72nd American Diabetes Association Scientific Sessions: Clinical updates review findings on risk of malignancy with pioglitazone, as well as various risk factors associated with insulin glargine use


A review of drug therapies and research presented at the 2012 Scientific Session of the American Diabetes Association.

The world's leading experts on diabetes convened for 5 days of scientific presentations, discussions, and analysis at the American Diabetes Association's 72nd Scientific Sessions, in Philadelphia.

Following are summaries of some of the cutting-edge research presented including insulin glargine and cancer risk, clarifying the risk of bladder malignancy and other cancers with pioglitazone, and insulin glargine and the risk of cardiovascular events in patients with type 2 diabetes or at risk for type 2 diabetes.

Insulin glargine probably does not promote cancer, according to database analyses

Although the short duration of follow-up precludes a definitive answer with respect to insulin glargine and cancer risk, the answer is now much clearer, "and there seems to be no link," said John Buse, MD, PhD, who led an analysis of a US database. When combined with the results of the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial, which were also released here and also failed to find a link between insulin glargine and cancer (see story below), Dr Buse said that he was confident about the safety of insulin glargine.

The initial alarm was sounded in 2009, when a potential association between insulin glargine and cancer, especially breast cancer, was suggested in 4 papers published in Diabetologia, Journal of the EASD (European Association for the Study of Diabetes). These studies had methodological limitations, and the observational studies presented here were meant to clarify the association.

Northern European database/meta-analysis. An analysis of databases from 5 countries (Denmark, Finland, Norway, Scotland, and Sweden) with more than 1.5 million person-years of observation found "no difference in risk of cancer, breast cancer, colorectal cancer, or prostate cancer between glargine and other insulins in any of the predefined primary and secondary hypotheses of the study," said Peter Boyle, MD, president of the International Prevention Research Institute, Lyon, France.

The Northern European Study of Insulin and Cancer included data from 447,821 patients with type 1 or type 2 diabetes taking insulin and 17,800 new cases of cancer. The average follow-up time was the longest for the 3 observational studies: 3.1 years for those taking insulin glargine and 3.5 years for those taking other insulins.

For the primary hypothesis, there was no difference in the risk of breast, prostate, or colorectal cancer between insulin glargine users and users of other insulins. Among users of insulin glargine versus other insulins, the hazard ratio (HR) for breast cancer in women was 1.12 (95% CI, 0.99–1.27), the HR for prostate cancer in men was 1.11 (95% CI, 1.00–1.24), and the HR for colorectal cancer in men and women was 0.86 (95% CI, 0.76–0.98).

For the secondary hypothesis, there was no increased risk of all cancers combined (HR: 0.98; 95% CI, 0.94–1.03), and an exploratory analysis found no increased risk of lung cancer or pancreatic cancer among glargine users relative to other insulins, reported Dr Boyle.

A meta-analysis of epidemiologic data from 21 independent studies comparing insulin glargine with other forms of insulin, including an analysis limited to new users, in more than 900,000 patients with almost 3 million person-years of follow-up produced similar findings. In the meta-analysis, the HR for all cancers was less than 1.0 (0.88; 95% CI, 0.79–0.97) among the glargine users relative to users of other insulins. The HR for all cancers did not change (0.91; 95% CI, 0.84–0.99) when updating the meta-analysis to include the Northern European data to the other 21 studies. There was no increased risk of any individual cancer examined in the meta-analysis or the updated meta-analysis among users of glargine.

Studies of glargine and malignancy now include more than 1 million patients with diabetes and more than 3 million person-years of observation. No excess risk of cancer of any form can be detected, said Dr Boyle.

Kaiser Permanente collaboration. The Northern and Southern California Kaiser Permanente study included 27,418 patients with diabetes who took insulin glargine (median duration of use: 1.2 years) and 100,757 patients who took neutral protamine Hagedorn (NPH; median duration of use: 1.4 years). Of these, there were 39,708 new users of NPH insulin and 6,548 new users of glargine.

Median follow-up overall was 2.3 years in the glargine users and 3.6 years in the NPH users.

