Outcome Reduction With An Initial Glargine Intervention Research Articles

Developing Research for Five Subtypes of Diabetes with Specific Characteristics

Recently, sub-classifications for adult-onset diabetes have been presented based on cluster analysis. There are 5 exclusive subtypes, with clusters ranging from 1 to 5: severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), respectively. The related variables known include GAD antibody, age at diagnosis, BMI, HbA1c, and HOMA2-B and HOMA2-IR. From the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the numerical numbers of the 5 subtypes are 241-1594-914-1595-2673, respectively. The prevalence percentages for the 5 subtypes in 3 countries are as follows: Japan: 5.4-19.0-7.2-28.9-39.5, Germany: 22.0-3.0-11.0-29.0-35.0, and Finland: 9.9-8.9-11.2-22.8-47.3, respectively.

Sex hormone-binding globulin and heart failure hospitalizations in patients with dysglycemia - Experiences from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial

Abstract Background Sex hormone-binding globulin (SHBG), which binds most of the circulating testosterone in blood, is linked to both dysglycemia and a variety of cardiovascular (CV) events. However, few studies have investigated the link between SHBG and heart failure. Purpose To investigate the relationship between SHBG levels and heart failure hospitalizations in men and women with dysglycemia. Methods The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial followed individuals with dysglycemia (impaired fasting glucose, impaired glucose tolerance or diabetes) and high cardiovascular risk for a median of 6.2 years. Incident CV events, including heart failure hospitalizations (defined as heart failure requiring overnight stay at hospital or attendance in an acute care setting) were collected and adjudicated. A subset of patients (n = 8,494) in whom blood samples were stored had SHBG levels analysed. Cox regression was used to estimate hazard ratios (HRs) of heart failure hospitalizations per standard deviation increase of SHBG. Adjustments were made for age, comorbidities, biochemical data (including testosterone) and pharmacological treatment. Analyses were performed separately in men and women. Results A total of 5,553 men and 2,848 women were included in whom heart failure hospitalizations were reported in 349 men and 123 women. Median SHBG levels were 35 nmol/L (25-47) in men and 39 nmol/L (27-55) in women. The primary outcome was more frequent in men with SHBG levels above median (n = 208/349 [59.6 %]; p<0.01) whilst no difference was seen for women (n = 69/123 [56.1%]; p = 0.24). A higher SHBG was associated with increased risk of heart failure hospitalizations in men (adjusted HR 1.15, 95% CI 1.03-1.28; p = 0.011) but not in women (adjusted HR 1.13; 95% CI 0.96-1.39; p = 0.14). Conclusions In this biomarker substudy within the ORIGIN trial comprising patients with dysglycemia and at high CV risk, increasing levels of SHBG were associated with heart failure hospitalizations independent of testosterone levels in men but not in women.

Identifying blood biomarkers for type 2 diabetes subtyping: a report from the ORIGIN trial.

Individuals with diabetes can be clustered into five subtypes using up to six routinely measured clinical variables. We hypothesised that circulating protein levels might be used to distinguish between these subtypes. We recently used five of these six variables to categorise 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into these subtypes: severe autoimmune diabetes (SAID, n=241), severe insulin-deficient diabetes (SIDD, n=1594), severe insulin-resistant diabetes (SIRD, n=914), mild obesity-related diabetes (MOD, n=1595) and mild age-related diabetes (MARD, n=2673). Forward-selection logistic regression models were used to identify a subset of 233 cardiometabolic protein biomarkers that were independent determinants of one subtype vs the others. We then assessed the performance of adding identified biomarkers (one after one, from the most discriminant to the least) to predict each subtype vs the others using area under the receiver operating characteristic curve (AUC ROC). Models were adjusted for age, sex, ethnicity, C-peptide level, diabetes duration and glucose-lowering medication usage at blood collection. A total of 25 biomarkers were independent determinants of subtypes, including 13 for SIDD, 2 for SIRD, 7 for MOD and 11 for MARD (all p<4.3 × 10-5). The performance of the biomarker sets (comprising 1 to 25 biomarkers), assessed through the AUC ROC, ranged from 0.611 to 0.734, 0.723 to 0.861, 0.672 to 0.742, and 0.651 to 0.751, for SIDD, SIRD, MOD and MARD, respectively. No biomarkers other than GAD antibodies were determinants of SAID. We identified 25 serum biomarkers, as independent determinants of type 2 diabetes subtypes, that could be combined into a diagnostic test for subtyping. ORIGIN trial, ClinicalTrials.gov NCT00069784.

