Among the new data presented at the 68th Scientific Sessions of the ADA were the results of phase 3 trials of the investigational agents liraglutide, ABT-335, saxagliptin, and alogliptin.
Liraglutide improves glycemic control, causes weight loss
Previous phase 2 studies of liraglutide as monotherapy had demonstrated sustained reductions in HbA1c levels with a low risk of hypoglycemia and clinically significant weight reduction.The phase 3 study was presented by Michael Nauck, MD, PhD, Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany.
Patients with type 2 diabetes underwent a medication washout period and then started a 3-week run-in phase with forced titration of metformin to 2,000 mg/d. After a 3-week maintenance period, 1,091 patients with fasting plasma glucose levels of 126 to 230 mg/dL were randomized to 1 of 3 doses of liraglutide (1.8, 1.2, or 0.6 mg once daily) plus metformin; glimepiride 4 mg/d plus metformin; or metformin monotherapy. The duration of the study was 26 weeks.
Patients randomized to liraglutide 1.2 or 1.8 mg had reductions in HbA1c of 0.9%. A total of 35% and 42% of these patients, respectively, achieved a target HbA1c of <7.0%, a significantly higher proportion of patients than the proportion of those randomized to placebo (11%) who achieved the HbA1c target (P<.05).
The HbA1c change demonstrated with liraglutide was not significantly different than the change demonstrated with glimepiride (1.0%).
Fasting plasma glucose levels were reduced by 28.1, 26.7, and 20.2 mg/dL in the liraglutide 1.8-, 1.2-, and 0.6-mg dosage groups, respectively; these reductions were similar to the 21.8-mg/dL decline observed in the glimepiride group and significantly superior to the 9.7-mg/dL increase observed in placebo recipients (P<.0001).
Median body weight decreased by 2.8, 2.5, and 1.8 kg in patients randomized to liraglutide 1.8, 1.2, and 0.6 mg, respectively. Weight decreased by 1.8 kg in the placebo recipients and increased by 0.8 kg in patients assigned to glimepiride.
No major hypoglycemic events were reported in any group.
Minor hypoglycemic events were reported in 2.5%, 0.8%, and 3.7% of the patients assigned to liraglutide 1.8, 1.2, and 0.6 mg, respectively; 2.5% patients assigned to placebo; and 16.9% of patients assigned to glimepiride.
"Weight reduction with liraglutide plus metformin was clearly unrelated to nausea, the incidence of which was modest and declined with time," Dr Nauck said.
Nausea was reported in 11% to 19% of patients assigned to liraglutide; the incidence was greatest during the initial weeks of therapy. After 16 weeks, the incidence of nausea in liraglutide recipients decreased to <4% of patients per week, he said.
A second study, a meta-analysis of 3 randomized, double-blind, controlled 26-week trials that included 2,713 patients with type 2 diabetes, demonstrated that the liraglutide 1.8-mg dosage increased beta-cell function by the homeostasis model assessment (HOMA) by 28% to 34% from baseline.
An NDA for liraglutide was filed in May 2008.
ABT-335 PLUS ROSUVASTATIN STUDY
Fenofibrate plus rosuvastatin effective in treatment of mixed dyslipidemia
An investigational fenofibric acid molecule (ABT-335), when used in combination with rosuvastatin, treats mixed dyslipidemia in patients with type 2 diabetes better than rosuvastatin monotherapy, said Peter H. Jones, MD, associate professor, Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston.
The combination of ABT-335 and rosuvastatin was evaluated in 276 patients with type 2 diabetes who were part of a larger phase 3 study of >1,400 patients with mixed dyslipidemia. The patients in this analysis had baseline low-density lipoprotein (LDL) cholesterol levels ≥130 mg/dL, high-density lipoprotein (HDL) cholesterol <40 mg/dL for men and <50 mg/dL for women, and triglyceride levels ≥150 mg/dL.
Patients were randomized in a double-blind fashion to 12 weeks of treatment with 135 mg of ABT-335 combined with rosuvastatin 10 or 20 mg; 135 mg of ABT-335 alone; or rosuvastatin 10, 20, or 40 mg alone. The rosuvastatin 40-mg arm was included to assess safety only.