Among patients who had been using NPH, another insulin with a similar indication for use, risk of breast, prostate, and colorectal cancer was not increased among patients switching to glargine compared to those who remained on NPH, said Laurel Habel, PhD, research scientist at Kaiser Permanente, Oakland, Calif.

Among the new insulin users, there was no increased risk of prostate or colorectal cancer among those initiating glargine versus NPH, but there was a suggestion of an increase in the risk of breast cancer with 2 years of glargine use (HR: 1.6, 95% CI, 1.0–2.8). Habel noted that the increase was only borderline statistically significant.

"We don't think there's a good biological reason as to why you'd only see an increase in breast cancer risk among new insulin users but not those switching from NPH," she said.

The results should be viewed cautiously, she said, because of the recent introduction of glargine and thus the relatively short duration of glargine use that could be studied. This is important since most carcinogens require several years to decades before an increase in cancer would appear.

MedAssurant database. The third analysis used data from the MedAssurant automated database, from which 43,306 new users of glargine and 9,147 new users of NPH were identified. Mean treatment times were 1.2 and 1.1 years, respectively.

Using the NPH group as the reference group, the adjusted HRs for breast cancer, prostate cancer, colon cancer, and all cancers were 1.1 (95% CI, 0.7–1.8), 1.2 (95% CI, 0.7–1.9), 0.9 (95% CI, 0.5–1.6), and 1.1 (95% CI, 1.0–1.3), respectively, for users of glargine, said Dr Buse, director of the Diabetes Center, University of North Carolina, Chapel Hill.

A subanalysis of patients who used insulin for at least 24 months found no increased risk of breast cancer among glargine users (adjusted HR: 0.7; 95% CI, 0.2–2.5) but Dr Buse cautioned that this finding was based on a total of only 14 cases of breast cancer overall (11 in the glargine group vs 3 in the NPH group).

The short duration of treatment was an obvious limitation to the analysis, he said, but "the study adds considerable number of outcomes to existing evidence on the relative safety of glargine."

According to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City, this information regarding insulin glargine and its cancer risk is extremely important.

"Insulin glargine has been a mainstay of type 1 and type 2 diabetes therapy for the last several years," Dr Wooten said. "Common adverse effects like hypoglycemia can be anticipated and handled but long-term and untoward effects like malignancies are a different story. Both physicians and patients would be quite reluctant to utilize a drug that has a cancer risk associated with it. Although these data is largely retrospective it does offer some relief to both practitioners and patients alike that insulin glargine is both a safe and effective drug."

Studies clarify risk of bladder malignancy, other cancers with pioglitazone

Follow-up as long as 9 years of patients taking pioglitazone as part of a double-blind randomized clinical trial followed by an observational period has found no increased risk of bladder malignancy or any other malignancy associated with pioglitazone.

"On the contrary, there were slightly lower rates of bladder malignancy during the follow-up phase of the study among those patients initially randomized to receive pioglitazone compared with placebo," said Robert Spanheimer, MD, vice president of Global Medical Affairs at Takeda Pharmaceuticals International, Deerfield, Ill.

The finding comes from an updated analysis of patients enrolled in PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events), and is in contrast to data from a case-control study published 2 weeks prior to the ADA scientific sessions (BMJ 2012;344:e3645). The case-control study from investigators in the United Kingdom showed that ever use of pioglitazone was associated with an 83% excess risk of bladder cancer compared with never use, and that the rate of bladder cancer increased significantly with longer duration of pioglitazone use.

Subsequent to the ADA sessions, a meta-analysis of 10 studies published in the Canadian Medical Association Journal (July 3, 2012; Epub ahead of print) found a 22% increased risk of bladder cancer associated with pioglitazone compared with those never exposed.

In 2011, FDA issued a warning that use of pioglitazone for longer than 1 year might be associated with an increase in the risk of bladder cancer.

The PROactive study investigated pioglitazone versus placebo for the secondary prevention of macrovascular events in 5,238 patients with type 2 diabetes followed for a minimum of 2.5 years. During the study, an imbalance in bladder malignancies was reported-14 (0.5%) in patients randomly assigned to pioglitazone versus 5 (0.2%) in those randomly assigned to placebo. After excluding cases that occurred in the first year of treatment, there were only 6 cases of diagnosed bladder cancer in the pioglitazone group and 2 in the placebo group.

