The Association Between Type 2 Diabetes and Cardiovascular Disease: The "For Your SweetHeart™" Survey.

INTRODUCTION: It is unclear whether patients and their loved ones appreciate that cardiovascular disease (CVD) is the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). The purpose of this survey was to evaluate the degree of awareness regarding the link between T2DM and CVD. METHODS: An online survey was conducted among US adults (general population) and adults with self-reported T2DM. RESULTS: Of 13,027 participants recruited, 1505 completed the survey (12% response rate): 501 with T2DM and 1004 from the general population, of whom 364 knew someone with T2DM (e.g., partner, friend, relative, colleague: "SweetHearts"). Of those with T2DM, 52% were unaware that patients with T2DM are at increased risk of CVD and related macrovascular events. People with T2DM were more likely to be aware of the increased risk of microvascular disease (blindness [57%], nephropathy [57%], neuropathy [64%]) than macrovascular disease (myocardial infarction [41%], stroke [43%]). Despite CVD being the leading cause of death in T2DM, 67% of those with T2DM and 69% of SweetHearts were unaware of this, similar figures to those of the general population (74%). People with T2DM indicated they would take preventive measures if they were aware of their increased CVD risk: 88% would modify their diet and 81% would talk to their healthcare provider. Respondents with T2DM (73%) indicated that a desire to live longer/spend more time with family would motivate them to decrease their CVD risk. CONCLUSIONS: Findings indicate that education regarding the association between T2DM and CVD in patients and their loved ones is warranted. Plain language summary available for this article. Please see Fig. 1 and the following link: https://doi.org/10.6084/m9.figshare.7546817 . FUNDING: The "For Your SweetHeart™" survey was supported by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance, and was developed in partnership with KRC Research.

Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes.

PURPOSE: To identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD) and assess incidence and risk factors for disease progression in a retrospective study. METHODS: Patients ≥18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C) were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan-Meier plots and multistate models. RESULTS: In the NAFLD cohort (N=18,754), 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM), and the mean body mass index was 38.2±10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression) during follow-up (median=842 days). Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year. CONCLUSIONS: In 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of disease progression, and mortality risk increased with disease stage. Early diagnosis and monitoring of disease progression, especially in patients with T2DM, is warranted.

Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial.

BACKGROUND: When patients with type 2 diabetes start their first injectable therapy, clinicians can choose between glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulins. In DURATION-3, exenatide once weekly was compared with insulin glargine (henceforth, glargine) as first injectable therapy. Here, we report the results of the final 3-year follow-up. METHODS: DURATION-3 was an open-label randomised trial done between May 13, 2008, and Jan 30, 2012. Patients with type 2 diabetes aged 18 years or older were enrolled at 72 sites worldwide. They were eligible when they had suboptimum glycaemic control (HbA1c 7.1-11.0% [54-97 mmol/mol]) despite maximum tolerated doses of metformin alone or with a sulfonylurea for at least 3 months, a stable bodyweight for at least 3 months, and a BMI of 25-45 kg/m(2) (23-45 kg/m(2) in South Korea and Taiwan). Patients were randomly assigned (1:1) by computer-generated random sequence with an interactive voice-response system (block size four, stratified by country and concomitant therapy) to once-weekly exenatide (2 mg subcutaneous injection) or once-daily glargine (titrated to target) to be given in addition to their existing oral glucose-lowering regimens. The primary efficacy measure at 3 years was change in HbA1c from baseline in patients given at least one dose of the assigned drug (ie, analyses by modified intention to treat). Patients, investigators, and data analysts were not masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00641056. FINDINGS: 456 patients underwent randomisation and received at least one dose of the assigned drug (233 given exenatide, 223 glargine). At 3 years, least-squares mean HbA1c change was -1.01% (SE 0.07) in the exenatide group versus -0.81% (0.07) in the glargine group (least-squares mean difference -0.20%, SE 0.10, 95% CI -0.39 to -0.02; p=0.03). Transient gastrointestinal adverse events characteristic of GLP-1 receptor agonists were more frequent with exenatide than glargine (nausea: 36 [15%] of 233 patients vs five [2%] of 223; vomiting: 15 [6%] vs six [3%]; diarrhoea: 32 [14%] vs 15 [7%]), although frequency of these events did decrease after week 26 in the exenatide group. The proportion of patients who reported serious adverse events in the exenatide group (36 patients [15%]) was the same as that in the glargine group (33 [15%]). The exposure-adjusted rate of overall hypoglycaemia was three times higher in patients given glargine (0.9 events per patient per year) than in those given exenatide (0.3 events per patient per year). INTERPRETATION: Efficacy of once-weekly exenatide is sustained for 3 years. GLP-1 receptor agonists could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin. FUNDING: Amylin Pharmaceuticals and Eli Lilly.

Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. METHODS: We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA(1c)) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886. FINDINGS: Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA(1c) was greater in patients in the liraglutide group (-1·48%, SE 0·05; n=386) than in those in the exenatide group (-1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08-0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. INTERPRETATION: Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes. FUNDING: Eli Lilly and Company and Amylin Pharmaceuticals LLC.

Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: To compare safety and efficacy of the extended-release formulation exenatide once weekly (EQW) vs exenatide twice daily (EBID) for 26 weeks in type 2 diabetes patients from China, India, Japan, South Korea and Taiwan. MATERIALS AND METHODS: A randomized, comparator-controlled, open-label study included 681 patients with type 2 diabetes inadequately controlled (hemoglobin A1c [HbA1c] ≥7 and ≤11%) with oral antihyperglycemic medications (OAMs). Patients added 2 mg EQW or 10 µg EBID to current OAMs. Safety was re-evaluated 10 weeks after last treatment. RESULTS: EQW was superior to EBID on HbA1c measures at week 26 (Least-squares mean treatment difference: -0.31% [95% confidence interval -0.49, -0.14%]). More EQW-treated patients achieved target HbA1c ≤7.0% (P = 0.003), ≤6.5% (P < 0.001), or ≤6.0% (P = 0.003). Fasting serum glucose reductions were greater among EQW-treated patients (P < 0.001). Blood glucose profiles improved in both treatment groups (P < 0.001). Weight loss occurred with both treatments, but was greater with EBID. Adverse events (≥10%, either group) were nausea, injection-site induration, dyslipidemia and vomiting. Injection-site induration was more frequent with EQW, whereas nausea, vomiting and hypoglycemia were less frequent. One episode each of major hypoglycemia (EBID) and pancreatitis (EQW) were reported. CONCLUSION: In this population, EQW and EBID showed efficacious glucose and weight control; safety and tolerability were consistent with observations in non-Asian patients. This trial was registered with ClinicalTrials.gov (no. NCT00917267).

Safety of exenatide once weekly for 52 weeks in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: An initial 26-week, randomized, open-label study compared the efficacy and safety of exenatide 10 mcg twice daily with exenatide 2 mg once weekly in Asian patients with type 2 diabetes who experienced inadequate glycemic control with oral antidiabetes medications. The aim of this study was to evaluate the safety of exenatide once weekly in Japanese patients, a subset of the initial patient population, who continued into this extension study for an additional 26 weeks of therapy on exenatide once weekly, followed by 10 weeks without exenatide once weekly. MATERIALS AND METHODS: Japanese patients initially assigned to exenatide twice daily (n = 62) switched to exenatide once weekly for the extended 26 weeks, and patients initially assigned to exenatide once weekly (n = 74) continued on this regimen for the remainder of the study (total treatment of 52 weeks). RESULTS: A total of 68% of patients reported one or more treatment-emergent adverse events during the extension period; the most common of these were nasopharyngitis (14%) and vomiting (6%). No major hypoglycemic episodes were reported. Improvements in glycated hemoglobin, fasting plasma glucose and postprandial glucose were maintained over 52 weeks of treatment. At week 52, bodyweight remained reduced from baseline. CONCLUSIONS: Exenatide once weekly added to oral antidiabetes medication was well tolerated in Japanese patients with type 2 diabetes, and was associated with glycemic control and weight loss through to 52 weeks, supporting the use of exenatide once weekly as an adjunctive treatment for type 2 diabetes in this patient population. The initial 26-week portion of this trial was registered with ClinicalTrials.gov (no. NCT00917267).

Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years.

BACKGROUND: Patients with type 2 diabetes mellitus are routinely treated with combinations of glucose-lowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide-1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. OBJECTIVE: This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. METHODS: In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatide-naïve before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a one-sample t test for within-group change in glycosylated hemoglobin (HbA(1c)). RESULTS: Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA(1c),7.2% [1.0%]), 44 were exenatide-naïve (baseline HbA(1c), 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA(1c), 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No identifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naïve patients experienced mean (SE) HbA(1c) reductions of -0.7% (0.2%) and weight reductions of -2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of -0.4% (0.1%) in HbA(1c) and no change in weight. CONCLUSIONS: Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naïve patients experienced improvements in HbA(1c) and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA(1c) and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896.

Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.

OBJECTIVE: To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS: Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA(1c) 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA(1c) reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were -1.53 vs. -1.48 (P = 0.620), -1.63 (P = 0.328), and -1.15 (P < 0.001), respectively. Weight changes (kg) were -2.0 vs. -2.0 (P = 0.892), +1.5 (P < 0.001), and -0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS: EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA(1c) reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.

Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks.

UNLABELLED: Aims/Introduction: To evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist, exenatide, in Japanese patients with type 2 diabetes mellitus suboptimally controlled despite therapeutic doses of a sulfonylurea alone or combined with a biguanide or thiazolidinedione. MATERIALS AND METHODS: Patients were randomized to a placebo or exenatide, either 5 or 10 µg, given subcutaneously b.i.d. in addition to oral therapy. Patients randomized to 10 µg exenatide received 5 µg b.i.d. for the first 4 weeks, followed by 10 µg b.i.d. for the last 20 weeks. RESULTS: A total of 179 patients received the study drug and composed the full analysis set (n = 35, placebo; n = 72, exenatide 5 µg; n = 72, exenatide 10 µg; 68% male; 58 ± 10 years; body mass index 25.5 ± 4.1 kg/m(2); HbA1c 8.2 ± 0.9%; means ± standard deviations). Baseline to end-point (least-squares means ± standard errors) HbA1c changes (%) were -0.28 ± 0.15 (placebo), -1.34 ± 0.11 (exenatide 5 µg) and -1.62 ± 0.11 (exenatide 10 µg) (both P < 0.001, exenatide vs placebo). Baseline to end-point bodyweight changes (kg) were -0.47 ± 0.39 (placebo), -0.39 ± 0.28 (exenatide 5 µg) and -1.54 ± 0.27 (exenatide 10 µg; P = 0.026, exenatide 10 µg vs placebo). Nausea, generally mild to moderate, was reported in 8.6% (placebo), 25.0% (exenatide 5 µg) and 36.1% (exenatide 10 µg) of patients. Mild to moderate hypoglycemia was reported in 22.9% (placebo), 51.4% (exenatide 5 µg) and 58.3% (exenatide 10 µg) of patients. CONCLUSIONS: Over 24 weeks, exenatide vs the placebo improved glycemic control, reduced bodyweight (10 µg) and was well tolerated in Japanese patients with type 2 diabetes mellitus suboptimally controlled, despite oral therapy including a sulfonylurea. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00084.x, 2011).