In general, the combination was superior to rosuvastatin alone in increasing HDL cholesterol and reducing triglycerides, with no significant effect on LDL cholesterol compared with rosuvastatin monotherapy.
"This agent [ABT-335] in combination with rosuvastatin has the ability to achieve the American Diabetes Association goals for HDL, LDL, non-HDL cholesterol, and triglycerides in patients with diabetic dyslipidemia, more so than monotherapy," said Dr Jones.
ABT-335 was also associated with reductions in apolipoprotein B and non-HDL cholesterol, he added.
The safety of the combination was comparable to the safety of rosuvastatin monotherapy, Dr Jones said. An elevation in blood creatinine was experienced by 1.9% to 5.8% of patients treated with combination therapy (rosuvastatin 10 and 20 mg, respectively), and myalgia was reported by 1.9% to 3.8% of patients treated with combination therapy.
An NDA for ABT-335 for use as monotherapy and in combination with statins has been submitted to FDA. A fixed-dose combination of ABT-335 and rosuvastatin is being codeveloped by Abbott and AstraZeneca; they plan to submit an NDA for this combination in 2009.
Once-weekly exenatide effective in improving glycemic control
An investigational once-weekly form of exenatide significantly improves hemoglobin A1c (HbA1c) and fasting plasma glucose levels compared with twice-daily exenatide, reported Daniel J. Drucker, MD, professor, division of endocrinology, department of medicine, University of Toronto, and director of the Banting and Best Diabetes Centre.
The once-weekly formulation of exenatide encapsulates the active medication into polymer-based microspheres that are degraded slowly after injection.
In the Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, 295 patients with type 2 diabetes were randomized to exenatide 2.0 mg once weekly or to exenatide 10 mcg twice daily (according to approved labeling).
Patients were either drug naïve or had been treated with ≥1 oral glucose-lowering therapy before study entry.
Baseline HbA1c was 8.3%, fasting plasma glucose was 169 mg/dL, body weight was 225 lb, and body mass index (BMI) was 35.0 kg/m2.
Patients who completed the randomized portion of the study were then entered into a 30-week open-label phase during which all patients received once-weekly exenatide.
During the randomized portion of the study, patients assigned to once-weekly exenatide demonstrated a 1.9% reduction from baseline in HbA1c compared with a 1.5% reduction from baseline in those assigned to twice-daily exenatide (P=.002 for between-group difference).
More patients assigned to treatment with once-weekly exenatide achieved an HbA1c ≤7% than those who were assigned to exenatide twice daily (77% vs 61%; P=.004), said Dr Drucker.
Among patients who began the study with a baseline HbA1c ≥9%, 29% of those treated with once-weekly exenatide achieved an HbA1c <6.5% compared with 13% of those patients who received twice-daily exenatide.
Fasting plasma glucose levels declined by 42.3 mg/dL in the group randomized to once-weekly exenatide compared with 25.3 mg/dL in patients treated with twice-daily exenatide (P<.0001).
Both formulations of exenatide were associated with a reduction in weight of 4 kg.
Approximately 90% of patients completed 30 weeks of treatment with exenatide once weekly. No major hypoglycemia was observed with either exenatide regimen. The cumulative incidence of patients reporting an episode of nausea was 26% for once-weekly exenatide versus 35% for twice-daily exenatide.
SITAGLIPTIN PLUS METFORMIN STUDY
Long-term data with sitagliptin plus metformin demonstrate continued glucose control
Data out to 2 years demonstrate that the combination of sitagliptin and metformin provides superior glucose control compared with either agent when used as monotherapy and significantly improves markers of beta-cell function in patients with type 2 diabetes, according to Debora Williams-Herman, MD, Merck Research Laboratories in Rahway, New Jersey.
The data were obtained from an extension of a 24-week, placebo-controlled study of 1,091 patients with type 2 diabetes. The initial 24-week study was followed by a 30-week active-controlled period in 762 patients, in which patients taking placebo were switched to metformin. A total of 587 patients were entered into a study extension out to 2 years.
