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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.

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

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.

© 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.

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.

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).

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.

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.

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. …

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.

OBJECTIVE To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7–9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline. RESULTS Significantly greater (P < 0.0001) reductions in A1C from a mean ± SD baseline of 7.9 ± 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: –1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg Q2W), and –1.0 ± 0.1% (20 mg Q2W) vs. –0.2 ± 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (–2.1 ± 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (–2.8 ± 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (–1.9 ± 0.3 kg, P = 0.0083) group than with placebo (–0.8 ± 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low. CONCLUSIONS Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.

OBJECTIVE Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program. RESEARCH DESIGN AND METHODS A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status. RESULTS CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia. CONCLUSIONS Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.

The consequences of hyperglycemia appearing during pregnancy were well described in 1917, when Elliot P. Joslin described Case 309, which “showed sugar in 1897 during pregnancy, but following confinement, with resulting dead baby, it disappeared, but returned in 9 years in the form of moderate to severe diabetes… . [W]ith our present knowledge, it is quite possible that such an outcome could be prevented by active treatment of the glycosuria from the very start” (1). Subsequently, O'Sullivan and Mahan's definition of gestational diabetes mellitus (GDM) in 1964 was a formal recognition of the mother's increased risk of future development of diabetes (2). They defined GDM if a pregnant woman undergoing a 3-h 100-g oral glucose tolerance test had glucose values exceeding 2 SDs above the mean on two of the four values. This landmark study described a population of pregnant women with a lifetime risk of diabetes exceeding 70% (3). Multiple studies worldwide have demonstrated a broad ethnic and geographic distribution of GDM, but all studies share the increased risk of subsequent diabetes after delivery (4). Assessment of diabetes risk postpartum is influenced by the criteria used to define GDM, the testing undertaken postpartum, and the length of follow-up. Diagnosis of carbohydrate intolerance in the first trimester of pregnancy may reflect the ascertainment of previously undiagnosed and, presumably, asymptomatic diabetes. Alternatively, pregnancy creates a metabolic stress that may push a woman with compensated type 1 or type 2 diabetes into a decompensated hyperglycemic state. Under these circumstances, one would anticipate a high rate of persistent hyperglycemia in the postpartum state. In fact, the presence of GDM doubles the risk of diabetes within 4 months postpartum, whereas a fasting plasma glucose >121 mg/dl during the pregnancy increased the risk 21-fold (5). Differential criteria for diagnosis of GDM affects the …

OBJECTIVE— Despite the high rates of gestational diabetes mellitus (GDM) among certain Pacific Islander and Asian ethnic groups in the U.S., little is known about the risk for adverse perinatal outcomes in these populations. We sought to examine ethnic differences in perinatal outcome among Asian and Pacific-Islander women with GDM. RESEARCH DESIGN AND METHODS— A retrospective review of all women referred to the largest outpatient GDM program in the state of Hawai‘i from 1995 to 2005 was conducted. Patients of Native-Hawaiian/Pacific-Islander, Japanese, Chinese, Filipino, and Caucasian ethnicity were included (n = 2,155). Treatment of all patients consisted of an outpatient education class, dietary management, self-monitoring of blood glucose, and insulin instruction (if indicated). Demographics, maternal and neonatal characteristics, and delivery information were evaluated. RESULTS— Neonates born to Native-Hawaiian/Pacific-Islander mothers and Filipino mothers had 4 and 2 times the prevalence of macrosomia, respectively, compared with neonates born to Japanese, Chinese, and Caucasian mothers. These differences persisted after adjustment for other statistically significant maternal and fetal characteristics. Ethnic differences were not observed for other neonatal or maternal complications associated with GDM, with the exception of neonatal hypoglycemia and hyperbilirubinemia. CONCLUSIONS— Significant ethnic differences in perinatal outcomes exist across Asian and Pacific-Islander women with GDM. This finding emphasizes the need to better understand ethnic-specific factors in GDM management and the importance of developing ethnic-tailored GDM interventions to address these disparities.

OBJECTIVE—To estimate the proportion of U.S. adults with diabetes who meet American Diabetes Association (ADA) clinical practice recommendations. RESEARCH DESIGN AND METHODS—Using data from the 1999–2002 National Health and Nutrition Examination Survey, 998 adults aged ≥18 years with self-reported diabetes were identified. The proportion of adults with diabetes meeting ADA recommendations for HbA1c (A1C), HDL cholesterol, LDL cholesterol, triglycerides, blood pressure, renal function, nutrient intake, smoking, pneumococcal vaccination, and physical activity was estimated. RESULTS—Among U.S. adults with diabetes in 1999–2002, 49.8% had A1C 81% of the sample reported not smoking at the time of the exam, only 38.2% reported ever having had a pneumococcal immunization, and 28.2% reported getting the recommended level of physical activity. Race, age, duration of diabetes, and education affected achievement of ADA recommendations. CONCLUSIONS—Achievement of ADA clinical practice recommendations is far from adequate in U.S. adults with diabetes.