1102-P: Identifying Blood Biomarkers for Type 2 Diabetes Subtyping: A Report from the ORIGIN Trial

Diabetes (DM) can be classified into 5 subtypes characterized by distinct progression in dysglycaemia and complications. Using 5 clinical variables, we categorized 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into 1/auto-immune DM (n=241) , 2/insulin-deficient DM (n=1594) , 3/insulin-resistant DM (n=914) , 4/obesity-related DM (n=1595) , 5/age-related DM (n=2673) .Yet, whether blood biomarkers are associated with these subtypes is unknown. Forward-selection logistic regression models were used to identify biomarkers that were each independent determinant of one cluster versus the others, among 233 selected cardiometabolic proteins measured at baseline. Models were adjusted for age, sex, ethnicity, C-peptide level, diabetes duration. A total of 13, 2, 7 and biomarkers were independent determinants of DM subtypes 2 to 5 respectively (all P&amp;lt;4.3x10-5) . A combination of 5 biomarkers that were distinctively associated with clusters (fig) , showed a diagnosis performance, through AUC-ROC curves, of 0.71, 0.86, 0.88, 0.82 to respectively distinguish cluster 2 to 5 from the others. No biomarkers other than GAD antibodies were determinants of cluster 1. We identified 5 serum biomarkers, as independent determinants of DM subtypes, that could be used as a diagnosis test for DM subtyping. Although this requires further validation in an independent population. Disclosure M.Pigeyre: n/a. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. L.Groop: None. S.Hess: Employee; Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. Funding NCT00069784 Canadian Institute of Health Research Sanofi

Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia: Data from the ORIGIN Trial

Background: Diabetes and cardiovascular disease increase the risk of incident cognitive dysfunction. Identification of novel biochemical markers for cognitive dysfunction may identify people at the highest risk while yielding insights regarding the pathophysiology of cognitive dysfunction. Objective: To identify cardiovascular biomarkers in serum that are independent predictors of cognitive dysfunction in individuals with dysglycemia. Methods: This analysis was conducted in 8,365 participants in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial whose stored serum was analyzed for 238 cardio-metabolic biomarkers and completed a baseline Mini-Mental State Examination (MMSE). Fine and Gray sub distribution hazard models accounting for the competing risk of death accounting for clinical risk factors and the baseline MMSE were used to identify biomarkers that predicted incident cognitive dysfunction (MMSE &lt; 24 or dementia) using forward selection with an inclusion p-value &lt; 0.0002 to account for multiplicity. Results: During a median follow-up period of 6.2 years, 939 individuals developed cognitive dysfunction. After accounting for 17 clinical risk factors, glargine allocation, and the baseline MMSE, three biomarkers (α-2 Macroglobulin, HR 1.19; 95% CI 1.12, 1.27; Macrophage Inflammatory Protein 1α, HR 1.11; 95% CI 1.06, 1.16; and Growth Hormone, HR 0.91; 95% CI 0.87, 0.96) independently predicted incident cognitive dysfunction (p &lt; 0.0002). Addition of these biomarkers to a model that included clinical risk factors, however, did not improve the ability to predict cognitive dysfunction. Conclusion: Addition of independent biomarkers to clinical risk factors for cognitive dysfunction in people with dysglycemia did not predict incident cognitive dysfunction better than clinical risk factors alone.

