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    Cardiovascular events and all-cause mortality with insulin versus glucagon-like peptide-1 analogue in type 2 diabetes. Anyanwagu Uchenna,Mamza Jil,Mehta Rajnikant,Donnelly Richard,Idris Iskandar Heart (British Cardiac Society) OBJECTIVES:To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU). METHODS:A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed. RESULTS:Mean age was 52.8±14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p<0.0001). Insulin was associated with significant increase in weight compared with GLP-1ar (1.78 vs -3.93 kg; p<0.0001) but haemoglobin A1c reduction was similar between both treatment groups (-1.29 vs -0.98; p=0.156). In a subgroup analysis of obese patients (body mass index >30 kg/m(2)) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively. CONCLUSIONS:In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent. 10.1136/heartjnl-2015-309164
    Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. Robinson Louise E,Holt Tim A,Rees Karen,Randeva Harpal S,O'Hare Joseph P BMJ open OBJECTIVES:To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight. DESIGN:Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active antidiabetic drug therapy or lifestyle intervention. PARTICIPANTS:Patients with type 2 diabetes. OUTCOME MEASURES:Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up. RESULTS:32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by -1.79 mm Hg (-2.94 to -0.64) and -2.39 mm Hg (-3.35 to -1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (-0.54 mm Hg (-1.15 to 0.07) vs placebo and -0.50 mm Hg (-1.24 to 0.24) vs active control). Body weight decreased by -3.31 kg (-4.05 to -2.57) compared to active control, but by only -1.22 kg (-1.51 to -0.93) compared to placebo. CONCLUSIONS:GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation. 10.1136/bmjopen-2012-001986
    Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Monami Matteo,Dicembrini Ilaria,Marchionni Niccolò,Rotella Carlo M,Mannucci Edoardo Experimental diabetes research Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for "exenatide," "liraglutide," "albiglutide," "semaglutide," and "lixisenatide" was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of -1.0 [-1.3; -0.6] kg/m(2). Considering the average BMI at baseline (32.4 kg/m(2)) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction. 10.1155/2012/672658
    Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. Baggio Laurie L,Drucker Daniel J The Journal of clinical investigation The peptide hormone glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and inhibits both gastric emptying and glucagon secretion. GLP-1 receptor (GLP-1R) agonists control glycemia via glucose-dependent mechanisms of action and promote weight loss in obese and diabetic individuals. Nevertheless, the mechanisms and cellular targets transducing the weight loss effects remain unclear. Two recent studies in the JCI provide insight into the neurons responsible for this effect. Sisley et al. reveal that GLP-1R agonist-induced weight loss requires GLP-1Rs in the CNS, while Secher et al. reveal that a small peptide GLP-1R agonist penetrates the brain and activates a subset of GLP-1R-expressing neurons in the arcuate nucleus to produce weight loss. Together, these two studies elucidate pathways that inform strategies coupling GLP-1R signaling to control of body weight in patients with diabetes or obesity. 10.1172/JCI78371
    Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: A meta-analysis. Song Xiaoyan,Jia Hetang,Jiang Yuebo,Wang Liang,Zhang Yan,Mu Yiming,Liu Yu Scientific reports This study assessed the effect of GLP-1 based therapies on atherosclerotic markers in type 2 diabetes patients. 31 studies were selected to obtain data after multiple database searches and following inclusion and exclusion criteria. Age and BMI of the participants of longitudinal studies were 59.8 ± 8.3 years and 29.2 ± 5.7 kg/m(2) (Mean±SD). Average duration of GLP-1 based therapies was 20.5 weeks. Percent flow-mediated diameter (%FMD) did not change from baseline significantly but when compared to controls, %FMD increased non-significantly following GLP-1-based therapies (1.65 [-0.89, 4.18]; P = 0.2; REM) in longitudinal studies and increased significantly in cross sectional studies (2.58 [1.68, 3.53]; P < 0.00001). Intima media thickness decreased statistically non-significantly by the GLP-1 based therapies. GLP-1 based therapies led to statistically significant reductions in the serum levels of brain natriuretic peptide (-40.16 [-51.50, -28.81]; P < 0.0001; REM), high sensitivity c-reactive protein (-0.27 [-0.48, -0.07]; P = 0.009), plasminogen activator inhibitor-1 (-12.90 [-25.98, 0.18]; P=0.05), total cholesterol (-5.47 [-9.55, -1.39]; P = 0.009), LDL-cholesterol (-3.70 [-7.39, -0.00]; P = 0.05) and triglycerides (-16.44 [-25.64, -7.23]; P = 0.0005) when mean differences with 95% CI in the changes from baselines were meta-analyzed. In conclusion, GLP-1-based therapies appear to provide beneficial effects against atherosclerosis. More randomized data will be required to arrive at conclusive evidence. 10.1038/srep10202
    Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Kapitza C,Forst T,Coester H-V,Poitiers F,Ruus P,Hincelin-Méry A Diabetes, obesity & metabolism AIM:Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS:In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS:Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS:Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide. 10.1111/dom.12076
    Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial. Meier Juris J,Rosenstock Julio,Hincelin-Méry Agnès,Roy-Duval Christine,Delfolie Astrid,Coester Hans-Veit,Menge Bjoern A,Forst Thomas,Kapitza Christoph Diabetes care OBJECTIVE:This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS:This was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG0030-0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed. RESULTS:In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG0030-0430 h compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, -6.0 [-7.8] h ⋅ mmol/L [-108.3 (-140.0) h ⋅ mg/dL] vs. liraglutide 1.2 mg and -4.6 [-6.3] h ⋅ mmol/L [-83.0 (-114.2) h ⋅ mg/dL] vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean ± SD HbA1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide (P < 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean ± SE increase 21 ± 7 IU/L for both; P < 0.05). CONCLUSIONS:Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles. 10.2337/dc14-1984
    Assessing the quality of reports of randomized clinical trials: is blinding necessary? Jadad A R,Moore R A,Carroll D,Jenkinson C,Reynolds D J,Gavaghan D J,McQuay H J Controlled clinical trials It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process. There is very little evidence in the literature to substantiate this. This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality. A multidisciplinary panel of six judges produced an initial version of the instrument. Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples. Seven were allocated randomly to perform the assessments under blind conditions. The final version of the instrument included three items. These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples. Blind assessments produced significantly lower and more consistent scores than open assessments. The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed. 10.1016/0197-2456(95)00134-4
    One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress. Bunck Mathijs C,Cornér Anja,Eliasson Bjorn,Heine Robert J,Shaginian Rimma M,Wu Yan,Yan Ping,Smith Ulf,Yki-Järvinen Hannele,Diamant Michaela,Taskinen Marja-Riitta Atherosclerosis OBJECTIVE:The objective of the present study was to investigate the effects of one-year treatment with exenatide or Insulin Glargine, followed by a 5-week off-drug period, on postprandial lipidaemia, glycaemia and measures of oxidative stress. METHODS:Sixty-nine metformin-treated patients with type 2 diabetes were randomised (using apermuted block randomisation scheme stratified by site and baseline HbA(1c) stratum (< or = 8.5% or >8.5%) of which 60 completed (exenatide n=30; Insulin Glargine n=30) the pre-treatment and on-drug meal test. Postprandial glucose, lipids and lipoproteins, and oxidative stress markers were studied at week -1, 51, and after a 5-week off-drug period following a breakfast and lunch mixed-meal containing 50 g fat, 75 g carbohydrates, and 35 g protein. RESULTS:51-Week exenatide treatment resulted in a significant reduction of prandial glucose, triglycerides, apo-B48, calculated VLDL-C, FFA and MDA excursions whereas Insulin Glargine predominantly reduced fasting glucose, FFA and MDA. Changes in markers of oxidative stress were related to changes in postprandial glucose and triglyceride excursions, independent of treatment arm. All postprandial measures returned to pre-treatment values in both groups after 5-week cessation of study treatment. CONCLUSION:Exenatide showed beneficial effects on postprandial glycaemia and lipidaemia, and these effects were related to changes in the oxidative stress markers MDA and oxLDL during one year of treatment as compared to Insulin Glargine. Following cessation of both exenatide and Insulin Glargine measures returned to pre-treatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy. 10.1016/j.atherosclerosis.2010.04.024