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.

OBJECTIVE—This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS—A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 ± 10 years with BMI of 34.2 ± 5.9 kg/m2 and HbA1c of 8.2 ± 1.1%. After 4 weeks of placebo, subjects self-administered 5 μg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 μg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. RESULTS—At week 30, HbA1c changes from baseline ± SE for each group were −0.78 ± 0.10% (10 μg), −0.40 ± 0.11% (5 μg), and +0.08 ± 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 μg), 32% (5 μg), and 13% (placebo) achieved HbA1c ≤7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (−2.8 ± 0.5 kg [10 μg], −1.6 ± 0.4 kg [5 μg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia. CONCLUSIONS—Exenatide was generally well tolerated and reduced HbA1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

There are events that occur during our lives that because of the significance or enormity of the event we vividly remember the time, place, and what we were doing at the time! Clearly, events related to our family life would be good examples as we all remember the time, place, and emotion surrounding the birth of a child, a marriage, or perhaps the untimely death of a parent or other loved one. We also seem to recall with uncanny details where we were and what we were doing when we first heard news of a remarkable achievement, a human tragedy, or natural disaster. For example, most people today will easily recall their circumstances on the morning of 11 September 2001. Those in our generation vividly remember when we first heard of the assassination of John F. Kennedy or watched the first lunar landing on our black-and-white televisions. With this in mind, we can vividly recall when the initial results of the Diabetes Control and Complications Trial (DCCT) were presented in Las Vegas in 1993 at the American Diabetes Association (ADA) Scientific Sessions. During the session, the significance of the findings was quite apparent. We realized there was no more guessing on what our standards of treatment were to be…now we had data! But, to be honest, we clearly did not appreciate the fact that 20 years later, we would be reflecting on that moment as just the beginning of a long and rewarding story. We agreed that the initial results at the time ushered in a new paradigm of treatment, but not one of us in attendance that day could have predicted what was to come of the DCCT and that the study would be as relevant today as it was then and continue to inform and provide new information …

OBJECTIVE—To assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes and to test the effectiveness of current American Diabetes Association screening guidelines. RESEARCH DESIGN AND METHODS—In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 patients with type 2 diabetes, aged 50–75 years, with no known or suspected coronary artery disease, were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. The prevalence of ischemia in 522 patients randomized to stress testing was assessed by adenosine technetium-99m sestamibi single-photon emission–computed tomography myocardial perfusion imaging. RESULTS—A total of 113 patients (22%) had silent ischemia, including 83 with regional myocardial perfusion abnormalities and 30 with normal perfusion but other abnormalities (i.e., adenosine-induced ST-segment depression, ventricular dilation, or rest ventricular dysfunction). Moderate or large perfusion defects were present in 33 patients. The strongest predictors for abnormal tests were abnormal Valsalva (odds ratio [OR] 5.6), male sex (2.5), and diabetes duration (5.2). Other traditional cardiac risk factors or inflammatory and prothrombotic markers were not predictive. Ischemic adenosine-induced ST-segment depression with normal perfusion (n = 21) was associated with women (OR 3.4). Selecting only patients who met American Diabetes Association guidelines would have failed to identify 41% of patients with silent ischemia. CONCLUSIONS—Silent myocardial ischemia occurs in greater than one in five asymptomatic patients with type 2 diabetes. Traditional and emerging cardiac risk factors were not associated with abnormal stress tests, although cardiac autonomic dysfunction was a strong predictor of ischemia.

OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.