The current study is a 6-year interim analysis of a planned 10-year follow-up of patients who completed the study. A total of 3,599 patients enrolled in the observational study. The mean follow-up was 5.8 years (maximum, 6.1 years) for the observational period alone and 8.7 years (maximum, 9.5 years) for the double-blind plus observational periods combined.

The total follow-up was 21,066 patient-years for the observational period alone, and 35,904 patient-years for the double-blind plus observational periods combined.

"With longer time after exposure, we're not seeing an increase in bladder cancer [with pioglitazone]," said Dr Spanheimer. "What we're seeing is with small numbers [of cases] and random distribution, over time the incidence is equaling out."

During the observational period only, there was no significant difference in the rate of any malignancy between the pioglitazone and placebo groups (9.0% vs 8.8%) and the rate of bladder malignancy (0.5% with pioglitazone vs 1.0% with placebo).

In comparing rates of malignancy during the double-blind period plus the observational period, there was again no significant difference between patients randomized to pioglitazone and those randomized to placebo with respect to any malignancy (9.9% vs 9.4%, respectively) and bladder malignancy (0.9% vs 0.8%, respectively).

When events during the first 365 days are excluded, "there were nominally fewer patients with diagnoses of bladder malignancy with pioglitazone in the combined period," said Dr Spanheimer, 15 (0.6%) versus 19 (0.7%), which was not statistically significant (HR: 0.75; 95% CI, 0.38–1.48).

A retrospective cohort study using a US database also found a similar incidence of bladder cancer between pioglitazone users and insulin users with type 2 diabetes. Data for this study were extracted from the i3 InVision Data Mart database, from which 38,588 pioglitazone users and 17,948 insulin users 45 years or older with type 2 diabetes were selected.

The mean follow-up time was 2.2 years in the pioglitazone group and 1.9 years in the insulin group; longest follow-up was 7 years.

The incident rate of bladder cancer per 100,000 person years was 113 (82 cases) for the pioglitazone group and 152 (44 cases) for the insulin group, for an adjusted HR of 0.92 for pioglitazone use (P=.64), reported Carlos Vallarino, PhD, a statistician at the Takeda Global Research and Development Center.

A composite of 9 other cancers (prostate, female breast, pancreatic, endometrial, non-Hodgkin's lymphoma, colorectal, kidney, lung, and malignant melanoma) was also examined, and the occurrence of such cancers was significantly lower by 22% among the pioglitazone recipients relative to insulin users (P<.0001).

To put the cancer risk in perspective, the crude incidence rate of bladder cancer are approximately 100 to 150 per 100,000 patient-years, or about "one sixth the risk of a cardiovascular event, and one sixteenth the risk of other cancers," said Dr Vallarino.

"Pioglitazone is a thiazolidinedione anti-diabetic agent that has been used for several years to treat type 2 diabetes as well as insulin resistance," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "Unfortunately, this class of drugs has come under much scrutiny because of various adverse effects. The fact that pioglitazone may not pose a cancer risk is important information since the thiazolidinedione class has unique pharmacologic effects that are different from other drug classes."

Both the PROactive study and the retrospective cohort study were sponsored by Takeda Global Research and Development Center, Inc., Deerfield, Ill.

Insulin glargine has no effect on cardiovascular outcomes in patients with type 2 diabetes or at risk for type 2 diabetes

The addition of basal insulin in patients with either impaired fasting glucose, impaired glucose tolerance, or recently or newly diagnosed type 2 diabetes plus additional risk factors for cardiovascular disease does not reduce the risk of adverse cardiovascular outcomes, according to data from a large multinational, randomized controlled trial.

In a trial known as ORIGIN (Outcome Reduction with an Initial Glargine Intervention), assigning patients to daily titrated insulin glargine to normalize fasting plasma glucose levels had a neutral effect on cardiovascular outcomes over a median of 6.2 years, said principal investigator Hertzel Gerstein, MD, while also having no effect on the rate of incident cancer compared with standard care.