    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Moher David,Liberati Alessandro,Tetzlaff Jennifer,Altman Douglas G, BMJ (Clinical research ed.) 10.1136/bmj.b2535
    Efficacy and safety of once-weekly dulaglutide in combination with sulphonylurea and/or biguanide compared with once-daily insulin glargine in Japanese patients with type 2 diabetes: a randomized, open-label, phase III, non-inferiority study. Araki E,Inagaki N,Tanizawa Y,Oura T,Takeuchi M,Imaoka T Diabetes, obesity & metabolism AIMS:To evaluate 0.75 mg of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, compared with once-daily insulin glargine for glycaemic control in Japanese patients with type 2 diabetes (T2D). METHODS:In this phase III, randomized, open-label, parallel-group, 26-week study, 361 patients with inadequately controlled T2D receiving sulphonylureas and/or biguanides, aged ≥20 years, with glycated haemoglobin (HbA1c) levels 7.0-10.0% (53-86 mmol/mol), inclusive, were randomized (1 : 1) to receive dulaglutide or glargine. Participants and investigators were not masked to treatment allocation. The primary measure was change from baseline in HbA1c at 26 weeks, analysed using a mixed-effects model for repeated measures, with a predefined non-inferiority margin of 0.4%. RESULTS:At week 26, least-squares (LS) mean (standard error) reductions in HbA1c were -1.44 (0.05)% [-15.74 (0.55) mmol/mol] in the dulaglutide group and -0.90 (0.05)% [-9.84 (0.55) mmol/mol] in the glargine group. The mean between-group treatment difference in HbA1c was -0.54% (95% CI -0.67, -0.41) [-5.90 mmol/mol (95% CI -7.32, -4.48)]; p < 0.001. Dulaglutide significantly reduced body weight compared with glargine at week 26 (LS mean difference -1.42 kg, 95% CI -1.89, -0.94; p < 0.001). The most frequent adverse events with dulaglutide treatment were nasopharyngitis and gastrointestinal symptoms. The incidence of hypoglycaemia was significantly lower with dulaglutide [47/181 (26%)] compared with glargine [86/180 (48%)], p < 0.001. CONCLUSION:In Japanese patients with T2D uncontrolled on sulphonylureas and/or biguanides, once-weekly dulaglutide was superior to once-daily glargine for reduction in HbA1c at 26 weeks. Although dulaglutide increased gastrointestinal symptoms, it was well tolerated, with an acceptable safety profile. 10.1111/dom.12540
    One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Gough S C L,Bode B W,Woo V C,Rodbard H W,Linjawi S,Zacho M,Reiter P D,Buse J B Diabetes, obesity & metabolism AIMS:To confirm, in a 26-week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. METHODS:Insulin-naïve adults with type 2 diabetes randomized to once-daily IDegLira, insulin degludec or liraglutide, in addition to metformin ± pioglitazone, continued their allocated treatment in this preplanned 26-week extension of the DUAL I trial. RESULTS:A total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52 weeks was reduced from baseline by 1.84% (20.2 mmol/mol) for the IDegLira group, 1.40% (15.3 mmol/mol) for the insulin degludec group and 1.21% (13.2 mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53 mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7 mmol/l) and insulin degludec (6.0 mmol/l), but higher for liraglutide (7.3 mmol/l). At 52 weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, -2.80 kg, p < 0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira. CONCLUSIONS:These 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability. 10.1111/dom.12498
    HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Weissman Peter N,Carr Molly C,Ye June,Cirkel Deborah T,Stewart Murray,Perry Caroline,Pratley Richard Diabetologia AIMS/HYPOTHESIS:The aim of this study was to compare the efficacy and safety of once-weekly albiglutide with once-daily insulin glargine (A21Gly,B31Arg,B32Arg human insulin) in patients with type 2 diabetes inadequately controlled on metformin with or without sulfonylurea. METHODS:This was a randomised, open-label, multicentre (n = 222), parallel-group, non-inferiority out-patient clinical trial, with 779 patients enrolled in the study. The study was conducted in 222 centres located in four countries. Patients aged ≥18 years with type 2 diabetes treated with metformin (±sulfonylurea) for at least 3 months with a baseline HbA1c 7.0-10.0% (53.0-85.8 mmol/mol) were randomly assigned (2:1) via a computer-generated randomisation sequence with a voice response system to receive albiglutide (30 mg once a week, n = 504) or insulin glargine (10 U once a day, n = 241) added to current therapy. Participants and investigators were not masked to treatment assignment. Doses of each medication were adjusted on the basis of the glycaemic response. The primary endpoint was change from baseline in HbA1c at week 52. RESULTS:In the albiglutide group, HbA1c declined from 8.28 ± 0.90% (67.0 ± 9.8 mmol/mol) (mean ± SD) at baseline to 7.62 ± 1.12% (59.8 ± 12.2 mmol/mol) at week 52. A similar reduction occurred in the insulin glargine group (8.36 ± 0.95% to 7.55 ± 1.04% [67.9 ± 10.4 to 59.0 ± 11.4 mmol/mol]). The model-adjusted treatment difference of 0.11% (95% CI -0.04%, 0.27%) (1.2 mmol/mol [95% CI -0.4, 3.0 mmol/mol]) indicated non-inferiority of albiglutide to insulin glargine based on the pre-specified non-inferiority margin of 0.3% (3.3 mmol/mol, p = 0.0086). Body weight increased in the insulin glargine group and decreased in the albiglutide group, with a mean treatment difference of -2.61 kg (95% CI -3.20, -2.02; p < 0.0001). Documented symptomatic hypoglycaemia occurred in a higher proportion of patients in the insulin glargine group than in the albiglutide group (27.4% vs 17.5%, p = 0.0377). CONCLUSIONS/INTERPRETATION:Albiglutide was non-inferior to insulin glargine at reducing HbA1c at week 52, with modest weight loss and less hypoglycaemia. Both drugs were well tolerated. Albiglutide may be considered an alternative to insulin glargine in this patient population. TRIAL REGISTRATION:ClinicalTrials.gov NCT00838916 (completed) FUNDING:This study was planned and conducted by GlaxoSmithKline. 10.1007/s00125-014-3360-3
    Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The Barcelona case-control study. Simó Rafael,Plana-Ripoll Oleguer,Puente Diana,Morros Rosa,Mundet Xavier,Vilca Luz M,Hernández Cristina,Fuentes Inmaculada,Procupet Adriana,Tabernero Josep M,Violán Concepción PloS one BACKGROUND:The aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population. METHODS:A nested case-control study was conducted within a defined cohort (275,164 type 2 diabetic patients attending 16 Primary Health Care Centers of Barcelona). Cases (n = 1,040) comprised those subjects with any cancer diagnosed between 2008 and 2010, registered at the Cancer Registry of Hospital Vall d'Hebron (Barcelona). Three control subjects for each case (n = 3,120) were matched by age, sex, diabetes duration, and geographical area. The treatments analyzed (within 3 years prior to cancer diagnosis) were: insulin glargine, insulin detemir, human insulin, fast-acting insulin and analogues, metformin, sulfonylureas, repaglinide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and alpha glucosidase inhibitors. Conditional logistic regressions were used to calculate the risk of cancer associated with the use of each drug adjusted by age, BMI, dose and duration of treatment, alcohol use, smoking habit, and diabetes duration. RESULTS:No differences were observed between case and control subjects for the proportion, dose or duration of exposure to each treatment. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin. CONCLUSIONS:Our results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population. 10.1371/journal.pone.0079968
    Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study. Inagaki Nobuya,Atsumi Yoshihito,Oura Tomonori,Saito Hitoshi,Imaoka Takeshi Clinical therapeutics BACKGROUND:Exenatide once weekly (QW) is an extended-release formulation of exenatide, a glucagon-like peptide-1 receptor agonist that reportedly improves glycemic control in patients with type 2 diabetes. OBJECTIVE:The goal of this study was to test the hypothesis that exenatide QW is noninferior to insulin glargine, as measured by change in glycosylated hemoglobin (HbA(1c)) from baseline to end point (week 26 [primary end point]) in Japanese patients with type 2 diabetes who have inadequate glycemic control with oral antidiabetes drugs. METHODS:In this open-label, parallel-group, multicenter, noninferiority registration study, patients were randomized (1:1) to add exenatide QW (2 mg) or once-daily insulin glargine (starting dose, 4 U) to their current oral antidiabetes drug treatment. The primary analysis was change in HbA(1c) from baseline to end point, evaluated by using a last-observation-carried-forward ANCOVA model, with a predefined noninferiority margin of 0.4%. Secondary analyses (a priori) included analysis of superiority for between-group comparisons of change in weight and the proportion of patients reaching HbA(1c) target levels of ≤7.0% or ≤6.5%. RESULTS:The baseline characteristics of the exenatide QW (215 patients) and insulin glargine (212 patients) treatment groups were similar: mean (SD) age, 57 (10) years and 56 (11) years, respectively; 66.0% and 69.8% male; mean HbA(1c), 8.5% (0.82%) and 8.5% (0.79%); and mean weight, 69.9 (13.2) kg and 71.0 (13.9) kg. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point (least squares mean difference, -0.43% [95% CI, -0.59 to -0.26]; P < 0.001), with the 95% CI upper limit less than the predefined noninferiority margin (0.4%). A significantly greater proportion of patients receiving exenatide QW compared with insulin glargine achieved HbA(1c) target levels of ≤7.0% (89 of 211 [42.2%] vs 44 of 210 [21.0%]) or ≤6.5% (44 of 214 [20.6%] vs 9 of 212 [4.2%]) at end point (P < 0.001 for both). Patient weight was reduced with exenatide QW compared with insulin glargine at end point (least squares mean difference, -2.01 kg [95% CI, -2.46 to -1.56]; P < 0.001). Exenatide QW was well tolerated, with a lower risk of hypoglycemia compared with insulin glargine but a higher incidence of injection-site induration. CONCLUSIONS:Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point; these results suggest that exenatide QW may provide an effective alternative treatment for Japanese patients who require additional therapy to control their diabetes. ClinicalTrials.gov identifier: NCT00935532. 10.1016/j.clinthera.2012.07.007
    Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Davies M J,Donnelly R,Barnett A H,Jones S,Nicolay C,Kilcoyne A Diabetes, obesity & metabolism AIM:The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (< or =7.4%) with minimal weight gain (< or =1 kg) compared with insulin glargine. METHODS:Patients [body mass index (BMI) >27 kg/m(2)] with elevated cardiovascular risk and type 2 diabetes inadequately controlled on two or three oral antidiabetes drugs (OADs) were randomized to add-on exenatide 5-10 microg b.i.d. (n = 118) or insulin glargine o.d. (titrated to target fasting plasma glucose < or =5.6 mmol/l; n = 117) for 26 weeks. RESULTS:The study population had baseline mean (s.d.) age of 56.5 (9.1) years and BMI of 34.1 (5.3) kg/m(2), and 58.5% of patients were taking two OADs. Mean baseline HbA1c was 8.65 (0.68)% in the exenatide group and 8.48 (0.66)% in the insulin glargine group. The proportions of patients achieving the composite endpoint of HbA1c < or =7.4% with weight gain < or =1 kg were 53.4% for the exenatide group and 19.8% for the insulin glargine group (p < 0.001 for exenatide vs. insulin glargine). Exenatide and insulin glargine did not demonstrate a significant difference in HbA1c improvements [least square (LS) mean [s.e.m.]: -1.25 [0.09]% and -1.26 [0.09]% respectively; p = 0.924], but had divergent effects on body weight (-2.73 [0.31] vs. +2.98 [0.31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia. CONCLUSIONS:Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine. 10.1111/j.1463-1326.2009.01154.x
    Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Nauck Michael A,Kemmeries Guido,Holst Jens J,Meier Juris J Diabetes OBJECTIVE:Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. RESEARCH DESIGN AND METHODS:Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m(2)) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg(-1) · min(-1)) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently. RESULTS:GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1-induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05). CONCLUSIONS:The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration. 10.2337/db10-0474
    Effects of the GLP-1 receptor agonist lixisenatide on postprandial glucose and gastric emptying--preclinical evidence. Werner Ulrich Journal of diabetes and its complications In addition to promoting glucose homeostasis, glucagon-like peptide 1 (GLP-1) has a number of extra-pancreatic effects that regulate appetite and body weight. GLP-1 delays gastric emptying, which is vital for postprandial glucose (PPG) control. As GLP-1 is rapidly degraded by protease dipeptidyl peptidase-4, a number of degradation-resistant GLP-1 receptor agonists (GLP-1RAs) have been developed for the treatment of Type 2 diabetes mellitus. These agents can be broadly categorized as being short- or long-acting, based on their pharmacokinetic profile. Short-acting agonists predominantly affect PPG and delay gastric emptying in a sustained manner, whereas long-acting agents largely affect fasting plasma glucose and their delay in gastric emptying appears to be subjected to tachyphylaxis. Lixisenatide is a "short-acting" once-daily prandial GLP-1RA. This review provides an overview of the preclinical studies that are currently available and that evaluate the efficacy of lixisenatide on gastric emptying and PPG levels. The preclinical evidence outlined in this review supports the efficacy of lixisenatide in reducing PPG excursions and delaying gastric emptying. Furthermore, in contrast to long-acting agents, the actions of lixisenatide do not appear to be subjected to tachyphylaxis. 10.1016/j.jdiacomp.2013.06.003
    GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Meier Juris J Nature reviews. Endocrinology In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient. 10.1038/nrendo.2012.140
    Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. Matthews Jessica E,Stewart Murray W,De Boever Erika H,Dobbins Robert L,Hodge Rebecca J,Walker Susan E,Holland M Claire,Bush Mark A, The Journal of clinical endocrinology and metabolism CONTEXT:Native glucagon-like peptide-1 increases insulin secretion, decreases glucagon secretion, and reduces appetite but is rapidly inactivated by dipeptidyl peptidase-4. Albiglutide is a novel dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin designed to have sustained efficacy in vivo. OBJECTIVES:The objectives were to investigate pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide in type 2 diabetes subjects. METHODS:In a single-blind dose-escalation study, 54 subjects were randomized to receive placebo or 9-, 16-, or 32-mg albiglutide on d 1 and 8. In a complementary study, 46 subjects were randomized to a single dose (16 or 64 mg) of albiglutide to the arm, leg, or abdomen. RESULTS:Significant dose-dependent reductions in 24-h mean weighted glucose [area under the curve((0-24 h))] were observed, with placebo-adjusted least squares means difference values in the 32-mg cohort of -34.8 and -56.4 mg/dl [95% confidence interval (-54.1, -15.5) and (-82.2, -30.5)] for d 2 and 9, respectively. Placebo-adjusted fasting plasma glucose decreased by -26.7 and -50.7 mg/dl [95% confidence interval (-46.3, -7.06) and (-75.4, -26.0)] on d 2 and 9, respectively. Postprandial glucose was also reduced. No hypoglycemic episodes were detected in the albiglutide cohorts. The frequency and severity of the most common adverse events, headache and nausea, were comparable with placebo controls. Albiglutide half-life ranged between 6 and 7 d. The pharmacokinetics or pharmacodynamic of albiglutide was unaffected by injection site. CONCLUSIONS:Albiglutide improved fasting plasma glucose and postprandial glucose with a favorable safety profile in subjects with type 2 diabetes. Albiglutide's long half-life may allow for once-weekly or less frequent dosing. 10.1210/jc.2008-1518
    Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials. Geiser Jeanne S,Heathman Michael A,Cui Xuewei,Martin Jennifer,Loghin Corina,Chien Jenny Y,de la Peña Amparo Clinical pharmacokinetics BACKGROUND AND OBJECTIVE:Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. METHODS:The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. RESULTS:Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree. CONCLUSION:The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection. 10.1007/s40262-015-0338-3
    Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Li Wei-Xin,Gou Jian-Feng,Tian Jin-Hui,Yan Xiang,Yang Lin Current therapeutic research, clinical and experimental BACKGROUND:Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of hypoglycemic drugs, including exenatide, liraglutide, albiglutide, lixisenatide, and taspoglutide. Insulin glargine is a standard agent used to supplement basal insulin in type 2 diabetes mellitus (T2DM). OBJECTIVE:The aim of this study was to review the efficacy and safety profiles of GLP-1 receptor agonists versus insulin glargine in type 2 diabetic patients who have not achieved treatment goals with oral hypoglycemic agents. METHODS:The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the database of ongoing trials were searched from inception through April 2010. Additional data were sought from relevant Web sites, the American Diabetes Association, reference lists of included trials and related (systematic) reviews, and industry. Randomized controlled trials (RCTs) were selected if they were ≥3 months in duration, compared GLP-1 receptor agonists with insulin glargine in patients with T2DM, and included ≥1 of the following outcomes: mortality, complications of T2DM, glycemie control, weight, lipids, blood pressure, adverse effects, and health-related quality of life. Quasirandomized controlled trials were excluded. The quality of the eligible studies