Optimal Dose of n-3 Polyunsaturated Fatty Acids for Cardiovascular Event Prevention.

Background: The n-3 polyunsaturated fatty acids (PUFA), represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid, have anti-atherogenic effects (e.g., neutral fat-lowering effects) and other beneficial effects such as antiplatelet, anti-inflammatory, plaque stabilizing, vascular endothelial function ameliorative, antihypertensive, and anti-arrhythmic effects. Epidemiological studies and clinical trials have assessed the inhibitory effects of n-3 PUFA on cardiovascular events.Methods and Results: Studies that reported positive outcomes, such as the Japan EPA Lipid intervention Study (JELIS) and the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT), noted a tendency toward the use of high-dose n-3 PUFA (1.8–4 g/day). The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione (GISSI-Prevenzione) trial and the JELIS had high EPA/arachidonic acid (AA) baseline ratios. In contrast, negative outcome studies, such as the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, Risk and Prevention study, A Study of Cardiovascular Events in Diabetes (ASCEND), and the Vitamin D and Omega-3 Trial (VITAL) had participants who tended to use low-dose n-3 PUFA (0.84–1 g/day) and to have low baseline EPA/AA.Conclusions: Differences in baseline EPA/AA ratio and the EPA/AA ratio threshold for the prevention of cardiovascular events seem to contribute to the different outcomes, together with the dose of n-3 PUFA.

Effects of basal insulin glargine and omega-3 on lower limb arterial disease outcome in patients with dysglycaemia: An analysis of the Outcome Reduction with an Initial Glargine INtervention (ORIGIN) trial.

The impact of insulin or omega-3 supplements on the incidence and progression of peripheral artery disease (PAD) in patients with dysglycaemia has not been well studied. The Outcome Reduction with an Initial Glargine INtervention (ORIGIN) trial randomized participants with dysglycaemia and cardiovascular risk factors to titrated insulin glargine vs standard care, and to either 1 g of omega-3 per day or placebo. We assessed incident PAD, defined as the composite of either asymptomatic or symptomatic PAD according to the randomized interventions in the 11 119 ORIGIN participants whose baseline ankle-brachial index (ABI) was >0.9 (no PAD), and PAD progression in the 971 ORIGIN participants whose baseline ABI was ≤0.9. Hazard ratios (HR) were adjusted for confounders. During a 6.2-year follow-up period, allocation to insulin glargine vs standard care had a neutral effect on the composite of PAD incidence (HR, 0.99; 95% CI, 0.86-1.15) and progression (HR, 0.88; 95% CI, 0.63-1.22). Similar findings were noted for allocation to omega-3 vs placebo for PAD incidence (HR, 1.02; 95% CI, 0.89-1.18) and progression (HR, 0.93; 95% CI, 0.67-1.28). In this large study, neither insulin glargine nor omega-3 affected the incidence or progression of PAD.

Testosterone, sex hormone-binding globulin and risk of cardiovascular events: A report from the Outcome Reduction with an Initial Glargine Intervention trial.

Testosterone and its binding protein sex hormone-binding globulin have been associated with cardiovascular disease and dysglycaemia. However, information on the prognostic implication in patients at high cardiovascular risk with dysglycaemia is inconsistent. The study objective was to determine whether testosterone and/or sex hormone-binding globulin predict cardiovascular events or death in dysglycaemic patients. Dysglycaemic males at high cardiovascular risk ( n = 5553) who participated in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial and provided baseline blood samples were studied. Testosterone and sex hormone-binding globulin were measured at baseline and used to estimate free testosterone. Low levels of total and free testosterone were defined as ≤300 ng/dl and ≤7 ng/dl, respectively. Patients were followed for six years for cardiovascular events (defined as the composite of cardiovascular death, non-fatal myocardial infarction or stroke) and all-cause mortality. The mean total and free testosterone levels were 416.6 ng/dl and 8.4 ng/dl, and low levels were present in 13% and 37% of the patients. The median sex hormone-binding globulin level was 35 nmol/l. In Cox regression models adjusted for age, previous diseases and pharmacological treatment, neither total nor free testosterone predicted cardiovascular events. However, a one-standard-deviation increase in sex hormone-binding globulin predicted both cardiovascular events (hazard ratio 1.07; 95% confidence interval 1.00-1.14; p = 0.03) and all-cause mortality (hazard ratio 1.13; 95% confidence interval 1.06-1.21; p < 0.01). Sex hormone-binding globulin, but not total testosterone, predicts cardiovascular disease and all-cause mortality in dysglycaemic males at high cardiovascular risk.