OBJECTIVE: Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analog with a prolonged duration of action compared with NPH human insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 diabetes who had been previously treated with multiple daily injections of NPH insulin and regular insulin. RESEARCH DESIGN AND METHODS: This study was a multicenter randomized parallel-group study in which subjects were randomized to receive premeal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. Dose titration of both basal insulins was based on capillary fasting whole blood glucose (FBG) levels; the goal was a premeal blood glucose concentration of 4.4-6.7 mmol/l. RESULTS: A total of 534 well-controlled type 1 diabetic subjects (mean GHb 7.7%, mean fasting plasma glucose [FPG] 11.8 mmo/l) were treated. A small decrease in GHb levels was noted with both insulin glargine (-0.16%) and NPH insulin (-0.21%; P > 0.05). Significant reductions in median FPG levels from baseline (-1.67 vs. -0.33 mmol/l with NPH insulin, P = 0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin glargine. After the 1-month titration phase, significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycemia (39.9 vs. 49.2%, P = 0.0219) or nocturnal hypoglycemia (18.2 vs. 27.1%, P = 0.0116) with a blood glucose level

OBJECTIVE: More than 100,000 people are hospitalized annually in the U.S. with diabetic ketoacidosis (DKA). Outcome differences have not been examined for these patients based on whether their primary care provider is a generalist or a diabetes specialist. The objective of this study was to investigate hospital charges and hospital length of stay (LOS) for patients with DKA according to the specialty of their primary care provider. RESEARCH DESIGN AND METHODS: We investigated all patients with a primary diagnosis of DKA during a 3.5-year period (n = 260) in a large urban teaching hospital. Hospital charges and LOS were studied regarding the specialty of the primary care provider. Demographic factors, severity of illness, laboratory data, and readmission rates were compared. RESULTS: Patients cared for by generalists and endocrinologists had a similar case mix and severity of DKA. The age-adjusted mean LOS for patients of generalists was 4.9 days (95% CI 4.5-5.4), and the mean LOS for patients of endocrinologists was 3.3 days (2.6-4.2) (P < 0.0043). Mean hospital charges differed (P < 0.0001) with an age- and sex-adjusted mean for patients of endocrinologists of $5,463 ($4,179-7,141) and a mean for patients of generalists of $10,109 ($9,151-11,166). The additional charges incurred by generalists were due in part to patients undergoing more procedures. No differences in diabetes-related complications occurred during admission, but the endocrinologist-treated group had a lower readmission rate for DKA during the study period than the generalist-treated group (2 vs. 6%, respectively) (P = 0.03). CONCLUSIONS: Endocrinologists provide more cost-effective care than generalists do when serving as primary care providers for patients hospitalized with DKA.

Controversy persists about whether hyperinsulinemia and hyperproinsulinemia are independent risk markers for coronary atherosclerosis. A common limitation of most previous studies has been imprecise categorization of disease status in normal and coronary artery disease (CAD) groups. We assessed the relationship of pancreatic β-cell secretory products and premature CAD in a casecontrol study of 134 nondiabetic subjects, aged ≤55 years old, carefully defined for CAD status by catheterization and/or thallium stress studies. Case patients comprised 66 patients with premature CAD, and control subjects (non-CAD group) included 68 patients without CAD but with traditional CAD risk factors and chest pain and/or abnormal electrocardiograms but normal catheterization and/or thallium stress studies. In addition to the CAD and non-CAD group comparison, both groups were compared with a reference group of 27 mixed lean and obese control volunteers. All CAD and non-CAD patients had a 3-h 75-g oral glucose tolerance test with measurement of fasting and post-glucose load immunoreactive insulin (IRI), specific insulin (INS), proinsulin-like material (PI), and C-peptide. Increased fasting insulin and fasting proinsulin levels both were statistically significantly associated with higher odds of being in either the premature CAD and the non-CAD groups when compared with the reference group in a polychotomous logistic regression model (odds ratio of at least 1.20 for a 20% increase in each β-cell secretory product in both comparisons, P ≤ 0.05). However, increased pancreatic β-cell secretory hormone levels did not show a statistically significant relative risk for being in the premature CAD group when compared with the non-CAD group. After adjustment for BMI, all statistically significant associations disappeared for IRI, INS, and PI when the odds favoring being in the CAD and non-CAD groups were compared versus the reference group. Furthermore, the odds of being in the premature CAD and non-CAD groups when compared with the reference group were not significantly associated to the ratio of PI to insulin and C-peptide. Thus, although there is a statistically significant association between the odds of having premature CAD with elevated insulin and proinsulin levels compared with the reference group, these findings are equally common in subjects with traditional CAD risk factors without detectable CAD. Furthermore, the association of higher insulin and proinsulin levels with the likelihood of a patient having or not having CAD disappears after adjustment for BMI, suggesting that insulin and proinsulin are not independent risk markers but are primarily dependent on obesity.