was assessed on the basis of the following aspects: randomization procedure, allocation concealment, blinding, incomplete outcome data (intent-to-treat [ITT] analysis), selective outcome reporting, and publication bias. RESULTS:A total of 410 citations were retrieved; 5 multicenter RCTs that met the inclusion criteria were identified. They were all open-label designs with an insulin glargine arm, predefined outcomes reported, and ITT analysis. One trial had an unclear randomization procedure and allocation concealment. Publication bias was not able to be determined. No data wete found with regard to mortality or diabetes-associated complications, and few data were found on quality of life. The results of the metaanalysis suggest that insulin glargine was significantly better in reducing the fasting blood glucose (mean difference [MD] [95% CI], 1.31 [1.04 to 1.58]; P < 0.001), but exhibits greater incidence of nocturnal hypoglycemia (risk ratio [RR] [95% CI], 0.40 [0.23 to 0.71]; P = 0.002) and influenza (RR [95% CI], 0.56 [0.32 to 0.98]; P = 0.04). GLP-1 receptor agonists are more conducive to reducing weight (MD [95% CI], -3.96 [-5.14 to -2.77]; P < 0.001), postprandial blood glucose (after breakfast, P < 0.001; after dinner, P < 0.001), and LDL-C (MD [95% CI], -0.18 [-0.28 to -0.08]; P < 0.001), but have significantly more gastrointestinal adverse effects (eg, nausea/ vomiting, P < 0.001). There were no significant differences between GLP-1 receptor agonists and insulin glargine in reducing glycosylated hemoglobin (HbA1c) levels (MD [95% CI], -0.03 [-0.13 to 0.08]) and the overall incidence of hypoglycemia (RR [95% CI], 0.69 [0.42 to 1.14]). CONCLUSIONS:Compared with insulin glargine, GLP-1 receptor agonists did not have a significant difference in regard to reducing HbA1c levels and they were significantly associated with decreased weight but increased gastrointestinal adverse events. It remains unclear whether GLP-1 receptor agonists influence mortality or diabetes-associated complications in patients with T2DM. More trials with longer follow-up are needed to determine the exact long-term efficacy and safety profiles of this new class of hypoglycemic drugs. 10.1016/j.curtheres.2010.08.003
    Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Karagiannis T,Liakos A,Bekiari E,Athanasiadou E,Paschos P,Vasilakou D,Mainou M,Rika M,Boura P,Matthews D R,Tsapas A Diabetes, obesity & metabolism AIM:To assess the efficacy and safety of recently approved once-weekly glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes. METHODS:We conducted a systematic review and meta-analysis of randomized controlled trials comparing any GLP-1 RA licensed for once-weekly dosing (albiglutide, dulaglutide or exenatide extended release) with placebo or other antidiabetic agents. We searched Medline, Embase, the Cochrane Library and grey literature for articles published up to December 2014 and extracted data in duplicate. RESULTS:In our systematic review we included 33 trials with a total of 16 003 participants. Compared with placebo the change in glycated haemoglobin (HbA1c) concentration was -0.66% [six studies; 95% confidence interval (CI) -1.14 to -0.19; I(2)  = 88%] with albiglutide, and -1.18% (seven studies; 95% CI -1.34 to -1.02; I(2)  = 65%) with dulaglutide. Based on data from placebo-controlled trials, we did not detect statistically significant weight-sparing benefits for albiglutide or dulaglutide. Compared with other antidiabetic agents, once-weekly GLP-1 RAs outperformed sitagliptin, daily exenatide and insulin glargine in terms of HbA1c-lowering (mean differences -0.40%; 95% CI -0.66 to -0.14; I(2)  = 85%, -0.44%; 95% CI -0.58 to -0.29; I(2)  = 40% and -0.28; 95% CI -0.45 to -0.10; I(2)  = 81%, respectively). The main adverse effects of treatment included gastrointestinal and injection site reactions. CONCLUSIONS:Given their dosing scheme and overall efficacy and safety profile, once-weekly GLP-1 RAs are a convenient therapeutic option for use as add-on to metformin. 10.1111/dom.12541
    Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Zinman Bernard,Philis-Tsimikas Athena,Cariou Bertrand,Handelsman Yehuda,Rodbard Helena W,Johansen Thue,Endahl Lars,Mathieu Chantal, Diabetes care OBJECTIVE:To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS:In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS:In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS:Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. 10.2337/dc12-1205
    The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Riddle Matthew C,Rosenstock Julio,Gerich John, Diabetes care OBJECTIVE:To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA(1c). RESEARCH DESIGN AND METHODS:In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA(1c) >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) <or=100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA(1c), hypoglycemia, and percentage of patients reaching HbA(1c) <or=7% without documented nocturnal hypoglycemia. RESULTS:Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA(1c) (6.96 vs. 6.97%). A majority of patients ( approximately 60%) attained HbA(1c) <or=7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (<or=72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P < 0.05). Moreover, rates of other categories of symptomatic hypoglycemia were 21-48% lower with glargine. CONCLUSIONS:Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA(1c) in a majority of overweight patients with type 2 diabetes with HbA(1c) between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care. 10.2337/diacare.26.11.3080
    Management of type 2 diabetes: NICE guidelines. Sibal Latika,Home Philip D Clinical medicine (London, England) 10.7861/clinmedicine.9-4-353
    Metrics Beyond Hemoglobin A1C in Diabetes Management: Time in Range, Hypoglycemia, and Other Parameters. Wright Lorena Alarcon-Casas,Hirsch Irl B Diabetes technology & therapeutics We review clinical instances in which A1C should not be used and reflect on the use of other glucose metrics that can be used, in substitution of or in combination with A1C and SMBG, to tailor an individualized approach that will result in better outcomes and patient empowerment. 10.1089/dia.2017.0029
    Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial. Heller Simon R,Bergenstal Richard M,White William B,Kupfer Stuart,Bakris George L,Cushman William C,Mehta Cyrus R,Nissen Steven E,Wilson Craig A,Zannad Faiez,Liu Yuyin,Gourlie Noah M,Cannon Christopher P, Diabetes, obesity & metabolism AIMS:To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE). METHODS:The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events. RESULTS:Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P  = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27-4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20). CONCLUSIONS:There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed. 10.1111/dom.12871
    Skin and adhesive issues with continuous glucose monitors: a sticky situation. Englert Kimberly,Ruedy Katrina,Coffey Julie,Caswell Kimberly,Steffen Amy,Levandoski Lucy, Journal of diabetes science and technology The purpose of this article is to describe challenges associated with successful use of continuous glucose monitoring (CGM) by young children with type 1 diabetes (T1D) and to detail the techniques and products used to improve the duration of sensor wear. The DirecNet Study Group conducted 2 studies in 169 children with T1D between the ages of 1 and 9 years who were instructed to wear a CGM device daily. Problems related to skin irritation and sensor adhesiveness in these young children presented challenges to daily use of the CGM. Study coordinators instituted a variety of techniques using commercially available products to attempt to overcome these problems. Three primary factors that contributed to reduced CGM use were identified: the limited body surface area in smaller children, ambient temperature and humidity, as well as the type and duration of physical activity. Using supplemental products to minimize the impact of these factors resulted in improved adherence and reduced skin irritation. Achieving satisfactory adhesion of the CGM sensor and transmitter may involve finding the right supplemental product or combination of products through trial and error. Optimizing adhesion and minimizing skin irritation can significantly improve duration of use and tolerability of CGM devices by young children. 10.1177/1932296814529893
