Carol H. Wysham

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

OBJECTIVE To compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA1c change at 26 weeks. RESEARCH DESIGN AND METHODS This 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 μg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500–3,000 mg) and pioglitazone (30–45 mg). Mean baseline HbA1c was 8.1% (65 mmol/mol). RESULTS Least squares mean ± SE HbA1c change from baseline to the primary end point was −1.51 ± 0.06% (−16.5 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, −1.30 ± 0.06% (−14.2 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, −0.99 ± 0.06% (−10.8 ± 0.7 mmol/mol) for exenatide, and −0.46 ± 0.08% (−5.0 ± 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient. CONCLUSIONS Both once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.

Diabetes Performance Measures: Current Status and Future Directions

Just as treatment guidelines for diabetes care were at the forefront of medical guideline development (1), diabetes has been a prominent focus of performance measurement and quality improvement initiatives for well over a decade. However, the constraints of pre-electronic health records (EHRs) data systems have consistently limited the clinical scope and sophistication of current diabetes quality measures. The U.S. health care system is nearing a tipping point in the use of more sophisticated EHR-based information systems, and widespread use of these systems will usher in a new era for diabetes quality measurement. New information system capabilities will enable improvements to existing measures and enable development of much more sophisticated measures that can accommodate personalization of clinical goals, patient preferences, and patient-reported data, thus moving both guidelines and measures toward personalization based on sophisticated assessment of the risks and benefits of certain clinical actions for a given patient at a given clinical encounter. To facilitate discussion of the future of performance measurement in diabetes in this era of rapid transition to EHRs, the American Diabetes Association (ADA) convened a consensus development conference in December 2010. Participating experts identified and discussed the following questions: 1. 1. What is the evidence that measuring quality, benchmarking, and providing feedback or incentives improve diabetes care? 2. 2. What are the limitations, burdens, and consequences (intended or unintended) of diabetes quality measures as currently structured? 3. 3. What should be the role of shared decision making, patient preferences, and patient-reported data in quality measures? 4. 4. What is the future of quality measurement in diabetes? 5. 5. How can quality monitoring be integrated into population surveillance efforts? This report summarizes the consensus meeting, and represents the expert opinion of its authors and not the official position of the ADA or any other participating organization. ### 1. What is the evidence that measuring quality, benchmarking, and providing feedback or incentives improve diabetes care? The first national effort to develop a …

Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial

OBJECTIVE This study was conducted to demonstrate the efficacy and safety of LixiLan (iGlarLixi), a novel, titratable, fixed-ratio combination of insulin glargine (iGlar) (100 units) and lixisenatide, compared with iGlar in patients with type 2 diabetes inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents. RESEARCH DESIGN AND METHODS After a 6-week run-in when iGlar was introduced and/or further titrated, and oral antidiabetic drugs other than metformin were stopped, 736 basal insulin-treated patients (mean diabetes duration 12 years, BMI 31 kg/m2) were randomized 1:1 to open-label, once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum dose of 60 units/day. The primary outcome was change in HbA1c levels at 30 weeks. RESULTS HbA1c decreased from 8.5% (69 mmol/mol) to 8.1% (65 mmol/mol) during the run-in period. After randomization, iGlarLixi showed greater reductions in HbA1c from baseline compared with iGlar (–1.1% vs. –0.6%, P < 0.0001), reaching a mean final HbA1c of 6.9% (52 mmol/mol) compared with 7.5% (58 mmol/mol) for iGlar. HbA1c <7.0% (53 mmol/mol) was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with iGlar (1.4 kg difference, P < 0.0001). Documented symptomatic hypoglycemia (≤70 mg/dL) was comparable between groups. Mild gastrointestinal adverse effects were very low but more frequent with iGlarLixi. CONCLUSIONS Compared with iGlar, a substantially higher proportion of iGlarLixi-treated patients achieved glycemic targets with a beneficial effect on body weight, no additional risk of hypoglycemia, and low levels of gastrointestinal adverse effects in inadequately controlled, basal insulin-treated, long-standing type 2 diabetes.

Five-Year Efficacy and Safety Data of Exenatide Once Weekly: Long-term Results From the DURATION-1 Randomized Clinical Trial

OBJECTIVE To evaluate the 5-year efficacy and safety of once weekly exenatide. PATIENTS AND METHODS The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 μg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 μg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. RESULTS Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, -1.6%; 95% CI, -1.8% to -1.4%; vs -1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (-28.8 mg/dL; 95% CI, -36.2 to -21.5 mg/dL), weight (-3.0 kg; 95% CI, -4.6 to -1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. CONCLUSION Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00308139.

