Risk of clinically relevant hypoglycaemia in patients with type 2 diabetes self-titrating insulin glargine U-100.

AIMS: We evaluated risk factors for clinically relevant hypoglycaemia (blood glucose <3 mmol/L) in patients with type 2 diabetes during insulin glargine self-titration. Data were from two clinical trials in which patients were able to improve glycaemic control by self-titration of insulin glargine using a simple algorithm. MATERIALS AND METHODS: We performed post hoc analyses of pooled treatment groups from each of two Phase 3 studies comparing LY2963016 with LANTUS: ELEMENT-2 (double-blind) and ELEMENT-5 (open label). Clinically relevant hypoglycaemia was analysed by category of HbA1c (<7%, 7%-8.5%, >8.5%) at Week 12 (titration period) and at Week 24 (overall study), and by subgroups of age (<65, ≥65 years) and previous insulin use (naïve or not). RESULTS: In the ELEMENT-2 study (N = 756), there were no overall differences in rate or incidence of hypoglycaemia among HbA1c categories. In the ELEMENT-5 study (N = 493), patients with HbA1c greater than 8.5% had a lower rate and incidence of hypoglycaemia throughout the study compared to those in the lower HbA1c categories. In both studies, patients 65 years of age or older, compared to those less than 65 years, had a higher rate and incidence of hypoglycaemia during the titration phase, had lower baseline HbA1c, and experienced smaller increases in dose, with no differences in HbA1c post baseline. The rate and incidence of hypoglycaemia was similar between naïve patients and patients previously using basal insulin, across all levels of glycaemic control. With the exception of the older subgroup, hypoglycaemia rates were similar during titration and maintenance periods. CONCLUSION: Our results support broader use of self-titration algorithms for patients with type 2 diabetes.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naïve at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, baseline A1C 6.8%-8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS: Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS: Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.

Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight.

OBJECTIVE: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for <10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in. RESULTS: Adjusted for duration of run-in, the mean ± SD change in HbA1c was -0.65 ± 0.02% (-7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, -0.48 ± 0.02% (-5.2 ± 0.2 mmol/mol) when the dose was unchanged, and -0.23 ± 0.07% (-2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P < 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894). CONCLUSIONS: Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control.

Similar Efficacy and Safety of Basaglar® and Lantus® in Patients with Type 2 Diabetes in Age Groups (< 65 Years, ≥ 65 Years): A Post Hoc Analysis from the ELEMENT-2 Study.

INTRODUCTION: To compare efficacy and safety of Basaglar® [insulin glargine 100 units/mL; LY insulin glargine (LY IGlar)] to Lantus® [insulin glargine 100 units/mL; SA insulin glargine (SA IGlar)] in older (≥ 65 years) or younger (< 65 years) patients with type 2 diabetes (T2D). METHODS: This subgroup analysis of a phase 3, randomized, double-blind, multinational, 24-week study compared LY IGlar and SA IGlar on several clinical efficacy (change in glycated hemoglobin (A1c), basal insulin dose, weight) and safety outcomes (incidence of adverse events, insulin antibodies, hypoglycemia incidence and rates) in patients either ≥ 65 or < 65 years. RESULTS: Compared with patients aged < 65 years (N = 542), patients aged ≥ 65 years (N = 214) had a significantly longer duration of diabetes; lower baseline A1c and body weight; and body mass index; and were more likely to report prestudy SA IGlar use. Compared to patients < 65 years, patients ≥ 65 years needed a lower basal insulin dose and experienced lower body weight gain. There were no significant treatment-by-age interactions for the clinical efficacy and safety outcomes, indicating that there was no differential treatment effect (LY IGlar vs SA IGlar) for patients ≥ 65 years vs those < 65 years. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. CONCLUSIONS: LY IGlar and SA IGlar exhibit similar efficacy and safety in patients with T2D who are ≥ 65 years and in those < 65 years. TRIAL REGISTRATION: ClinicalTrials.gov trial registration: NCT01421459. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim.