In ORIGIN, 12,537 patients (average age: 63.5 years) from 40 countries were recruited. Participants were 50 years and older with either type 2 diabetes that was stable on 0 or 1 oral glucose-lowering agent (88% of the cohort), impaired fasting glucose, or impaired glucose tolerance, and had either a prior cardiovascular event or were at high risk of an event based on predefined criteria.

They were randomly assigned to open-label nightly insulin glargine titrated to achieve a fasting plasma glucose (FPG) ≤95 mg/dL or standard approaches to glycemic control. The mean FPG at randomization was 125 mg/dL. After 1 year, 50% of the group assigned to insulin glargine had an FPG of 94 mg/dL or less. None of the patients assigned to standard care were using insulin at baseline; by the end of the study, 11.4% were using insulin and 60% were using metformin.

The hazard ratio (HR) for the first coprimary outcome-a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes-was 1.02 (2.94 events per 100 person-years in the glargine group vs 2.85 per 100 person-years in the standard care group), a nonsignificant difference between the groups.

There was also no significant difference between groups in the occurrence of the second coprimary outcome (5.52 per 100 person-years vs 5.28 per 100 person-years in the glargine and standard care groups, respectively), which included the components of the first coprimary outcome plus the outcomes of revascularization and hospitalization for heart failure.

The HR for cancer was 1.0. "There was no evidence of an effect [of the drug] whatsoever on cancer or on cancer death," said Dr Gerstein. "This is the longest, most extensively done study on the effect of insulin versus no insulin on cancers. We had about 1,000 cancers over the period of time."

Glycosylated hemoglobin (HbA1c) levels at the end of the trial were 6.2% (insulin glargine) and 6.5% (standard care).

The study confirmed weight gain and hypoglycemia as adverse effects of insulin glargine. Patients randomly assigned to insulin gained an average of 3.5 lb during the study. Fifty-seven percent randomly assigned to insulin glargine had at least 1 episode of hypoglycemia during the study compared with 25% randomly assigned to standard care (17 per 100 person-years vs 5 per 100 person-years). The rates of severe hypoglycemia requiring assistance were 6% in the glargine group vs 2% in the standard care group (1.0 per 100 person-year vs 0.31 per 100 person-years).

The effect of daily insulin glargine on progression to type 2 diabetes in 1,456 patients who were at high risk for diabetes was also examined as part of the study. "The message here is that using insulin for about 6 years does seem to slow the progression of diabetes in these individuals," Dr Gerstein said.

There was a 28% reduction in the diagnosis of new diabetes in persons randomly assigned to insulin glargine versus usual care (incidence: 25% vs 31%, respectively) at the time of the first oral glucose tolerance test. A second glucose tolerance test at a mean of 100 days later showed that this effect was durable, he said, with a 20% reduction in the development of diabetes compared with standard care.

"We believe this is because giving insulin to those with somewhat elevated glucose levels allows the pancreas to rest during this period, essentially helping it to work longer," he said. The durability beyond 3 months after stopping insulin remains unknown.

"This study demonstrates that long-term insulin glargine use has a neutral effect on cardiovascular risks as well as cancer risk," according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "On the one hand, these data is encouraging as it demonstrates that insulin glargine is safe and does not contribute to any long-term cancer or cardiovascular events. However, the data may also be somewhat disappointing, since insulin glargine has greatly improved the diabetic care of patients, one may have expected improved results in cardiovascular outcomes in those patients receiving insulin glargine."

This study has been published online in the New England Journal of Medicine. The ORIGIN study is supported by Sanofi.

Novel long-acting basal insulin lowers intra-day glucose variability, nocturnal hypoglycemia compared with insulin glargine

An investigational pegylated long-acting basal insulin-LY2605541-improves glycemic control compared with insulin glargine while also reducing the rate of nocturnal hypoglycemia and promoting weight loss. LY2605541 was studied in multiple clinical trials in patients with type 1 diabetes and type 2 diabetes.

LY2605541 is insulin lispro modified with a 20-kDa polyethylene glycol moiety. Its large hydrodynamic size slows insulin absorption and reduces its clearance, prolonging its activity. It is not affected by renal impairment and has a preferential hepatic effect compared with human insulin.