TWO TREATMENT APPROACHES FOR HUMAN REGULAR U-500 INSULIN IN PATIENTS WITH TYPE 2 DIABETES NOT ACHIEVING ADEQUATE GLYCEMIC CONTROL ON HIGH-DOSE U-100 INSULIN THERAPY WITH OR WITHOUT ORAL AGENTS: A RANDOMIZED, TITRATION-TO-TARGET CLINICAL TRIAL

OBJECTIVE To compare the efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D). METHODS We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m(2); glycated hemoglobin [HbA1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA1c change from baseline. RESULTS After 24 weeks, both treatments demonstrated significant HbA1c reductions (TID, -1.12%; BID, -1.22%; both, P<.001) and clinical equivalence (difference, -0.10%; 95% confidence interval, -0.33 to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 242.7 to 343.1 units; BID, 249.0 to 335.0 units) were observed. Incidence and rate of documented symptomatic hypoglycemia (≤70 mg/dL) were lower for TID versus BID (P = .003 and P = .02, respectively); severe hypoglycemia was similar between treatments. Weight gain was similar in both groups (TID, 5.4 kg; BID, 4.9 kg). CONCLUSION Initiation and titration of U-500R using either algorithm (TID or BID) improves glycemic control effectively and safely with fewer injections in patients with T2D treated with high-dose/high-volume U-100 insulin. These results provide clinicians with a practical framework for using U-500R in severely insulin-resistant patients with suboptimally controlled T2D.

Response to Comment on: American Diabetes Association. Standards of Medical Care in Diabetes—2011. Diabetes Care 2011;34(Suppl. 1):S11–S61

We appreciate the opportunity to respond to the letter of Basevi et al. (1). The new recommendations by the American Diabetes Association (ADA) for gestational diabetes mellitus (GDM) screening and diagnosis are level B recommendations (“supportive evidence from well-conducted cohort studies”). As described in our Standards of Medical Care (2), the ADA adopted the consensus recommendations of an international group convened by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), on the basis of the group’s extensive review of published and unpublished data from the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The cut points chosen represent those that confer an odds ratio of 1.75, compared with the mean values, for a number of prespecified adverse pregnancy outcomes (3). The recommendation for universal GDM screening is not a major change. Prior ADA recommendations were to screen all but very low-risk women (in the U.S., a very small minority of pregnant women), either with a oneor two-step protocol. The fasting plasma glucose (FPG) cut point is only slightly lower than the prior recommendation (95 mg/dL [5.3 mmol/L]). Using an FPG cut point of 126 mg/dL (7 mmol/L) to diagnose GDM is not the standard of care inmost systems. In fact, in the HAPO study, women with FPG.105 mg/dL (5.8 mmol/L) were unblinded and not included in the untreated observational cohort for ethical reasons. The main critique of the recommendations is that more women will be diagnosed with GDM because only one abnormal oral glucose tolerance test value is required. The IADPSG group’s analyses showed that values at any of the three oral glucose tolerance time points were informative of risk. By definition, women identified with the new criteria whowould not have been identified by prior ADA criteria will have milder GDM. We disagree that treatment of GDM has limited benefit beyond reduction in shoulder dystocia. The U.S. study (with diagnostic criteria similar to the IADPSG criteria) showed significant reductions in rates of primary cesarean section and in preeclampsia and gestational hypertension with identification and treatment of mild GDM (4). Both the U.S. and Australian studies showed significant reductions in macrosomia (a known risk factor for future obesity and diabetes) (4,5). The latter study showed improved postpartum measures of maternal quality of life and lower rates of depression (5). In the U.S. study, 93% of treated womenwere managed with lifestyle therapy alone. It is likely that the more hyperglycemic women requiring insulin treatment would have been diagnosed by prior criteria. For years GDM has been defined differently throughout the world—a patchwork that stymies epidemiological analyses and harmonization of clinical research and care. Prior diagnostic criteria were not based on evidence for pregnancyrelated outcomes. The IADPSG recommendations are a highly rational way to identify women at higher risk of adverse pregnancy outcomes—outcomes that can be reduced primarily with lifestyle interventions. The ADA therefore joined numerous diabetes and obstetrical organizations worldwide in adopting these recommendations.