Plain language summary available for this article.The aim of this phase 3 clinical study was to compare the efficacy and safety of two drugs, Basaglar^® (LY IGlar) and Lantus (SA IGlar), in patients with type 2 diabetes that were either 65 years of age and/or older or younger than 65 years of age. This study ran for 24 weeks. The factors used to measure efficacy were changes in glycated hemoglobin (A1c), insulin dose, and weight. The safety outcomes were incidence of adverse events, incidence and levels of insulin antibodies, and the incidence and rate of low blood sugar. Compared with patients less than 65 years of age (N = 542), patients 65 years of age and older (N = 214) had diabetes for a significantly longer time period; had a lower baseline A1c, body weight, and body mass index; and were more likely to report that they used SA IGlar prestudy. Compared to patients less than 65 years of age, patients equal to or older than 65 years of age showed significantly smaller increases in insulin dose and body weight. There were no significant treatment-by-age interactions for the efficacy and safety outcomes, indicating that there was no difference in treatment effect (LY IGlar vs SA IGlar) for patients equal to or older than 65 years of age vs those less than 65 years of age. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. LY IGlar and SA IGlar have similar efficacy and safety in patients with T2D who are equal to or older than 65 years of age and in those less than 65 years of age.

Basal insulin or premix analogue therapy in type 2 diabetes patients.

BACKGROUND: We sought to compare the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) given twice daily with once-daily insulin glargine in patients with type 2 diabetes beginning insulin therapy and who did not use thiazolidinediones, which are contraindicated with insulin in the European Union, in a subpopulation (N=157) of the INITIATE study. METHODS: At baseline, HbA(1c) was >/=8.0% on >/=1000 mg/day metformin alone or in combination with other oral antidiabetic drugs (OADs; e.g. sulphonylurea or alpha-glucosidase inhibitors). Metformin was adjusted up to 2550 mg/day and other OADs were discontinued. Starting insulin doses were subsequently adjusted weekly for 26 weeks by algorithm-directed titration. RESULTS: The proportion of patients achieving a HbA(1c) below 7.0% at 28 weeks was greater with BIAsp 30 than with insulin glargine (65% vs 41%, P=0.003). The mean reduction in HbA(1c) was greater for BIAsp 30 than for insulin glargine: -2.89+/-1.6% vs -2.46+/-1.6%, respectively (P=0.035). Postprandial glucose increments were lower for the BIAsp 30 group after breakfast (P=0.003) and dinner (P=0.033); post-lunch values were not significantly different. No major hypoglycemic episodes were recorded. Nocturnal hypoglycemia was reported by 25% of subjects in the BIAsp 30 group and by 10% in the insulin glargine group (P=0.021). Weight gain was 5.6+/-4.6 and 3.0+/-4.3 kg (P=0.0004) for BIAsp 30 and insulin glargine, respectively. CONCLUSIONS: BIAsp 30, given twice daily in combination with metformin, was more effective than insulin glargine, given once daily in combination with metformin, at controlling blood glucose in insulin-naïve patients with type 2 diabetes, but was associated with increased weight gain and minor hypoglycemic events.

Evolution of a pulmonary insulin delivery system (Exubera) for patients with diabetes.

Many patients with diabetes fail to meet recommended glycemic goals regardless of the recognition of optimal glycemic control as a key component for improving clinical outcomes and quality of life in patients with diabetes. Patient- and physician-related barriers to the adoption of insulin therapy include fear and anxiety about injecting insulin, concerns about side effects, and personal health beliefs in regard to the use of insulin. There is an unmet need for an alternative insulin therapy that provides optimal glycemic control, is well tolerated, and improves patient adherence. Of the several inhaled insulin devices that are in various stages of development, the Exubera (INH) formulation is the first to be approved for use in the United States and in Europe. Exubera is a novel, rapid-acting inhaled human insulin formulation that has been developed for prandial insulin use. Clinical studies have shown that INH consistently improves glycemic control, in combination with longer-acting subcutaneous (SC) insulin regimens in patients with type 1 or type 2 diabetes, or is used to supplement or replace oral antidiabetic therapy in patients with type 2 diabetes. INH has demonstrated long-term safety and tolerability, with a risk for hypoglycemia similar to that of SC insulin, and no clinically meaningful changes in pulmonary function have been noted with its use. Patients treated with INH in clinical studies reported high levels of satisfaction with treatment, and many patients with diabetes choose inhaled insulin when it is offered as a treatment option. Taken together, these findings suggest that INH represents an important new development in the treatment of diabetes that may improve glycemic control in many patients with diabetes.