To update estimates of the economic burden of undiagnosed diabetes, prediabetes, and gestational diabetes mellitus in 2012 in the U.S. and to present state-level estimates. Combined with published estimates for diagnosed diabetes, these statistics provide a detailed picture of the economic costs associated with elevated glucose levels.This study estimated health care use and medical expenditures in excess of expected levels occurring in the absence of diabetes or prediabetes. Data sources that were analyzed include Optum medical claims for ∼4.9 million commercially insured patients who were continuously enrolled from 2010 to 2012, Medicare Standard Analytical Files containing medical claims for ∼2.6 million Medicare patients in 2011, and the 2010 Nationwide Inpatient Sample containing ∼7.8 million hospital discharge records. The indirect economic burden includes reduced labor force participation, missed workdays, and reduced productivity. State-level estimates reflect geographic variation in prevalence, risk factors, and prices.The economic burden associated with diagnosed diabetes (all ages) and undiagnosed diabetes, gestational diabetes, and prediabetes (adults) exceeded $322 billion in 2012, consisting of $244 billion in excess medical costs and $78 billion in reduced productivity. Combined, this amounts to an economic burden exceeding $1,000 for each American in 2012. This national estimate is 48% higher than the $218 billion estimate for 2007. The burden per case averaged $10,970 for diagnosed diabetes, $5,800 for gestational diabetes, $4,030 for undiagnosed diabetes, and $510 for prediabetes.These statistics underscore the importance of finding ways to reduce the burden of prediabetes and diabetes through prevention and treatment.

Diabetes is the seventh leading cause of death in the U.S. and increases the risk of death twofold over age-matched individuals. Even these are conservative numbers, as diabetes has been found to be underreported on death certificates (1). These findings are even more remarkable for the recent decline seen in diabetes mortality rates due to improved management of cardiovascular risk factors (2). Despite remarkable advances in our understanding of the disease and pharmacological interventions for its treatment, diabetes remains the leading cause of renal failure, nontraumatic lower-limb amputation, and blindness in working-age adults. Improved therapeutics and health care delivery have brought remarkable declines in the incidence of both diabetic microvascular and macrovascular complications, with a 50% reduction in amputations from their peak in 1997 and ∼35% reduction in the incidence of end-stage renal disease (3). Similarly, 10-year coronary heart disease risk dropped from 21% in 2000 to 16% in 2008 (4). The observed decline in the event rates of complications and death due to diabetes is swamped by the increase in the number of individuals affected by the disease. The multiplier effect of a growing population with diabetes converts a declining incidence of complications into an increase in the total number of events observed. Among adults aged 18–79 years, the number of individuals with diagnosed diabetes in …

OBJECTIVE—To estimate the cost-effectiveness of screening overweight and obese individuals for pre-diabetes and then modifying their lifestyle based on the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS—A Markov simulation model was used to estimate disease progression, costs, and quality of life. Cost-effectiveness was evaluated from a health care system perspective. We considered two screening/treatment strategies for pre-diabetes. Strategy 1 included screening overweight subjects and giving them the lifestyle intervention included in the DPP if they were diagnosed with both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Strategy 2 included screening followed by lifestyle intervention for subjects diagnosed with either IGT or IFG or both. Each strategy was compared with a program of no screening. RESULTS—Screening for pre-diabetes and treating those identified as having both IGT and IFG with the DPP lifestyle intervention had a cost-effectiveness ratio of $8,181 per quality-adjusted life-year (QALY) relative to no screening. If treatment was also provided to subjects with only IGT or only IFG (strategy 2), the cost-effectiveness ratio increased to $9,511 per QALY. Changes in screening-related parameters had small effects on the cost-effectiveness ratios; the results were more sensitive to changes in intervention-related parameters. CONCLUSIONS—Screening for pre-diabetes in the overweight and obese U.S. population followed by the DPP lifestyle intervention has a relatively attractive cost-effectiveness ratio.

Individuals with diabetes are increasingly persuing employment in fields previously restricted as a result of the development of chronic complications. Improved glycemic control resulting from use of sophisticated insulin delivery and monitoring systems has also led to the recognition of recurrent hypoglycemia as a potential major clinical and occupational hazard. No data concerning the occupational safety of individuals with insulin-treated diabetes mellitus (ITDM) are available. We review the literature on diabetic drivers in an effort to examine the impact of certification of ITDMs as commercial drivers. In the absence of significant worldwide experience with ITDMs as commercial drivers, the discussion is necessarily based on projected accident rates derived from data on frequency of hypoglycemia. These studies are universally flawed by variable definitions of hypoglycemia, ascertainment bias, and patient selection. They do, however, provide a worst-case/best-case scenario for discussion. It is imperative that any expansion of employment opportunities for ITDMs be followed carefully with prospective studies to assess the impact on public safety.