Once weekly exenatide: efficacy, tolerability and place in therapy.

Exenatide once weekly is the first glucose‐lowering agent available to patients with type 2 diabetes mellitus (T2DM) which is administered once per week. This long‐acting formulation contains the same active ingredient as exenatide twice daily, except that the exenatide is encapsulated in dissolvable microspheres. Following subcutaneous injection, exenatide once weekly microspheres remain in place under the skin and slowly degrade, releasing active exenatide continuously into circulation. In randomized clinical trials, exenatide once weekly was associated with significant glycaemic improvement and moderate weight loss in patients with T2DM when administered as monotherapy or in combination with a variety of oral antidiabetic agents. Exenatide once weekly also lowered blood glucose more effectively than titrated basal insulin in patients on metformin or metformin plus sulphonylurea background therapy. Gastrointestinal side effects (nausea, vomiting and diarrhoea) were the most common tolerability issues associated with exenatide once weekly administration, but they occurred at lower rates than in patients on other glucagon‐like peptide receptor agonists (i.e., exenatide twice daily or liraglutide). Issues regarding the place of exenatide once weekly in T2DM pharmacotherapy are discussed.

EFFECT OF TOTAL DAILY DOSE ON EFFICACY, DOSING, AND SAFETY OF 2 DOSE TITRATION REGIMENS OF HUMAN REGULAR U-500 INSULIN IN SEVERELY INSULIN-RESISTANT PATIENTS WITH TYPE 2 DIABETES

OBJECTIVE To examine the influence of baseline U-100 insulin total daily dose (TDD) on clinical outcomes in severely insulin-resistant patients with inadequately controlled type 2 diabetes treated with human regular U-500 insulin (U-500R) from the perspective of current dosing recommendations. METHODS Data from a recent prospective, randomized trial comparing thricedaily (TID) and twice-daily (BID) U-500R in 325 patients transitioned from high-dose/high-volume U-100 insulin were analyzed across baseline U-100 TDD units and units/kg subgroups (≤300 units [n = 224, 68.9%] and >300 units [n = 101, 31.1%]; ≤2 units/kg [n = 96, 29.5%] and >2 units/kg [n = 229, 70.5%]). Subgroup effects on treatment differences were evaluated, and outcomes between treatment-pooled subgroups were compared. RESULTS At 24 weeks, significant reductions in glycated hemoglobin (HbA1c) were observed for all subgroups (range: -1.01% to -1.38%, P<.05). Within-subgroup treatment effects were similar with no treatment-by-subgroup interactions; however, a greater reduction was noted in the >300 units subgroup (P = .04). No TID/BID differences within subgroups or treatment-by-subgroup interactions were observed for TDD or weight increase from baseline. Overall hypoglycemia rates were similar between treatments (within subgroups) and showed no interactions. However, rates were higher in the >300 units subgroup for severe hypoglycemia (P = .04) and in both higher-dose subgroups for documented symptomatic hypoglycemia ≤70 mg/dL (P<.001, units; P = .001, units/kg). CONCLUSION Both TID and BID U-500R were efficacious and safe across TDD subgroups, though higher hypoglycemia rates were observed in higher-dose, treatment-pooled subgroups. U-500R dosing recommendations have been updated accordingly. ABBREVIATIONS AE = adverse event BID = twice daily HbA1c = glycated hemoglobin QID = 4 times daily RCT = randomized clinical trial T2D = type 2 diabetes TDD = total daily dose TID = thrice daily U-500R = human regular U-500 insulin.

Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed‐ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan‐L trial

To assess the impact of baseline characteristics on clinical outcomes in the LixiLan‐L trial, a randomized open‐label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed‐ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose‐lowering drugs.

Baseline factors associated with glycaemic response to treatment with once-weekly dulaglutide in patients with type 2 diabetes.

Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient‐boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient‐boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction [coefficient estimates: −0.6% (−6.6 mmol/mol); p < 0.0001]. Age ≤65 years, lower FSG level, FSI level ≤55 pmol/L and eGFR ≤100 mL/min/1.73 m2 were associated with greater decreases in HbA1c, but the effect was very small [coefficient estimates: −0.05% to −0.2% (−0.6 to −2.2 mmol/mol)]. These data indicate that higher baseline HbA1c, reflecting poor glycaemic status, is the major factor associated with greater reduction in HbA1c in response to dulaglutide treatment.