Where Are We Now? A Clinicians' Guide to the Use of Follow-On Insulin for Patients with Diabetes.

Insulin has been used as a standard treatment for patients with diabetes for almost 100 years. Over time, advances in insulin development have improved its pharmacologic properties. (Online access: http://courses.elseviercme.com/t2dm/666). Most recently, the US Food and Drug Administration approved a novel, follow-on basal insulin agent, with more expected to be commercially available in the near future. With the imminent availability of follow-on basal insulin agents, clinicians need to be aware of the potential benefits and concerns in order to facilitate informed decision making and to provide the best possible advice and guidance to their patients with diabetes. This program will review how follow-on insulin products are developed, manufactured, and receive regulatory approval; evaluate clinical trial data for new and emerging follow-on basal insulin agents; and provide practical information and guidance on how they may be incorporated into clinical practice. While it is unknown how follow-on basal insulins will affect patient outcomes, they have the potential to increase access to treatment among patients with diabetes and reduce healthcare costs.

Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial.

OBJECTIVE: Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections. RESEARCH DESIGN AND METHODS: Patients were randomized to 6 months' treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study. RESULTS: HbA1c decreased similarly in the inhaled (-0.7%) and subcutaneous (-0.6%) insulin groups (adjusted treatment group difference: -0.07%, 95% CI -0.32 to 0.17). HbA1c < 7.0% was achieved in more patients receiving inhaled (46.9%) than subcutaneous (31.7%) insulin (odds ratio 2.27, 95% CI 1.24-4.14). Overall hypoglycemia (events per subject-month) was slightly lower in the inhaled (1.4 events) than in the subcutaneous (1.6 events) insulin group (risk ratio 0.89, 95% CI 0.82-0.97), with no difference in severe events. Other adverse events, with the exception of increased cough in the inhaled insulin group, were similar. No difference in pulmonary function testing was seen. Further studies are underway to assess tolerability in the longer term. Insulin antibody binding increased more in the inhaled insulin group. Treatment satisfaction was greater in the inhaled insulin group. CONCLUSIONS: Inhaled insulin appears to be effective, well tolerated, and well accepted in patients with type 2 diabetes and provides glycemic control comparable to a conventional subcutaneous regimen.

Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial.

OBJECTIVE: Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population. RESEARCH DESIGN AND METHODS: In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 +/- 10 years, diabetes duration 12 +/- 7 years, BMI 34.0 +/- 7.0 kg/m(2), HbA(1c) 9.1 +/- 1.2%, mean +/- SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 micro g TID, 90 microg BID, or 120 microg BID). RESULTS: Treatment with pramlintide 120 micro g BID led to a sustained reduction from baseline in HbA(1c) (-0.68 and -0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P < 0.05). The proportion of patients achieving an HbA(1c) <8% was approximately twofold greater with pramlintide (120 microg BID) than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with pramlintide 120 micro g BID was accompanied by a mean weight loss (-1.4 kg vs. +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea. CONCLUSIONS: Mealtime amylin replacement with pramlintide 120 microg BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes.

Insulin detemir for the treatment of obese patients with type 2 diabetes.

The risk for developing type 2 diabetes (T2DM) is greater among obese individuals. Following onset of the disease, patients with T2DM become more likely to be afflicted with diabetic micro- and macrovascular complications. Decreasing body weight has been shown to lower glycosylated hemoglobin and improve other metabolic parameters in patients with T2DM. Medications used to lower blood glucose may increase body weight in patients with T2DM and this has been repeatedly shown to be the case for conventional, human insulin formulations. Insulin detemir is a neutral, soluble, long-acting insulin analog in which threonine-30 of the insulin B-chain is deleted, and the C-terminal lysine is acetylated with myristic acid, a C14 fatty acid chain. Insulin detemir binds to albumin, a property that enhances its pharmacokinetic/pharmacodynamic profile. Results from clinical trials have demonstrated that treatment with insulin detemir is associated with less weight gain than either insulin glargine or neutral protamine Hagedorn insulin. There are many potential reasons for the lower weight gain observed among patients treated with insulin detemir, including lower risk for hypoglycemia and therefore decreased defensive eating due to concern about this adverse event, along with other effects that may be related to the albumin binding of this insulin that may account for lower within-patient variability and consistent action. These might include faster transport across the blood-brain barrier, induction of satiety signaling in the brain, and preferential inhibition of hepatic glucose production versus peripheral glucose uptake. Experiments in diabetic rats have also indicated that insulin detemir increases adiponectin levels, which is associated with both weight loss and decreased eating.