    The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial. Hempe James M,Liu Shuqian,Myers Leann,McCarter Robert J,Buse John B,Fonseca Vivian Diabetes care OBJECTIVE:This study tested the hypothesis that intensive treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial disproportionately produced adverse outcomes in patients with diabetes with a high hemoglobin glycation index (HGI = observed HbA1c - predicted HbA1c). RESEARCH DESIGN AND METHODS:ACCORD was a randomized controlled trial of 10,251 patients with type 2 diabetes assigned to standard or intensive treatment with HbA1c goals of 7.0% to 7.9% (53 to 63 mmol/mol) and less than 6% (42 mmol/mol), respectively. In this ancillary study, a linear regression equation (HbA1c = 0.009 × fasting plasma glucose [FPG] [mg/dL] + 6.8) was derived from 1,000 randomly extracted participants at baseline. Baseline FPG values were used to calculate predicted HbA1c and HGI for the remaining 9,125 participants. Kaplan-Meier and Cox regression were used to assess the effects of intensive treatment on outcomes in patients with a low, moderate, or high HGI. RESULTS:Intensive treatment was associated with improved primary outcomes (composite of cardiovascular events) in the low (hazard ratio [HR] 0.75 [95% CI 0.59-0.95]) and moderate (HR 0.77 [95% CI 0.61-0.97]) HGI subgroups but not in the high HGI subgroup (HR 1.14 [95% CI 0.93-1.40]). Higher total mortality in intensively treated patients was confined to the high HGI subgroup (HR 1.41 [95% CI 1.10-1.80]). A high HGI was associated with a greater risk for hypoglycemia in the standard and intensive treatment groups. CONCLUSIONS:HGI calculated at baseline identified subpopulations in ACCORD with harms or benefits from intensive glycemic control. HbA1c is not a one-size-fits-all indicator of blood glucose control, and taking this into account when making management decisions could improve diabetes care. 10.2337/dc14-1844
    Variability in the relationship between mean plasma glucose and HbA1c: implications for the assessment of glycemic control. Kilpatrick Eric S,Rigby Alan S,Atkin Stephen L Clinical chemistry BACKGROUND:Previous studies have shown a single linear relationship between mean plasma glucose (MPG) and hemoglobin A(1c) (HbA(1c)). We examined the relationship in different treatment groups of patients with type 1 diabetes participating in the Diabetes Control and Complications Trial (DCCT). METHODS:Seven-point glucose profiles (premeal, postmeal, and bedtime) and HbA(1c) were measured quarterly during the DCCT. We studied measurements from (a) intensively treated patients at study commencement, (b) intensively treated patients after stabilization of their glycemia (from 6 months onward), and (c) conventionally treated patients from 6 months onward. Only complete glucose profile and HbA(1c) pairings were considered (n = 589, 11 483, and 11 855, respectively). RESULTS:From 6 months into the trial, conventionally treated patients had consistently higher MPG concentrations than intensively treated patients at any given HbA(1c) value (mean difference, 1.6 mmol/L at 7% HbA(1c), increasing to 2.8 mmol/L at 11% HbA(1c)). Similarly, at the same HbA(1c), the MPG of intensively treated patients at baseline was higher than in the same individuals after 6 months of intensive treatment (1.2 mmol/L difference at 7% HbA(1c), increasing to 4.6 mmol/L at 11% HbA(1c)). CONCLUSIONS:The relationship between MPG and HbA(1c) is not constant but differs depending on the glycemic control of the population being studied. Having lower mean glucose at the same HbA(1c) may help explain why intensive DCCT treatment appeared intrinsically linked to both increased hypoglycemia and decreased microvascular complications compared with conventional treatment. These findings may also have implications for expressing HbA(1c) as mean blood glucose equivalent. 10.1373/clinchem.2006.079756
    Hemoglobin A1c and mean glucose in patients with type 1 diabetes: analysis of data from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial. ,Wilson Darrell M,Xing Dongyuan,Beck Roy W,Block Jennifer,Bode Bruce,Fox Larry A,Hirsch Irl,Kollman Craig,Laffel Lori,Ruedy Katrina J,Steffes Michael,Tamborlane William V Diabetes care OBJECTIVE:To determine the relationship between mean sensor glucose concentrations and hemoglobin A(1c) (HbA(1c)) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial. RESEARCH DESIGN AND METHODS:Near-continuous glucose sensor data (≥ 4 days/week) were collected for 3 months before a central laboratory-measured HbA(1c) was performed for 252 subjects aged 8-74 years, the majority of whom had stable HbA(1c) values (77% within ± 0.4% of the patient mean). RESULTS:The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA(1c) was 24.4 mg/dL (22.0-26.7) for each 1% change in HbA(1c), with an intercept of -16.2 mg/dL (-32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA(1c) of 6.9-7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL. CONCLUSIONS:There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA(1c) values should be used with caution. 10.2337/dc10-1054
    Factors associated with nocturnal hypoglycemia in at-risk adolescents and young adults with type 1 diabetes. Wilson Darrell M,Calhoun Peter M,Maahs David M,Chase H Peter,Messer Laurel,Buckingham Bruce A,Aye Tandy,Clinton Paula K,Hramiak Irene,Kollman Craig,Beck Roy W, Diabetes technology & therapeutics BACKGROUND:Hypoglycemia remains an impediment to good glycemic control, with nocturnal hypoglycemia being particularly dangerous. Information on major contributors to nocturnal hypoglycemia remains critical for understanding and mitigating risk. MATERIALS AND METHODS:Continuous glucose monitoring (CGM) data for 855 nights were studied, generated by 45 subjects 15-45 years of age with hemoglobin A1c (HbA1c) levels of ≤8.0% who participated in a larger randomized study. Factors assessed for potential association with nocturnal hypoglycemia (CGM measurement of <60 mg/dL for ≥30 min) included bedtime blood glucose (BG), exercise intensity, bedtime snack, insulin on board, day of the week, previous daytime hypoglycemia, age, gender, HbA1c level, diabetes duration, daily basal insulin, and daily insulin dose. RESULTS:Hypoglycemia occurred during 221 of 885 (25%) nights and was more frequent with younger age (P<0.001), lower HbA1c levels (P=0.006), medium/high-intensity exercise during the preceding day (P=0.003), and the occurrence of antecedent daytime hypoglycemia (P=0.001). There was a trend for lower bedtime BG levels to be associated with more frequent nocturnal hypoglycemia (P=0.10). Bedtime snack, before bedtime insulin bolus, weekend versus weekday, gender, and daily basal and bolus insulin were not associated with nocturnal hypoglycemia. CONCLUSIONS:Awareness that HbA1c level, exercise, bedtime BG level, and daytime hypoglycemia are all modifiable factors associated with nocturnal hypoglycemia may help patients and providers decrease the risk of hypoglycemia at night. Risk for nocturnal hypoglycemia increased in a linear fashion across the range of variables, with no clear-cut thresholds to guide clinicians or patients for any particular night. 10.1089/dia.2014.0342
    Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. Cohen Robert M,Holmes Yancey R,Chenier Thomas C,Joiner Clinton H Diabetes care OBJECTIVE:Discordances between HbA1c and other measures of glycemic control are common in clinical practice and remain unexplained. We developed a measure of discordance between HbA1c and fructosamine (FA) (glycosylated serum proteins) to conduct a systematic evaluation. We termed this the glycosylation gap (GG) and sought to determine its relationship to diabetic nephropathy. RESEARCH DESIGN AND METHODS:Measurements of HbA1c and FA on the same sample in 153 people were used to calculate GG, defined as the difference between measured HbA1c and HbA1c predicted from FA based on the population regression of HbA1c on FA. RESULTS:GG had a broad distribution (range, -3.2% to 5.5%); 40% of samples had values indicating major differences in prediction of complications risk by the measured versus predicted HbA1c. GG was highly correlated (r = 0.81) between measurements repeated in 65 patients 23 +/- 2 weeks apart, indicating that the discordances are reliable and not explained by differences in turnover of underlying proteins. In 40 patients with type 1 diabetes of >or = 15 years' duration, an increase in GG by 1% was associated with a 2.9-fold greater frequency of increasing nephropathy stage (P = 0.0014). GG was -0.8 +/- 0.2% in subjects with no nephropathy, -0.3 +/- 0.2% with microalbuminuria/hypertension, and 0.7 +/- 0.3% in subjects with proteinuria or renal dysfunction (P < 0.05). GG correlated better with nephropathy than did either HbA1c or FA alone in this population. CONCLUSIONS:The glycosylation gap may be a useful clinical research tool for evaluating physiologic sources of variation in diabetic complications beyond glycemic control. 10.2337/diacare.26.1.163