Insulin resistance and cardiovascular outcomes in the ORIGIN trial.

In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (Clinicaltrials.gov: NCT000069784), titrated doses of basal insulin glargine targeting fasting normoglycaemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycaemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes. Self-titration of insulin doses targeting a fasting plasma glucose ≤5.3 mmoL/L (95 mg/dL) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose-lowering oral agent at randomization. Normoglycaemia was defined as a fasting plasma glucose <5.6 mmol/L and HbA1c <6% at the 2-year visit. The median of the natural logarithm of insulin doses (expressed per kg of fat-free mass), recorded at every visit from randomization until either the penultimate visit or the first occurrence of a cardiovascular outcome, was analysed. Higher median insulin doses did not reflect incident cardiovascular events overall or in the subset that achieved normoglycaemia. When the dose taken before a cardiovascular event or the penultimate visit was analysed, the adjusted hazard of the composite of cardiovascular death, myocardial infarction or stroke was 0.94 (95% CI 0.88, 1.00) per unit higher dose overall, and 0.91 (95% CI 0.81, 1.01) in the normoglycaemic subset. Insulin resistance may not promote cardiovascular outcomes in individuals with dysglycaemia.

Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study

BackgroundEarly stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type 2 diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared with standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) or moderate chronic kidney disease (Stage 3). MethodsΤwo co-primary composite cardiovascular outcomes were assessed. The first was the composite end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were prespecified, including microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers. ResultsComplete renal function data were available in 12,174 of 12,537 ORIGIN participants. A total of 8114 (67%) had no chronic kidney disease, while 4060 (33%) had chronic kidney disease stage 1-3. When compared with nonchronic kidney disease participants, the risk of developing the composite primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in those with mild to moderate chronic kidney disease was 87% higher; hazard ratio (HR) 1.87; 95% confidence interval (CI), 1.71-2.04 (P < .0001). The presence of chronic kidney disease 1-3 was also associated with a greater than twofold higher risk for both all-cause mortality (HR 2.17; 95% CI, 1.98-2.38; P < .0001) and cardiovascular mortality (HR 2.39; 95% CI, 2.13-2.69; P < .0001). Moreover, patients with mild to moderate chronic kidney disease had significantly higher risk for nonfatal myocardial infarction (50%), nonfatal stroke (68%), any stroke (84%), the above composite primary end point plus revascularization or heart failure requiring hospitalization (59%), or a major coronary artery disease event (56%). Furthermore, in patients with chronic kidney disease and early diabetes mellitus type 2, the primary end point occurred 83% more frequently as compared with nonchronic kidney disease participants (HR 1.83; 95% CI, 1.67-2.01; P < .001) and in patients with prediabetes and chronic kidney disease 67% more frequently (HR 1.67; 95% CI,1.25-2.24; P < .001). ConclusionsIn high-risk patients with dysglycemia (prediabetes and early diabetes), mild and moderate chronic kidney disease significantly increased cardiovascular events.

Early Treatment with Basal Insulin Glargine in People with Type 2 Diabetes: Lessons from ORIGIN and Other Cardiovascular Trials.

Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing β cells to chronic hyperglycemia and excessive glycemic variability. Initiation of intensive insulin therapy at diagnosis of type 2 diabetes mellitus (T2DM) to achieve normoglycemia has been shown to reverse glucotoxicity, resulting in recovery of residual β-cell function. The United Kingdom Prospective Diabetes Study (UKPDS) 10-year post-trial follow-up reported reductions in cardiovascular outcomes and all-cause mortality in persons with T2DM who initially received intensive glucose control compared with standard therapy. In the cardiovascular outcome trial, outcome reduction with an initial glargine intervention (ORIGIN), a neutral effect on cardiovascular disease was observed in the population comprising prediabetes and T2DM. Worsening of glycemic control was prevented over the 6.7 year treatment period, with few serious hypoglycemic episodes and only moderate weight gain, with a lesser need for dual or triple oral treatment versus standard care. Several other studies have also highlighted the benefits of early insulin initiation as first-line or add-on therapy to metformin. The decision to introduce basal insulin to metformin must, however be individualized based on a risk–benefit analysis. The landmark ORIGIN trial provides many lessons relating to the concept and application of early insulin therapy for the prevention and safe and effective induction and maintenance of glycemic control in type 2 diabetes. Funding: Sanofi.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0153-3) contains supplementary material, which is available to authorized users.

New Medications for the Treatment of Diabetes

New Medications for the Treatment of Diabetes

Glycemia Lowering and Risk for Heart Failure: Recent Evidence from Studies of Dipeptidyl Peptidase Inhibition.

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

Heart failure in SAVOR-TIMI 53: The hindsight of diabetic retinopathy.

Heart failure in SAVOR-TIMI 53: The hindsight of diabetic retinopathy.

Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial.

Hypoglycemia is a leading risk of glucose-lowering therapy. Treatment with insulin glargine compared with standard care early in the course of dysglycemia in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial provides information on the frequency and predictors of hypoglycemia in this setting. A total of 12,537 people with high cardiovascular risk and dysglycemia treated with one or no oral glucose-lowering agents were randomized to add glargine titrated to a fasting glucose level of ≤5.3 mmol/L (≤95 mg/dL) or to use standard therapies. Independent associations of both nonsevere hypoglycemia (symptomatic and confirmed with a glucose level of ≤3 mmol/L [≤54 mg/dL]) and severe hypoglycemia with characteristics at baseline, treatment allocation, and average HbA1c were assessed by Cox proportional hazards models. During a median follow-up period of 6.2 years, 28% of participants reported nonsevere hypoglycemia, and 3.8% reported severe hypoglycemia. Prior use of a sulfonylurea and allocation to glargine independently predicted a higher risk for both categories of participants. Nonsevere events were independently associated with younger age, lower BMI, the presence of diabetes, and higher baseline HbA1c level. Severe events were associated with older age, hypertension, higher serum creatinine level, and lower cognitive function, but not baseline glycemic status. Progressively higher on-treatment HbA1c level was associated with a lower risk of nonsevere events in both treatment groups; a lower risk of severe events in the glargine group, and a higher risk of severe events with standard care. Hypoglycemia was relatively uncommon in the ORIGIN trial, but was more frequent with sulfonylurea use at baseline and allocation to glargine. Nonsevere and severe events were associated with different clinical characteristics, awareness of which may guide individualized therapy.

Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial.

As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA1c level is close to normal. The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level ≤5.3mmol/l. Microvascular outcomes during a median follow-up of 6.2years were examined in participants whose baseline HbA1c was above or below the median of 6.4% (46.4mmol/mol). Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA1c level was ≥6.4% (46.4mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA1c level was ≥6.4% (46.4mmol/mol), the median post-randomisation change in HbA1c was -0.65% (interquartile range -0.16, -0.91%) after allocation to insulin glargine and -0.33% (-0.83, 0.13%) after allocation to standard care (median HbA1c difference 0.33%; p < 0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA1c was <6.4% (p < 0.0001). In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA1c level ≥6.4% (46.4mmol/mol). A neutral effect was seen in those with a lower baseline HbA1c level. ClinicalTrials.gov NCT00069784.