Efficacy and safety of CP-945,598, a selective cannabinoid CB1 receptor antagonist, on weight loss and maintenance.

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.

Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors.

The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Achieving glycemic control is a critical component of this process. The selection of drug therapy for reducing blood glucose is made more challenging when patients already have complications or comorbid conditions (eg, high risk for hypoglycemia, obesity, renal impairment). Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antihyperglycemic drugs that block degradation of incretin hormones. By enhancing and prolonging incretin effects, DPP-4 inhibitors stimulate glucose-dependent insulin secretion and also reduce glucagon secretion. This results in improved glycemic control, as reflected by decreases in glycated hemoglobin (HbA1c), fasting plasma glucose, and postprandial plasma glucose. Dipeptidyl peptidase-4 inhibitors also have the potential to improve beta-cell function. In randomized clinical trials, the DPP-4 inhibitors saxagliptin and sitagliptin reduced HbA1c by 0.5% to 0.8%, compared with placebo, whether used as monotherapy or in combination with another agent. As initial combination therapy with metformin, saxagliptin and sitagliptin have demonstrated reductions in HbA1c of 2.5% and 1.9%, respectively. The efficacy of the DPP-4 inhibitors was maintained during treatment for up to 2 years, and did not differ in the elderly compared with younger adults. Dipeptidyl peptidase-4 inhibitors offer efficacy similar to other drug classes, and are well tolerated with a lower risk of hypoglycemia, weight-neutral effects, and a low propensity for drug-drug interactions. On the basis of their clinical profiles, the DPP-4 inhibitors are emerging as an attractive option for improving glycemic control in patients with type 2 diabetes. Saxagliptin and sitagliptin are approved for use as initial therapy in combination with metformin, as monotherapy, as well as in combination with metformin, a sulfonylurea, or a thiazolidinedione in patients not adequately controlled by these agents alone.

Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial.

OBJECTIVE To examine the efficacy and safety of rimonabant, a selective cannabinoid receptor type-1 antagonist, in patients with type 2 diabetes receiving insulin monotherapy. RESEARCH DESIGN AND METHODS Patients (n = 368; A1C > or =7%) were randomized to 20 mg/day rimonabant or placebo in this 48-week, double-blind, placebo-controlled multicenter trial. Change in baseline A1C to week 48 (primary outcome) and changes in body weight, waist circumference, and lipid levels (secondary outcomes) were assessed. RESULTS Rimonabant significantly reduced baseline A1C versus placebo (-0.89 vs. -0.24%; P < 0.0001), and significantly greater improvements were observed in cardiometabolic risk factors. More rimonabant patients achieved >10% reduction in mean total daily insulin dose versus placebo (P = 0.0012), and fewer required rescue medication (P < 0.0001). Hypoglycemia, nausea, dizziness, anxiety, and depression were more frequent with rimonabant. CONCLUSIONS Rimonabant improved glycemic control and cardiometabolic risk factors in patients with type 2 diabetes receiving insulin.

Titration of inhaled human insulin (Exubera) in a treat-to-target regimen for patients with type 2 diabetes.

