia [self-treated plasma glucose

OBJECTIVE Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes. RESEARCH DESIGN AND METHODS In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m2) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52–1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65–1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25–0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44–1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. CONCLUSIONS In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.

To determine (1) the medium-term effect of rosiglitazone and glipizide on intra-stent neointima hyperplasia, (2) restenosis pattern as assessed by intra-vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) in patients with T2DM and coronary artery disease. A total of 462 patients with T2DM were randomized to rosiglitazone or glipizide for up to 18 months in the APPROACH trial, and had evaluable baseline and follow-up IVUS examinations. There was no significant difference in the size of plaque behind stent between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (-5.6 mm(3) vs. 1.9 mm(3); P = 0.61) or with a drug-eluting stent (12.1 mm(3) vs. 5.5 mm(3); P = 0.09). Similarly, there was no significant difference in percentage intimal hyperplasia volume between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (24.1% vs. 19.8%; P = 0.38) or with a drug-eluting stent (9.8% vs. 8.3%; P = 0.57). QCA data (intra-stent late loss, intra-stent diameter stenosis or binary restenosis) were not different between the rosiglitazone and glipizide groups. This study suggests that both rosiglitazone and glipizide have a similar effect on neointimal growth at medium term follow-up, a finding that warrants investigation in dedicated randomized trials.

Impaired fasting glucose and impaired glucose tolerance reflect perturbations in glucose metabolism and define a prediabetic state in which risk for type 2 diabetes mellitus (T2DM) is increased. There is overlap between prediabetes and the metabolic syndrome, which itself increases the risk for T2DM and cardiovascular disease. The utility of medical interventions to prevent progression to diabetes in prediabetic individuals, many of whom also manifest metabolic syndrome, has been examined in several large clinical trials. Intensive lifestyle intervention consistently results in drastic reductions in the incidence of T2DM and reversal of metabolic syndrome. Additionally, pharmacotherapies-including metformin, acarbose, thiazolidinediones, glucagon-like peptide 1 receptor agonists, and renin-angiotensin inhibitors-also reduce diabetes incidence with variable effects on metabolic syndrome components. Taken together, we recommend that prediabetic patients undergo intensive lifestyle intervention, with the addition of pharmacotherapy based on the presence of specific features of the metabolic syndrome, for diabetes prevention.

OBJECTIVE The Diabetes Prevention Program (DPP) trial investigated rates of progression to diabetes among adults with prediabetes randomized to treatment with placebo, metformin, or intensive lifestyle intervention. Among women in the DPP, diabetes risk reduction with metformin was greater in women with prior gestational diabetes mellitus (GDM) compared with women without GDM but with one or more previous live births. RESEARCH DESIGN AND METHODS We asked if genetic variability could account for these differences by comparing β-cell function and genetic risk scores (GRS), calculated from 34 diabetes-associated loci, between women with and without histories of GDM. RESULTS β-Cell function was reduced in women with GDM. The GRS was positively associated with a history of GDM; however, the GRS did not predict progression to diabetes or modulate response to intervention. CONCLUSIONS These data suggest that a diabetes-associated GRS is associated with development of GDM and may characterize women at risk for development of diabetes due to β-cell dysfunction.

Background The Stop Atherosclerosis in Native Diabetics Study (SANDS) reported cardiovascular benefit of aggressive versus standard treatment targets for both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) in diabetic individuals. Objective In this analysis, we examined within trial cost-effectiveness of aggressive targets of LDL-C ≤70 mg/dL and systolic BP ≤115 mmHg versus standard targets of LDL-C ≤100 mg/dL and systolic BP ≤130 mmHg. Design Randomized, open label blinded-to-endpoint 3-year trial. Data Sources SANDS clinical trial database, Quality of Wellbeing survey, Centers for Medicare and Medicaid Services, Wholesale Drug Prices. Target Population American Indians ≥age 40 years with type 2 diabetes and no previous cardiovascular events. Time Horizon April 2003 to July 2007. Perspective Health payer. Interventions Participants were randomized to aggressive versus standard groups with treatment algorithms defined for both. Outcome Measures Incremental cost-effectiveness. Results of Base-Case Analysis Compared with the standard group, the aggressive group had slightly lower costs of medical services (−$116) but a 54% greater cost for BP medication ($1,242) and a 116% greater cost for lipid-lowering medication ($2,863), resulting in an increased cost of $3,988 over 3 years. Those in the aggressively treated group gained 0.0480 quality-adjusted life-years (QALY) over the standard group. When a 3% discount rate for costs and outcomes was used, the resulting cost per QALY was $82,589. Results of Sensitivity Analysis The use of a 25%, 50%, and 75% reduction in drug costs resulted in a cost per QALY of $61,329, $40,070, and $18,810, respectively. Limitations This study was limited by use of a single ethnic group and by its 3-year duration. Conclusions Within this 3-year study, treatment to lower BP and LDL-C below standard targets was not cost-effective because of the cost of the additional medications required to meet the lower targets. With the anticipated availability of generic versions of the BP and lipid-lowering drugs used in SANDS, the cost-effectiveness of this intervention should improve.