Self-monitoring of blood glucose: a prerequisite for diabetes management in outcome trials.

Evidence for the value of self-monitoring of blood glucose (SMBG) with regard to the achievement of treatment targets, detection of postprandial glucose excursions, and minimization of glycemic variability is increasing. In large clinical trials, SMBG is a key component for the optimization of diabetes treatment in insulin-treated diabetes. It also plays an essential role in outcome studies. However, details of SMBG use in both the methods and results sections of clinical articles are frequently scarce. Also, a discussion of the SMBG data and its impact on insulin therapy is valuable. In the recently completed Outcome Reduction with an Initial Glargine INtervention (ORIGIN) trial, SMBG was described in detail and insulin titration was largely driven by SMBG. Both aspects largely contributed to the fact that near-normal control was achieved over a long-term period.

Cost implications of the use of basal insulin glargine in people with early dysglycemia: The ORIGIN trial

AimsThe cost implications of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial were evaluated using a prespecified analysis plan. MethodsPurchasing power parity-adjusted country-specific costs were applied to consumed healthcare resources by participants from each country. Subgroup analyses were conducted on subgroups based on baseline metabolic status and diabetes duration. ResultsThe total undiscounted cost per participant in the insulin glargine arm was $13,491 ($13,080 to $14,254) versus $11,189 ($10,568 to $12,147) for standard care, an increase of $2303 ($1370 to $3235; p<0.0001); the discounted increase was $2099 ($1276 to $2923; P<0.0001). The greater number of mainly generic oral anti-diabetic agents in the standard group partially offset the higher cost of basal insulin glargine. As the trial progressed and the standard group required more anti-diabetic medications, the annual cost difference decreased, reaching $68 (−$160 to $295) in the last year. The subgroup whose baseline diabetes duration was≥6years achieved cost-savings during the trial. ConclusionsFrom a global perspective basal insulin glargine use in ORIGIN incurred greater costs than standard care using older generic drugs. Nevertheless, the cost difference fell with time such that the intervention was cost-neutral by the last year.