The analysis included a subset of 203 patients who underwent a frequently sampled meal tolerance test at baseline and Week 54, as well as 125 patients who did so at 104 weeks.
The mean reduction from baseline HbA1c was 1.8% at 1 year and 1.7% at 2 years in patients treated with sitagliptin 50 mg plus metformin 1,000 mg twice daily, said Dr Williams-Herman.
In patients treated with sitagliptin 50 mg plus metformin 500 mg twice daily, the mean reduction in HbA1c was 1.4% (147 patients were treated for 1 y and 96 patients were treated for 2 y).
Among patients treated with metformin 1,000 mg twice daily as monotherapy, the mean reduction in HbA1c was 1.3% (134 patients were treated for 1 y and 87 patients were treated for 2 y), and among those receiving metformin 500 mg twice daily as monotherapy, the mean reduction in HbA1c was 1.0% at 1 year and 1.1% at 2 years.
Among patients treated with sitagliptin 100 mg once daily as monotherapy, there was a mean reduction from baseline in HbA1c of 0.8% at 1 year and 1.2% at 2 years.
After 54 weeks, the changes in static and dynamic beta-cell responsiveness and disposition indices (insulin secretion rate in the context of changes in insulin sensitivity) were greater with sitagliptin plus metformin compared with either agent administered as monotherapy.
Saxagliptin associated with improvement in HbA1c without causing weight gain
Saxagliptin, a selective, reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) in phase 3 clinical trials, was associated with significant reductions in hemoglobin A1c (HbA1c) levels, fasting plasma glucose levels, and postprandial glucose levels without promoting weight gain in treatment-naïve patients with type 2 diabetes, reported Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center at Medical City, and clinical professor of medicine, University of Texas Southwestern Medical Center, Dallas.
Saxagliptin was studied in 401 treatment-naïve patients with type 2 diabetes who had an HbA1c level of ≥7% but ≤10%. In the 24-week double-blind study, patients were randomized to 1 of 3 doses of saxagliptin (2.5, 5, or 10 mg) or placebo.
Relative to placebo, patients randomized to saxagliptin demonstrated reductions in HbA1c levels of 0.62%, 0.64%, and 0.73% at the 2.5-, 5-, and 10-mg dose levels, respectively (P<.0001 vs placebo for all).
Reductions were observed relative to placebo as early as Week 4, which was the first assessment point, said Dr Rosenstock.
An HbA1c target of <7% was achieved by 35%, 38%, and 41% of the patients randomized to the 2.5-, 5-, and 10-mg doses of saxagliptin compared with 24% of the patients assigned to placebo (P<.05 for the 5-and 10-mg dose groups vs placebo; not significant at the 2.5-mg dose).
Saxagliptin significantly reduced fasting plasma glucose in all treatment arms. The adjusted mean placebo-subtracted difference in fasting plasma glucose was 21 mg/dL, 15 mg/dL, and 23 mg/dL in patients assigned to saxagliptin 2.5, 5, and 10 mg, respectively (P<.0075 for all), with reductions observed as early as Week 2.
Postprandial glucose area under the curve (AUC) was also reduced in each of the active treatment arms compared with placebo, said Dr Rosenstock.
The frequency of adverse events was similar across all treatment groups and placebo. The most commonly reported adverse events were upper respiratory tract infection, headache, urinary tract infection, nasopharyngitis, and sinusitis.
There were no cases of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL) in any group.
Saxagliptin was not associated with weight gain at any dosage. The mean changes in body weight from baseline were –1.2, –0.1, and –0.1 kg in the saxagliptin 2.5-, 5-, and 10-mg dosage groups, respectively, and –1.4 kg in the group assigned to placebo.
An NDA for saxagliptin was filed in July 2008.
Alogliptin works as monotherapy to improve glycemic control
The investigational dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin improved glycemic control when used as monotherapy in a phase 3 study, reported Ralph DeFronzo, MD, professor of medicine and chief of the Diabetes Division at the University of Texas Health Science Center, San Antonio.