In an open-label, randomly assigned, crossover study, LY2605541 was compared with insulin glargine in 137 patients with type 1 diabetes in an attempt to demonstrate noninferiority of LY2605541 on the outcome of daily mean blood glucose. Prior to entering the study, patients had been treated for at least 6 months with insulin glargine and their glycated hemoglobin A1c level was ≤10.5%.

Basal insulin was administered once a day in the morning and titrated according to treat-to-target algorithms for both insulin glargine and LY2605541. Prandial insulin was titrated at the discretion of the treating investigator.

As reported by Julio Rosenstock, MD, director at Dallas Diabetes and Endocrine Center at Medical City, Dallas, daily mean blood glucose declined from a baseline of 161 ng/mL to 152 ng/mL after 8 weeks of insulin glargine, and to 144 mg/mL after 8 weeks of LY2605541, which met the statistical criterion for noninferiority and superiority of LY2605541 versus insulin glargine (P<.001).

The mean change in A1c over 8 weeks was also significantly superior (P<.001) with LY2605541 (-0.6%) compared with insulin glargine group (-0.4%). Inter-day fasting blood glucose variability was significantly less after 8 weeks in the LY2605541 group versus the insulin glargine group (49 mg/mL vs 57 mg/mL, respectively; P<.001). Average daily blood glucose readings (self-monitored) were a mean of 10 mg/dL lower in the LY2605541 group versus the glargine group (P<.01).

Prandial insulin doses were 24% lower from baseline to week 8 in patients assigned to LY2605541 (P<.001).

Mean change in weight over 8 weeks (least square means) was +0.7 kg with insulin glargine and -1.2 kg with LY2605541 (P<.001).

LY2605541 was associated with more total hypoglycemic events (relative risk: 1.2; P=.04) but a significantly lower rate of nocturnal hypoglycemia versus insulin glargine (0.9 events/30 days vs 1.1 events/30 days; P=.01). "The reduction in nocturnal hypoglycemia with LY2605541 suggests that prandial insulin may be a major contributor to the modest increase in total hypoglycemia," according to the investigators.


Two 12-week studies of LY2605541 compared with insulin glargine in patients with type 2 diabetes were presented by Richard M. Bergenstal, MD, executive director, International Diabetes Center at Park Nicollet, Minn. In these studies, glycemic control was similar between groups, intra-day glucose variability was lower with LY2605541, nocturnal hypoglycemic events were fewer with LY2605541, and LY2605541 treatment resulted in weight loss.

In an open-label study, parallel study, 289 adults with type 2 diabetes for at least 1 year who were on morning NPH or insulin glargine were randomly assigned in a 2:1 ratio to morning administration to LY2605541 or insulin glargine.

The primary end point-the reduction in fasting plasma glucose (FPG) measured by self-monitoring of blood glucose from baseline to week 12-was not significantly different between the LY2605541 and glargine groups (mean FPG at week 12 was 118 mg/dL in patients randomly assigned to LY2605541 versus 117 mg/dL in those randomly assigned to insulin glargine).

Intra-day blood glucose variability, as measured by 8-point self-monitored blood glucose standard deviation, was reduced with LY2605541 versus insulin glargine (34 vs 39 mg/dL, P=.031).

Body weight declined by 0.58 kg from baseline to week 12 in the LY2605541 group and increased by 0.31 kg in the glargine group (P=.01).

After adjusting for baseline nocturnal hypoglycemia, patients assigned to LY2605541 had a 48% reduction in the rate of nocturnal hypoglycemic events compared with glargine (0.25 events/patient/30 days vs 0.39 events/patient/30 days; P=.021).

Mean increases in levels of alanine aminotransferase and aspartate aminotransferase were higher by 9 U/L and 4 U/L, respectively, with LY2605541 versus glargine (P<.001 and P=.001, respectively), but remained within the normal range.

Seventy-six patients from this study formed the population of a substudy in which hypoglycemia and glucose variability were assessed using continuous glucose monitoring of interstitial glucose.