OBJECTIVE: This study assessed the feasibility of safely achieving target glycated hemoglobin (A1C) of < or =7% by intensifying structured insulin titration regimens using inhaled human insulin (Exubera [EXU] [Pfizer Inc., New York, NY] [insulin human (recombinant DNA origin)] inhalation powder) in patients with type 2 diabetes inadequately controlled on combination oral antidiabetes agents (OADs). METHODS: In a randomized, open-label, parallel, 24-week multicenter trial, 107 type 2 diabetes patients with mean baseline A1C of 8.6% taking two or more OADs were randomized to adjust EXU before meals following either weekly office visits or more intense twice-weekly telephone/office consultations, using a simple but structured insulin titration algorithm seeking to attain specific premeal glucose levels. Primary outcome was the percentage of patients reaching A1C < or =7%; secondary measures were changes in A1C, eight-point self-monitored blood glucose values, postprandial glucose levels during a meal tolerance, and frequency of hypoglycemia. RESULTS: A1C improved whether EXU was systematically titrated once (6.8%) or twice weekly (6.8%), and two-thirds of patients in both groups attained A1C < or =7% (69% and 67%, respectively). Relative to baseline, glucose profiles were reduced at all time points measured, and postprandial glucose levels during meal tolerance improved to a similar extent in both groups. There were 538 hypoglycemic events with twice-weekly and 343 with once-weekly EXU titration; other adverse events were similar between groups. CONCLUSIONS: Added to oral therapy, premeal inhaled insulin can safely achieve < or =7% A1C in most patients with type 2 diabetes inadequately controlled while taking two or more OADs if a once- or twice-weekly structured insulin titration regimen is used.

Safety and efficacy of inhaled human insulin (exubera) during discontinuation and readministration of therapy in adults with type 2 diabetes: a 3-year randomized controlled trial.

OBJECTIVE: This study assessed pulmonary safety following discontinuation and readministration of inhaled human insulin {Exubera [EXU] [Pfizer Inc., New York, NY] (insulin human [recombinant DNA origin]) inhalation powder} in adults with type 2 diabetes (T2DM). METHODS: Patients were randomized to receive EXU (n = 316) or subcutaneous (SC) insulin (n = 311) for 2 years (comparative phase), followed by 6 months of SC insulin (washout phase) and 6 months of original therapy (readministration). Highly standardized lung function tests were performed throughout all phases. RESULTS: Small, nonprogressive treatment group differences were observed to occur early during the comparative phase for parameters such as change from baseline for forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). These differences resolved during washout and recurred to the same small magnitude during readministration. Both treatment groups maintained similar glycemic control and hypoglycemic event rates. In the EXU group, insulin antibody (IAb) levels reached a plateau at 9 months, declined to near baseline levels during washout, and increased during readministration to levels observed in the comparative phase. CONCLUSIONS: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy were consistent with a reversible, nonprogressive, and nonstructural pathologic effect on lung function in adults with T2DM. EXU readministration was not associated with an augmented IAb response.

Safety and efficacy of inhaled human insulin (Exubera) during discontinuation and readministration of therapy in adults with type 1 diabetes: A 3-year randomized controlled trial.

OBJECTIVE: To assess pulmonary safety during discontinuation and readministration of inhaled human insulin (EXU; Exubera((R)) insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes. METHODS: Patients were randomized to receive basal insulin plus either pre-meal EXU (n=290) or a short-acting subcutaneous (SC) insulin (n=290) for 2 years (comparative phase), followed by 6 months of SC insulin (washout) and 6 months of their original therapy (readministration). Highly standardized lung function tests were performed throughout. RESULTS: Small treatment group differences favoring SC insulin in change from baseline forced expiratory volume in 1s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)) occurred early and were non-progressive. These differences resolved during washout and recurred at the same magnitude during readministration. Both groups maintained glycemic control, and hypoglycemic event rates were similar. In the EXU group, insulin antibody (IAb) levels plateaued at 12 months, declined to near baseline levels during washout and increased during readministration to levels observed in the comparative phase. CONCLUSIONS: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathological effect on lung function. EXU readministration is not associated with an augmented IAb response.

Two-year pulmonary safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 2 diabetes.

OBJECTIVE: The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)). RESULTS: Small differences in FEV(1) favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV(1) annual rate of change were -0.007 l/year (90% CI -0.021 to 0.006) between months 0 and 24 and 0.000 l/year (-0.016 to 0.016) during months 3-24. Treatment group differences in DL(CO) annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7-7.3% vs. subcutaneous insulin 7.8-7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference -12.4 mg/dl [90% CI -19.7 to -5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (-1.3 kg [-1.9 to -0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU. CONCLUSIONS: Two-year prandial EXU therapy showed a small nonprogressive difference in FEV(1) and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.