In the 26-week double-blind study, 329 patients with type 2 diabetes and a mean baseline hemoglobin A1c (HbA1c) of 7.9% were randomized to alogliptin 12.5 or 25 mg or placebo once daily.
Hyperglycemic rescue (defined as a fasting plasma glucose ≥275 mg/dL after >1 wk of treatment but before 4 wk of treatment, a single fasting plasma glucose ≥250 mg/dL from 4 wk of treatment but before 8 wk of treatment, a single fasting plasma glucose ≥225 mg/dL from 8 wk of treatment but before 12 wk of treatment, or an HbA1c ≥8.5% and ≤0.5% reduction in HbA1c compared with baseline from 12 wk of treatment through the end of the study period) was a defined end point of the study.
Hyperglycemic rescue causing discontinuation of treatment occurred significantly less often with alogliptin compared with placebo (P≤.001). The incidence of hyperglycemic rescue was 29.2% in patients assigned to placebo compared with 9.8% of patients assigned to alogliptin 12.5 mg and 7.6% of patients assigned to alogliptin 25 mg.
At Week 26, the mean changes from baseline in HbA1c were significantly greater with alogliptin 12.5 mg (–0.56%) and with alogliptin 25 mg (–0.59%) than with placebo (–0.02%; P<.001 for both), said Dr DeFronzo.
Mean changes from baseline in HbA1c were greater in patients with baseline HbA1c ≥8.0% (alogliptin 12.5 mg, –0.70%; alogliptin 25 mg, –0.91%; placebo, –0.15%).
In addition, significantly greater changes from baseline in fasting plasma glucose were observed for alogliptin 12.5 mg (–10.3 mg/dL) and alogliptin 25 mg (–16.4 mg/dL) compared with placebo (+11.3 mg/dL; P<.001 for both) at Week 26.
A greater proportion of patients achieved HbA1c levels ≤7.0% with alogliptin 12.5 mg (47%; P=.001) and with alogliptin 25 mg (44%; P=.008) than with placebo (23%) at Week 26.
The incidence of hypoglycemia was low and was similar across groups (alogliptin 12.5 mg, 3.0%; alogliptin 25 mg, 1.5%; placebo, 1.6%).
There was no significant difference relative to placebo in change from baseline body weight with either alogliptin dose.
An NDA for alogliptin was filed in January 2008.
Intensive glycemic control associated with increased mortality in high-risk patients
An intense glucose-lowering strategy in high-risk patients with type 2 diabetes was associated with an excess of mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the US counterpart to the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study.
ADVANCE was conducted in 20 countries throughout Asia, Australia, Europe, and North America. In the trial, intensive glycemic control significantly reduced the risk of kidney disease in type 2 diabetes and had no effect on overall mortality or cardiovascular disease (CVD) events.
ACCORD was sponsored by the National Heart, Lung, and Blood Institute. This trial was terminated prematurely because an interim safety review identified an increase in death in the intensive treatment group (hemoglobin A1c [HbA1c] goal <6%) compared with standard glycemic control (HbA1c goal, 7.0%–7.9%).
ACCORD included 10,251 high-risk middle-aged or older adults (mean age, 62 y) with type 2 diabetes from the United States and Canada. The participants were considered at high risk if they had a history of prior myocardial infarction (MI) or stroke or subclinical CVD or major cardiovascular risk factors (≥2 of the following: elevated low-density lipoprotein [LDL] cholesterol, a low level of high-density lipoprotein [HDL] cholesterol, hypertension, an elevated body mass index, or cigarette smoking). The HbA1c levels achieved in the 2 treatment strategies were 6.4% in those randomized to the intensive strategy and 7.5% in patients randomized to standard glycemic control.
Patients assigned to the intensive strategy had clinic visits every 2 months and were required to monitor their blood glucose levels 2 to 4 times daily. Patients assigned to standard control had clinic visits every 4 months and were required to carry out self-monitoring only daily.
Fifty-two percent of patients in the intensive treatment group required treatment with insulin plus 3 oral agents to achieve their glycemic target, compared with 16% in the standard group. Choice of therapy was at the discretion of the treating physician.