    Evaluating quality of glycemic control: graphical displays of hypo- and hyperglycemia, time in target range, and mean glucose. Rodbard David Journal of diabetes science and technology There is need for readily understandable graphical displays of glucose data to facilitate interpretation by clinicians and researchers. (1) Display of the percentage of glucose values above a specified threshold for hyperglycemia (%High) versus percentage of glucose values below a specified threshold for hypoglycemia (%Low). If all glucose values fell within the target range, then all data points would fall at the origin. (2) After an intervention, one can plot the change in percentage of glucose values above a specified threshold for hyperglycemia versus the change in percentage of glucose values below a specified threshold defining hypoglycemia: The quadrants of this graph correspond to (a) increased risk of both hyper- and hypoglycemia, (b) decreased hyperglycemia but increased risk of hypoglycemia, (c) decreases in both hypo- and hyperglycemia, and (d) decreased hypoglycemia but increased hyperglycemia. (3) A 2-dimensional triangular graph can be used for simultaneous display of %High, %Low, and percentage in target range. (4) Display of risk of hyper- versus risk of hypoglycemia based on both frequency and severity of departures from the target range can be used. (5) Graphs (1) and (4) can also be presented using percentile scores relative to a reference population. (6) It is also useful to analyze %Hypoglycemia or risk of hypoglycemia versus mean glucose. These methods are illustrated with examples from representative cases and shown to be feasible, practical, and informative. These new types of graphical displays can facilitate rapid analysis of risks of hypo- and hypoglycemia simultaneously and responses to therapeutic interventions for individuals or in clinical trials. 10.1177/1932296814551046
    Display of glucose distributions by date, time of day, and day of week: new and improved methods. Rodbard David Journal of diabetes science and technology OBJECTIVE:There is a need for improved methods for display of glucose distributions to facilitate comparisons by date, time of day, day of the week, and other variables for data obtained using self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM). METHOD:Stacked bar charts are utilized for multiple ranges of glucose values, e.g., very low, low, borderline low, target range, borderline high, high, and very high. Glucose ranges for these categories can be defined by the user, e.g., <40, 40-70, 71-80, 81-140, 141-180, 181-250, and 251-400 mg/dl. Glucose distributions can be displayed by time of day, in relation to meals, by date, or by day of week. The graphic display can be generated using general purpose spreadsheet software such as Microsoft Excel or with special purpose software. RESULT:Stacked bar charts are extremely compact and effective. They facilitate comparison of multiple days, multiple time segments within a day, preprandial and postprandial glucose levels, days of the week, treatment periods, patients, and groups of patients. They are superior to use of pie charts in terms of compactness and in their ability to facilitate comparisons using multiple criteria and multiple subsets of the data. One can identify episodes of hypoglycemia and hyperglycemia and can display standard errors of estimates of percentages. Interpretation of these graphs is readily learned and requires minimal training. CONCLUSION:Use of stacked bar charts is generally superior to use of pie charts for display of glucose distributions and can potentially facilitate the analysis and interpretation of SMBG and CGM data. 10.1177/193229680900300619
    Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis. Mazze Roger S,Strock Ellie,Wesley David,Borgman Sarah,Morgan Blaine,Bergenstal Richard,Cuddihy Robert Diabetes technology & therapeutics BACKGROUND:Efforts to mimic euglycemia depend upon targets from epidemiologic studies that rely on episodic measurements reduced to statistical summaries, leaving open the question, "What is normal glycemia?" We postulated that portrayal of euglycemia was possible through application of continuous glucose monitoring (CGM) and a novel analytical tool, the ambulatory glucose profile (AGP). METHODS:Individuals with normal glucose tolerance (NGT) and with diabetes used CGM for 30 days. AGP analysis, which graphs CGM data by time without regard to date, was used to characterize glucose exposure, variability, and stability. RESULTS:Sixty-two subjects completed the study, employing CGM for 28 +/- 4 days averaging 99 +/- 18 (range, 33-125) readings per day. NGT subjects (n = 32) had a mean CGM of 102 +/- 7 mg/dL, ranging between 94 and 117 mg/dL and averaging 105 +/- 8 mg/dL daytime and 97 +/- 6 mg/dL overnight. Glucose variability, as expressed by the interquartile range, was 21 +/- 4 mg/dL (range, 14-29 mg/dL). Stability in glycemic control (hourly change in the median) for NGT subjects averaged 3 +/- 1 mg/dL/h. Subjects with diabetes (n = 30) were significantly higher on all glycemic characteristics with the exception of the percentage of hypoglycemic (CGM <70 mg/dL) episodes for type 2 diabetes (2.9%), compared to 2.7% for subjects with NGT. CONCLUSIONS:CGM technologies enabled collection of verified data under normal living conditions, providing an exceptional vantage point from which to obtain important clinical information. This will facilitate an understanding of the range of euglycemic patterns, provide a sensitive means of detecting impaired glucose tolerance, and help set realistic treatment goals for individuals with diabetes. 10.1089/dia.2007.0293
    Diurnal glucose patterns of exenatide once weekly: a 1-year study using continuous glucose monitoring with ambulatory glucose profile analysis. Mazze Roger,Strock Ellie,Morgan Blaine,Wesley David,Bergenstal Richard,Cuddihy Robert Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists OBJECTIVE:To use continuous glucose monitoring (CGM) to characterize diurnal glucose patterns produced by a novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration. METHODS:We performed a subgroup analysis of patients with type 2 diabetes who participated in a multicenter trial (DURATION-1: Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus) comparing once-weekly with twice-daily formulations of exenatide. We are the only center to use CGM with ambulatory glucose profile (AGP) analysis to characterize glucose exposure, variability, and stability in participants assigned to exenatide once weekly. RESULTS:Seven of the 303 patients in the larger study population were included in the subgroup analysis. Mean age (57.6 +/- 7 years), weight (102 +/- 17 kg), body mass index (34 +/- 3 kg/m2), and duration of diabetes (5 +/- 2 years) were comparable to characteristics of the larger study population. At 30 weeks and 52 weeks, participants treated with exenatide once weekly had a mean reduction in hemoglobin A1c level of 1.3 +/- 0.3% and 1.0 +/- 0.3%, respectively (P<.05). CGM analysis revealed a significant (P<.01) decrease in diurnal glucose exposure for 4 participants during nocturnal and daytime periods. Excess glucose exposure (compared with reference values) decreased in 6 of 7 participants, as did glucose variability. Glucose stability improved in 5 participants. The percentage of glucose values less than 70 mg/dL initially increased during the first half of the study then decreased to baseline levels by study end. CONCLUSIONS:Individual glucose profiles revealed that changes in hemoglobin A1c did not consistently parallel alterations in glucose exposure, variability, and stability. AGPs provided a visual representation of improved glucose responses to exenatide once weekly. 10.4158/EP09046.ORR
    Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP). Bergenstal Richard M,Ahmann Andrew J,Bailey Timothy,Beck Roy W,Bissen Joan,Buckingham Bruce,Deeb Larry,Dolin Robert H,Garg Satish K,Goland Robin,Hirsch Irl B,Klonoff David C,Kruger Davida F,Matfin Glenn,Mazze Roger S,Olson Beth A,Parkin Christopher,Peters Anne,Powers Margaret A,Rodriguez Henry,Southerland Phil,Strock Ellie S,Tamborlane William,Wesley David M Diabetes technology & therapeutics Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients. 10.1089/dia.2013.0051
    Does Time-in-Range Matter? Perspectives From People With Diabetes on the Success of Current Therapies and the Drivers of Improved Outcomes. Runge Ava S,Kennedy Lynn,Brown Adam S,Dove Abigail E,Levine Brian J,Koontz Sophie P,Iyengar Varun S,Odeh Sarah A,Close Kelly L,Hirsch Irl B,Wood Richard Clinical diabetes : a publication of the American Diabetes Association After assessing patient perspectives on the success of current diabetes therapies and the factors that have the greatest impact on daily life, we show that time-in-range is a crucial outcome for people with diabetes and that current therapies are falling short on this metric. We also show that patients feel significant stress and worry, and they believe they are falling short in diet, exercise, and weight maintenance. In addition, they believe diet and exercise and in-range blood glucose are the biggest drivers of improved diabetes management and mindset. Together, these findings support the need for therapies that improve outcomes including and beyond A1C. 10.2337/cd17-0094
    Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes. Lu Jingyi,Ma Xiaojing,Zhou Jian,Zhang Lei,Mo Yifei,Ying Lingwen,Lu Wei,Zhu Wei,Bao Yuqian,Vigersky Robert A,Jia Weiping Diabetes care OBJECTIVE:Continuous glucose monitoring (CGM) has provided new measures of glycemic control that link to diabetes complications. This study investigated the association between the time in range (TIR) assessed by CGM and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS:A total of 3,262 patients with type 2 diabetes were recruited. TIR was defined as the percentage of time spent within the glucose range of 3.9-10.0 mmol/L during a 24-h period. Measures of glycemic variability (GV) were assessed as well. DR was determined by using fundus photography and graded as ) non-DR; ) mild nonproliferative DR (NPDR); ) moderate NPDR; or ) vision-threatening DR (VTDR). RESULTS:The overall prevalence of DR was 23.9% (mild NPDR 10.9%, moderate NPDR 6.1%, VTDR 6.9%). Patients with more advanced DR had significantly less TIR and higher measures of GV (all for trend <0.01). The prevalence of DR on the basis of severity decreased with ascending TIR quartiles (all for trend <0.001), and the severity of DR was inversely correlated with TIR quartiles ( = -0.147; < 0.001). Multinomial logistic regression revealed significant associations between TIR and all stages of DR (mild NPDR, = 0.018; moderate NPDR, = 0.014; VTDR, = 0.019) after controlling for age, sex, BMI, diabetes duration, blood pressure, lipid profile, and HbA. Further adjustment of GV metrics partially attenuated these associations, although the link between TIR and the presence of any DR remained significant. CONCLUSIONS:TIR assessed by CGM is associated with DR in type 2 diabetes. 10.2337/dc18-1131
    Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials. Beck Roy W,Bergenstal Richard M,Riddlesworth Tonya D,Kollman Craig,Li Zhaomian,Brown Adam S,Close Kelly L Diabetes care OBJECTIVE:This study evaluated the association of time in range (TIR) of 70-180 mg/dL (3.9-10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials. RESEARCH DESIGN AND METHODS:In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications. RESULTS:Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51-78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25-56), for each 10 percentage points lower TIR ( < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics. CONCLUSIONS:Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics-especially when measured with continuous glucose monitoring-add value as outcome measures in many studies. 10.2337/dc18-1444
    Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring. Bergenstal Richard M,Beck Roy W,Close Kelly L,Grunberger George,Sacks David B,Kowalski Aaron,Brown Adam S,Heinemann Lutz,Aleppo Grazia,Ryan Donna B,Riddlesworth Tonya D,Cefalu William T Diabetes care While A1C is well established as an important risk marker for diabetes complications, with the increasing use of continuous glucose monitoring (CGM) to help facilitate safe and effective diabetes management, it is important to understand how CGM metrics, such as mean glucose, and A1C correlate. Estimated A1C (eA1C) is a measure converting the mean glucose from CGM or self-monitored blood glucose readings, using a formula derived from glucose readings from a population of individuals, into an estimate of a simultaneously measured laboratory A1C. Many patients and clinicians find the eA1C to be a helpful educational tool, but others are often confused or even frustrated if the eA1C and laboratory-measured A1C do not agree. In the U.S., the Food and Drug Administration determined that the nomenclature of eA1C needed to change. This led the authors to work toward a multipart solution to facilitate the retention of such a metric, which includes renaming the eA1C the glucose management indicator (GMI) and generating a new formula for converting CGM-derived mean glucose to GMI based on recent clinical trials using the most accurate CGM systems available. The final aspect of ensuring a smooth transition from the old eA1C to the new GMI is providing new CGM analyses and explanations to further understand how to interpret GMI and use it most effectively in clinical practice. This Perspective will address why a new name for eA1C was needed, why GMI was selected as the new name, how GMI is calculated, and how to understand and explain GMI if one chooses to use GMI as a tool in diabetes education or management. 10.2337/dc18-1581
    Estimation of the glycation gap in diabetic patients with stable glycemic control. Rodríguez-Segade Santiago,Rodríguez Javier,García Lopez José M,Casanueva Felipe F,Camiña Félix Diabetes care OBJECTIVE:The glycation gap (the difference between measured A1C and the value predicted by regression on fructosamine) is stable and is associated with microvascular complications of diabetes but has not hitherto been estimated within a clinically useful time frame. We investigated whether two determinations 30 days apart suffice for a reasonably reliable estimate if both A1C and fructosamine exhibit stability. RESEARCH DESIGN AND METHODS:We studied 311 patients with type 1 or type 2 diabetes for whom simultaneous measurements of A1C and serum fructosamine had been made on at least two occasions separated by 1 month (t(0) and t(1)). Glycemia was deemed stable if A1C(t(1)) - A1C(t(0)) and fructosamine(t(1)) - fructosamine(t(0)) were both less than their reference change values (RCVs). Instantaneous glycation gaps [gg(t(0)) and gg(t(1))] and their mean (GG), were calculated using the data from all stable patients for the required regression. RESULTS:Stable glycemia was shown by 144 patients. In 90% of unstable case subjects, a change in medication was identified as the cause of instability. Among 129 stable patients with an average of eight gg determinations prior to t(0), GG correlated closely with the mean of these prior determinations (r(2) = 0.902, slope 1.025, intercept -0.038). CONCLUSIONS:The glycation gap can be calculated reliably from pairs of A1C and fructosamine measurements taken 1 month apart if these measurements satisfy the RCV criteria for glycemic control. 10.2337/dc11-2450
    Evidence for consistency of the glycation gap in diabetes. Nayak Ananth U,Holland Martin R,Macdonald David R,Nevill Alan,Singh Baldev M Diabetes care OBJECTIVE:Discordance between HbA(1c) and fructosamine estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether it is consistent is uncertain. This study aims to coanalyze paired glycosylated hemoglobin (HbA(1c))-fructosamine estimations by using fructosamine to determine a predicted HbA(1c), to calculate a glycation gap (G-gap) and to determine whether the G-gap is consistent over time. RESEARCH DESIGN AND METHODS:We included 2,263 individuals with diabetes who had at least two paired HbA(1c)-fructosamine estimations that were separated by 10 ± 8 months. Of these, 1,217 individuals had a third pair. The G-gap was calculated as G-gap = HbA(1c) minus the standardized fructosamine-derived HbA(1c) equivalent (FHbA(1c)). The hypothesis that the G-gap would remain consistent in individuals over time was tested. RESULTS:The G-gaps were similar in the first, second, and third paired samples (0.0 ± 1.2, 0.0 ± 1.3, and 0.0 ± 1.3, respectively). Despite significant changes in the HbA(1c) and fructosamine, the G-gap did not differ in absolute or relative terms and showed no significant within-subject variability. The direction of the G-gap remained consistent. CONCLUSIONS:The G-gap appears consistent over time; thus, by inference any key underlying mechanisms are likely to be consistent. G-gap calculation may be a method of exploring and evaluating any such underlying mechanisms. 10.2337/dc10-1767
    Metrics to Evaluate Quality of Glycemic Control: Comparison of Time in Target, Hypoglycemic, and Hyperglycemic Ranges with "Risk Indices". Rodbard David Diabetes technology & therapeutics OBJECTIVE:We sought to cross validate several metrics for quality of glycemic control, hypoglycemia, and hyperglycemia. RESEARCH DESIGN AND METHODS:We analyzed the mathematical properties of several metrics for overall glycemic control, and for hypo- and hyperglycemia, to evaluate their similarities, differences, and interrelationships. We used linear regression to describe interrelationships and examined correlations between metrics within three conceptual groups. RESULTS:There were consistently high correlations between %Time in range (%TIR) and previously described risk indices (M, Blood Glucose Risk Index [BGRI], Glycemic Risk Assessment Diabetes Equation [GRADE], Index of Glycemic Control [IGC]), and with J-Index (J). There were also high correlations among %Hypoglycemia, Low Blood Glucose Index (LBGI), percentage of GRADE attributable to hypoglycemia (GRADE), and Hypoglycemia Index, but negligible correlation with J. There were high correlations of percentage of time in hyperglycemic range (%Hyperglycemia) with High Blood Glucose Index (HBGI), percentage of GRADE attributable to hyperglycemia (GRADE), Hyperglycemia Index, and J. %TIR is highly negatively correlated with %Hyperglycemia but very weakly correlated with %Hypoglycemia. By adjusting the parameters used in IGC, Hypoglycemia Index, Hyperglycemia Index, or in M, one can more closely approximate the properties of BGRI, LBGI, or HBGI, and of GRADE, GRADE, or GRADE. CONCLUSIONS:Simple readily understandable criteria such as %TIR, %Hypoglycemia, and %Hyperglycemia are highly correlated with and appear to be as informative as "risk indices." The J-Index is sensitive to hyperglycemia but insensitive to hypoglycemia. 10.1089/dia.2017.0416