Change of heart: Mixed evidence on omega-3 FAs

In 2010, Americans spent more than $1 billion on nonprescription fish oil products. These dietary supplements remain the most commonly used natural products. Fish oil can be used as a source of long chain omega-3 polyunsaturated fatty acids (FAs), but data for their cardiovascular benefits are conflicting. Omega-3 FAs may have antiplatelet activity and may lower triglyceride concentrations and decrease the risk of arrhythmias. In the past 12 months, clinical trials, observational studies, and a meta-analysis have evaluated the potential value of omega-3 FAs on cardiovascular outcomes and all-cause mortality, with varying results. In July 2012, results from the Outcome Reduction With an Initial Glargine Intervention (ORIGIN) study were published.1.ORIGIN trial investigatorsn-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.N Engl J Med. 2012; 367: 309-318Crossref PubMed Scopus (648) Google Scholar The study evaluated the potential benefits of long-term use of omega-3 FA 1 g/d in patients with type 2 diabetes or at high risk of developing diabetes. Researchers followed more than 12,000 patients for 6 years. Between 50% and 70% of participants were taking statins, antiplatelet agents, beta blockers, and ACE inhibitors or angiotensin-receptor blockers. The study's primary outcome, death from cardiovascular causes, was not reduced by omega-3 FA, despite a 14.5 mg/dL decrease in triglyceride concentrations. The negative results may have been due to patients already being on optimal therapy, an inadequate dosage of omega-3 FA, or patients not at high enough cardiovascular risk.■Patients seeking omega-3 fatty acid supplementation are best served by adding fish to their diet.■For effective primary and secondary prevention of cardiovascular disease, patients should focus on reducing risk factors. ■Patients seeking omega-3 fatty acid supplementation are best served by adding fish to their diet.■For effective primary and secondary prevention of cardiovascular disease, patients should focus on reducing risk factors. In September 2012, a group of researchers conducted a meta-analysis of omega-3 FA studies including 20 randomized clinical trials involving almost 70,000 people.2.Rizos E.C. Ntzani E.E. Bika E. et al.Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.JAMA. 2012; 308: 1024-1033Crossref PubMed Scopus (810) Google Scholar The studies included primary or second prevention trials of at least 1 year in duration and assessed the effects of omega-3 FA through either diet or supplements on all-cause mortality, sudden death, myocardial infarction (MI), or stroke. Two-thirds of studies were secondary prevention, and the mean dosage of omega-3 FA was 1.51 g/d. Overall, the meta-analysis identified no benefits from omega-3 FA. In April 2013, researchers published data from the Cardiovascular Health Study.3.Mozaffarian D. Lemaitre R.N. King I.B. et al.Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.Ann Intern Med. 2013; 158: 515-525Crossref PubMed Scopus (214) Google Scholar Unlike most other studies, in which participants eat a diet supplemented with omega-3 FA or use dietary supplements, this study's investigators used measurements of plasma concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid from almost 2,700 adults 74 years and older without documented cardiovascular disease. Their analysis also incorporated assessments of cardiovascular risk factors first measured in 1992 and data on outcomes collected until 2008. The researchers found that individuals with the highest concentrations of omega-3 FA were associated with a 27% reduction in risk of all-cause death. The decrease was due primarily to a reduced risk of cardiovascular death—specifically, death due to arrhythmias. DHA concentrations had the strongest inverse association with arrhythmic deaths, and EPA levels were inversely correlated with risk of nonfatal MI. The ingestion of fish oil and omega-3 FA supplements has increased dramatically in the past 24 years since the first reports of their benefits. The original studies demonstrating large benefits predated the current widespread use of statins, however. Newer studies have yielded contradictory data due to different designs and populations (primary vs. secondary prevention), concomitant use of drugs, self-reports of dietary omega-3 FA ingestion, and variable dosages and quality of some fish oil products. Encourage patients interested in omega-3 FA supplementation to substitute fish such as salmon or sea trout, in appropriately sized portions, for red meat once or twice a week. For secondary prevention of cardiovascular disease, omega-3 FA supplements likely have little additional benefit when combined with optimal therapies, including statins and ACE inhibitors. For primary prevention, especially in older patients, omega-3 FA supplementation may offer some benefits, although evidence remains conflicting. As always, patients interested in effective primary and secondary prevention should focus on reducing cardiovascular risk factors, especially smoking cessation.

Placing the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial in context

The results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial were presented at the American Diabetes Association meeting in June 2012. The purpose of this study was to assess whether there would be any reduction in cardiovascular (CV) events if insulin glargine was started early in the course of diabetes. Therefore, the selected patients were those who were at high risk of CV events, but with impaired fasting glucose, impaired glucose tolerance or recent onset of type 2 diabetes. After 6.5 years, no differences were seen in primary outcomes, namely CV death, myocardial infarction, stroke, revascularisation procedures or hospitalisation for heart failure. However, the early institution of insulin therapy using glargine was found to be an effective means of maintaining glycaemic control in this patient group. As expected, patients on glargine insulin experienced slightly increased rates of both non-severe and severe hypoglycaemia, and slight weight gain. Neither of these problems was considered to be a limiting factor in the early use of glargine insulin. A second arm of the study was designed to assess the role of omega-3 fatty acids in the prevention of CV events. The results of this arm showed no benefit and do not support the use of omega-3 fatty acids as prophylactic therapy in these patients. While the ORIGIN trial is unlikely to alter clinical practice regarding the treatment of either dysglycaemia or new-onset diabetes, it has demonstrated that glargine insulin is relatively safe when used early in diabetes and can maintain near-normal glycaemic control for over six years, without increased cancer risk and with a neutral effect on CV outcomes.