During 3.5 years of follow-up (planned follow-up, 5 y), 257 patients (5.1%) in the intensive group died, compared with 203 (4.0%) in the standard control group, a 22% increase (P=.04) in the group randomized to the intensive strategy. There was no subgroup identified among intensively treated patients that was more likely to die in response to intensive therapy.
The primary outcome of the trial (the first occurrence of a major fatal or nonfatal cardiovascular event) was achieved by 10% fewer patients assigned to the intensive strategy, but this difference failed to achieve statistical significance (P=.16).
Intensive therapy was associated with a 35% increase in cardiovascular death (P=.02) and a 24% reduction in nonfatal MI (P=.004). There was no difference between the 2 strategies in the occurrence of nonfatal stroke or heart failure.
Intensive blood glucose control associated with renal benefits
Intensive blood glucose control in patients with type 2 diabetes resulted in a significant reduction in the risk of microvascular complications compared with standard blood glucose control in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study. This reduction in microvascular complications was driven by a reduction in the occurrence of nephropathy.
No evidence of an increased risk of death was observed among ADVANCE patients randomized to intensive blood glucose control. This is in contrast with the results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was terminated prematurely because of an increased rate of death in patients whose blood glucose was intensively controlled.
There was no significant effect of intensive blood glucose control on macrovascular risk in ADVANCE, but the aggressive treatment of cardiovascular risk factors in the group randomized to standard control and the smaller-than-targeted difference in achieved hemoglobin A1c (HbA1c) levels between the 2 randomized groups may have contributed to this lack of a significant effect, according to Anushka Patel, MBBS, PhD, study director of ADVANCE, director of the cardiovascular division at The George Institute for International Health, and associate professor at the University of Sydney, Australia.
ADVANCE was an international study funded by the Australian Government's National Health and Medical Research Council and Servier. It was carried out independently of the government and industry sponsor. The trial included 11,140 high-risk patients with type 2 diabetes who were randomized to a target HbA1c level of ≤6.5% (intensive control) or standard guidelines-based HbA1c targets.
"The intensive glucose control strategy we're reporting is a pragmatic, flexible approach that in many ways reflects the approach to glucose control practiced by diabetologists, family doctors, and many others," said Stephen MacMahon, DSc, PhD, MPH, coprincipal investigator of ADVANCE, and professor of cardiovascular medicine and epidemiology, University of Sydney.
The average achieved HbA1c levels were 6.5% in the intensive arm and 7.3% in the standard arm (average difference in HbA1c between the 2 arms over the course of the trial, 0.7%).
The incidence of combined major macrovascular and microvascular events was reduced by 10% (P=.01) in the participants randomized to intensive blood glucose lowering.
The intensive control strategy was associated with a 14% reduction (P=.01) in the risk of microvascular events (a coprimary end point) compared with standard control, driven by a 21% reduction (P=.006) in the risk of the development or progression of kidney disease in the intensive arm. There was no significant effect of the intensive intervention on retinopathy.
The incidence of a composite of death and macrovascular complications, the other coprimary outcome, was not significantly affected by intensive glucose control: 10% in the intensive treatment group and 10.6% in the standard treatment group achieved this outcome (P=.32).
The overall rate of cardiovascular events was only 2.2% per year, much lower than the anticipated 3% per year, which may have prevented the study from having sufficient power to detect a difference in cardiovascular events between the 2 strategies. The final difference in HbA1c levels between the 2 groups (0.7%) was less than the 1% difference in HbA1c the investigators sought to achieve.
As expected, the incidence of hypoglycemia was higher in the intensive group. Severe hypoglycemic events occurred in 2.7% of the intensive arm versus 1.5% in the standard arm (P<.001).
"The study makes it clear for clinicians and their patients the kind of goals that we should be aiming for. We can conclude that getting them down to HbA1c levels of less than 7% or even approaching 6.5% can benefit patients [with regard to] diabetic kidney disease, and essentially protect 1 in 5 over a few years from developing this very bad complication, which is a feared complication indeed," said Dr MacMahon.