At 12 weeks, LY2605541-treated patients spent less time with interstitial glucose <70 mg/dL than glargine-treated patients during the nocturnal period (11 min vs 38 min, P=.024) and during the 24-hour period (25 min vs 83 min, P<.001). Significantly fewer LY2605541-treated patients than glargine-treated patients experienced any hypoglycemia (50.0% vs 78.3%, P=.036), including nocturnal hypoglycemia (20.5% vs 47.8%, P=.027).

Both treatments resulted in similar mean glucose values during the 24-hour period. Intra-day glucose variability was lower in LY2605541-treated patients compared with glargine-treated patients for both nocturnal (1.00 mmol/L vs 1.35 mmol/L, P=.061) and diurnal (2.03 mmol/L vs 2.50 mmol/L, P=.039) periods.

"Insulin glargine has been a major improvement in insulin delivery as it provides a basal insulin formulation which mimics the way the body deals with carbohydrate utilization," according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City.

"Insulin lispro is an ultra-short acting insulin compound," Dr Wooten continued. "The process of pegylation involves attachment of a drug-in this case, insulin lispro-to a nontoxic polyethylene glycol [PEG] moiety. This new PEG-insulin lispro compound has several desirable pharmaceutical characteristics, including sustained absorption, considerably higher serum concentration, a slower rate of clearance, and a longer half-life, allowing for more constant therapeutic concentrations. This study demonstrates the effectiveness of pegylated insulin lispro compared to conventional insulin glargine. Pegylated insulin may further the advancement of insulin administration."

The studies are sponsored by Eli Lilly and Company.

Phase 3 data with albiglutide indicates similar glycemic control to insulin lispro, but not as potent as liraglutide

The investigational glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide was noninferior to insulin lispro in achieving glycemic control in patients with type 2 diabetes not adequately controlled on intermediate- or long-acting insulin. However, albiglutide could not demonstrate noninferiority to liraglutide in a separate phase 3 study that involved patients who had inadequate glycemic control on oral agents.

GlaxoSmithKline announced that it plans to commence global submissions for albiglutide for the treatment of type 2 diabetes in early 2013.

In a 52-week randomized open-label multicenter study, 563 patients with type 2 diabetes who were being treated with basal insulin and had a glycated hemoglobin (HbA1c) level of 7% to 10% (with or without oral agents) were assigned to albiglutide, 30 mg once weekly with the option to titrate to 50 mg once weekly, and continued on metformin and/or a thiazolidinedione. Insulin glargine was titrated to a target fasting plasma glucose of 80 to 130 mg/dL.

Insulin lispro was administered 3 times daily and the dosage was adjusted according to a prespecified algorithm based on blood glucose monitoring.

Reductions in HbA1c levels from baseline were 0.82% and 0.66% with albiglutide and insulin lispro, respectively, meeting the primary non-inferiority end point at week 26 (P<.0001 for noninferiority; analysis by last observation carried forward), said Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center at at Medical City, Dallas. By week 52, among those who completed the study, HbA1c declined by 1.01% in the albiglutide group and 0.85% in the insulin lispro group (P=.0861).

Weight changes were sustained to week 52: -0.96 kg in those assigned to albiglutide and +1.66 kg in patients assigned to insulin lispro.

The mean dose of insulin glargine increased from baseline in both groups 54 U versus 52 U with albiglutide and insulin lispro, respectively.

There was a higher rate of nausea in the albiglutide recipients versus insulin lispro recipients (13.0% vs 2.1%, respectively), as well as vomiting (7.0% vs 1.4%) and injection-site reactions (9.5% vs 5.3%), but the rate of hypoglycemic events was less with albigultide compared with insulin lispro (32.6% vs 49.8%).

"Unfortunately there is not always enough data available that allows practitioners to evaluate how to utilize those different drug classes in caring for their patients," according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "This albiglutide study provides some concrete data that demonstrates the drug's efficacy in treating patients with type-2 diabetes who may be inadequately controlled on a regimen that includes a basal insulin product."

In a separate 32-week, open-label, parallel-group, phase 3 study, the efficacy and safety of once-weekly albiglutide was compared with once-daily liraglutide in 812 patients with type 2 diabetes inadequately controlled (A1c 7% to 10%) on metformin, a thiazolidinedione, a sulfonylurea, or any combination of these.