    Metrics for glycaemic control - from HbA to continuous glucose monitoring. Kovatchev Boris P Nature reviews. Endocrinology As intensive treatment to lower levels of HbA characteristically results in an increased risk of hypoglycaemia, patients with diabetes mellitus face a life-long optimization problem to reduce average levels of glycaemia and postprandial hyperglycaemia while simultaneously avoiding hypoglycaemia. This optimization can only be achieved in the context of lowering glucose variability. In this Review, I discuss topics that are related to the assessment, quantification and optimal control of glucose fluctuations in diabetes mellitus. I focus on markers of average glycaemia and the utility and/or shortcomings of HbA as a 'gold-standard' metric of glycaemic control; the notion that glucose variability is characterized by two principal dimensions, amplitude and time; measures of glucose variability that are based on either self-monitoring of blood glucose data or continuous glucose monitoring (CGM); and the control of average glycaemia and glucose variability through the use of pharmacological agents or closed-loop control systems commonly referred to as the 'artificial pancreas'. I conclude that HbA and the various available metrics of glucose variability reflect the management of diabetes mellitus on different timescales, ranging from months (for HbA) to minutes (for CGM). Comprehensive assessment of the dynamics of glycaemic fluctuations is therefore crucial for providing accurate and complete information to the patient, physician, automated decision-support or artificial-pancreas system. 10.1038/nrendo.2017.3
    REPLACE-BG: A Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults With Well-Controlled Type 1 Diabetes. Aleppo Grazia,Ruedy Katrina J,Riddlesworth Tonya D,Kruger Davida F,Peters Anne L,Hirsch Irl,Bergenstal Richard M,Toschi Elena,Ahmann Andrew J,Shah Viral N,Rickels Michael R,Bode Bruce W,Philis-Tsimikas Athena,Pop-Busui Rodica,Rodriguez Henry,Eyth Emily,Bhargava Anuj,Kollman Craig,Beck Roy W, Diabetes care OBJECTIVE:To determine whether the use of continuous glucose monitoring (CGM) without confirmatory blood glucose monitoring (BGM) measurements is as safe and effective as using CGM adjunctive to BGM in adults with well-controlled type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:A randomized noninferiority clinical trial was conducted at 14 sites in the T1D Exchange Clinic Network. Participants were ≥18 years of age (mean 44 ± 14 years), had T1D for ≥1 year (mean duration 24 ± 12 years), used an insulin pump, and had an HbA ≤9.0% (≤75 mmol/mL) (mean 7.0 ± 0.7% [53 ± 7.7 mmol/mol]); prestudy, 47% were CGM users. Participants were randomly assigned 2:1 to the CGM-only ( = 149) or CGM+BGM ( = 77) group. The primary outcome was time in range (70-180 mg/dL) over the 26-week trial, with a prespecified noninferiority limit of 7.5%. RESULTS:CGM use averaged 6.7 ± 0.5 and 6.8 ± 0.4 days/week in the CGM-only and CGM+BGM groups, respectively, over the 26-week trial. BGM tests per day (including the two required daily for CGM calibration) averaged 2.8 ± 0.9 and 5.4 ± 1.4 in the two groups, respectively ( < 0.001). Mean time in 70-180 mg/dL was 63 ± 13% at both baseline and 26 weeks in the CGM-only group and 65 ± 13% and 65 ± 11% in the CGM+BGM group (adjusted difference 0%; one-sided 95% CI -2%). No severe hypoglycemic events occurred in the CGM-only group, and one occurred in the CGM+BGM group. CONCLUSIONS:Use of CGM without regular use of confirmatory BGM is as safe and effective as using CGM with BGM in adults with well-controlled T1D at low risk for severe hypoglycemia. 10.2337/dc16-2482
    International Consensus on Use of Continuous Glucose Monitoring. Danne Thomas,Nimri Revital,Battelino Tadej,Bergenstal Richard M,Close Kelly L,DeVries J Hans,Garg Satish,Heinemann Lutz,Hirsch Irl,Amiel Stephanie A,Beck Roy,Bosi Emanuele,Buckingham Bruce,Cobelli Claudio,Dassau Eyal,Doyle Francis J,Heller Simon,Hovorka Roman,Jia Weiping,Jones Tim,Kordonouri Olga,Kovatchev Boris,Kowalski Aaron,Laffel Lori,Maahs David,Murphy Helen R,Nørgaard Kirsten,Parkin Christopher G,Renard Eric,Saboo Banshi,Scharf Mauro,Tamborlane William V,Weinzimer Stuart A,Phillip Moshe Diabetes care Measurement of glycated hemoglobin (HbA) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes. 10.2337/dc17-1600
    Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring. Malka Roy,Nathan David M,Higgins John M Science translational medicine The amount of glycated hemoglobin (HbA1c) in diabetic patients' blood provides the best estimate of the average blood glucose concentration over the preceding 2 to 3 months. It is therefore essential for disease management and is the best predictor of disease complications. Nevertheless, substantial unexplained glucose-independent variation in HbA1c makes its reflection of average glucose inaccurate and limits the precision of medical care for diabetics. The true average glucose concentration of a nondiabetic and a poorly controlled diabetic may differ by less than 15 mg/dl, but patients with identical HbA1c values may have true average glucose concentrations that differ by more than 60 mg/dl. We combined a mechanistic mathematical model of hemoglobin glycation and red blood cell kinetics with large sets of within-patient glucose measurements to derive patient-specific estimates of nonglycemic determinants of HbA1c, including mean red blood cell age. We found that between-patient variation in derived mean red blood cell age explains all glucose-independent variation in HbA1c. We then used our model to personalize prospective estimates of average glucose and reduced errors by more than 50% in four independent groups of greater than 200 patients. The current standard of care provided average glucose estimates with errors >15 mg/dl for one in three patients. Our patient-specific method reduced this error rate to 1 in 10. Our personalized approach should improve medical care for diabetes using existing clinical measurements. 10.1126/scitranslmed.aaf9304
    The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c. Beck Roy W,Bergenstal Richard M,Cheng Peiyao,Kollman Craig,Carlson Anders L,Johnson Mary L,Rodbard David Journal of diabetes science and technology BACKGROUND:As the use of continuous glucose monitoring (CGM) increases, there is a need to better understand key metrics of time in range 70-180 mg/dL (TIR) and hyperglycemia and how they relate to hemoglobin A1c (A1C). METHODS:Analyses were conducted utilizing datasets from four randomized trials encompassing 545 adults with type 1 diabetes (T1D) who had central-laboratory measurements of A1C. CGM metrics were calculated and compared with each other and A1C cross-sectionally and longitudinally. RESULTS:Correlations among CGM metrics (TIR, time >180 mg/dL, time >250 mg/dL, mean glucose, area under the curve above 180 mg/dL, high blood glucose index, and time in range 70-140 mg/dL) were typically 0.90 or greater. Correlations of each metric with A1C were lower (absolute values 0.66-0.71 at baseline and 0.73-0.78 at month 6). For a given TIR percentage, there was a wide range of possible A1C levels that could be associated with that TIR level. On average, a TIR of 70% and 50% corresponded with an A1C of approximately 7% and 8%, respectively. There also was considerable spread of change in A1C for a given change in TIR, and vice versa. An increase in TIR of 10% (2.4 hours per day) corresponded to a decrease in A1C of 0.6%, on average. CONCLUSIONS:In T1D, CGM measures reflecting hyperglycemia (including TIR and mean glucose) are highly correlated with each other but only moderately correlated with A1C. For a given TIR or change in TIR there is a wide range of possible corresponding A1C values. 10.1177/1932296818822496
    Time in Range Is Associated with Carotid Intima-Media Thickness in Type 2 Diabetes. Lu Jingyi,Ma Xiaojing,Shen Yun,Wu Qiang,Wang Ren,Zhang Lei,Mo Yifei,Lu Wei,Zhu Wei,Bao Yuqian,Vigersky Robert A,Jia Weiping,Zhou Jian Diabetes technology & therapeutics Time in range (TIR) is an emerging metric of glycemic control and is reported to be associated with microvascular complications of diabetes. We sought to investigate the association of TIR obtained from continuous glucose monitoring (CGM) with carotid intima-media thickness (CIMT) as a surrogate marker of cardiovascular disease (CVD). Data from 2215 patients with type 2 diabetes were cross-sectionally analyzed. TIR of 3.9-10.0 mmol/L was evaluated with CGM. CIMT was measured using high-resolution B-mode ultrasonography and abnormal CIMT was defined as a mean CIMT ≥1.0 mm. Logistic regression models were used to examine the independent association of TIR with CIMT. Compared with patients with normal CIMT, those with abnormal CIMT had significantly lower TIR ( < 0.001). The prevalence of abnormal CIMT progressively decreased across the categories of increasing TIR ( for trend <0.001). In a fully adjusted model controlling for traditional risk factor of CVD, each 10% increase in TIR was associated with 6.4% lower risk of abnormal CIMT. Stratifying the data by sex revealed that TIR was significantly associated with CIMT in males but not in females. In a subset of patients ( = 612) with complete data on diabetic retinopathy and albuminuria, we found that the relationship between TIR and CIMT remained to be significant, regardless of the status of microvascular complications. TIR is associated with CIMT in a large sample of patients with type 2 diabetes, suggesting a link between TIR and macrovascular disease. 10.1089/dia.2019.0251