Patients were randomly assigned to albiglutide, 30 mg once weekly titrated to 50 mg at week 6, or liraglutide, 0.6 mg once daily titrated to 1.2 mg at week 2 and 1.8 mg at week 3.

The change from baseline in HbA1c (the primary end point of the study) was -0.78% in patients randomly assigned to albiglutide and -0.99% in patients randomly assigned to liraglutide (treatment difference: 0.21%). Although albiglutide significantly reduced HbA1c from baseline (P<.001), it did not meet the criterion for noninferiority-an upper bound of the 95% confidence interval (CI) for treatment difference <0.3% (the 95% CI was 0.08% to 0.34%), said Richard Pratley, MD, lead investigator and medical director of the Florida Hospital Diabetes Institute in Orlando.

Weight loss from baseline was greater in the liraglutide group (-2.19 kg) than in the albiglutide group (-0.64 kg).

Injection-site reactions occurred with more frequency in the albiglutide group (12.9% vs. 5.4%); most were mild in intensity.

Gastrointestinal adverse events were reported by 35.9% of patients assigned to albiglutide and 49.0% assigned to liraglutide. The incidence and event frequency of nausea and vomiting was less in the albiglutide group (9.9% and 5.0%, respectively) versus the liraglutide group (29.2% and 9.3%, respectively).

Because adherence to GLP-1 receptor agonists may be related, in part, to gastrointestinal adverse events or injection frequency, the authors conclude that albiglutide could become "an attractive therapeutic option for patients with type 2 diabetes."

The studies are sponsored by GlaxoSmithKline.

GLP-1 receptor agonist reduces glycemia when added to thiazolidinedione or basal insulin

Once-daily lixisenatide improved glycemic control in an international randomized study of patients with type 2 diabetes insufficiently controlled by pioglitazone with or without metformin, according to Michel Pinget, MD, principal investigator of the GetGoal-P study.

"Compared with placebo, lixisenatide significantly decreased glycated hemoglobin [HbA1c]-the primary end point-and fasting plasma glucose [FPG] levels at week 24," said Dr Pinget.

Lixisenatide is a selective injectable glucagon-like peptide-1 receptor agonist in development that previously had been shown to improve glycemic control significantly in hyperglycemic patients with type 2 diabetes as monotherapy and in combination with metformin, a sulfonylurea, or basal insulin with or without a sulfonylurea.

In GetGoal-P, conducted at 150 centers in 13 countries, 484 patients with type 2 diabetes whose HbA1c levels remained at 7% or greater despite treatment with by ≥ 30 mg/day pioglitazone (with or without metformin) were randomly assigned to lixisenatide, 20 µg once daily, or placebo.

The mean HbA1c level at baseline was 8.08% in the lixisenatide group and 8.05% in the placebo group. Mean body mass index was 33.7 kg/m2 and 34.4 kg/m2 in the 2 groups, respectively.

Lixisenatide produced a significantly greater reduction in HbA1c versus placebo from baseline to week 24 (0.90% vs 0.34%; P<.0001) and a greater proportion of patients assigned to lixisenatide achieved an HbA1c <7.0% (52.3% with lixisenatide vs 26.4% with placebo; P<.0001).

The mean change in FPG from baseline to week 24 was -1.16 mmol/L and -0.32 mmol/L in the patients randomly assigned to lixisenatide and placebo, respectively (P<.0001).

Significantly fewer patients on lixisenatide required rescue therapy compared with placebo (3.8% vs 11.3%; P=.0011).

The rate of adverse events was similar between the 2 groups (lixisenatide, 72.4%; placebo; 72.7%) as was the proportion of serious adverse events (2.5% vs 1.9%, respectively). Some 6.5% of the lixisenatide group and 5.0% of placebo recipients discontinued due to adverse events at week 24, mainly due to gastrointestinal (GI) events. As expected, the rate of GI events was greater in patients assigned to lixisenatide compared with placebo (36.5% vs 28.6)

There was a reduction in body weight compared with baseline in the lixisenatide group compared with an increase in body weight in the placebo recipients. Symptomatic hypoglycemia rates were low in both groups (lixisenatide, 3.4%; placebo, 1.2%). There were no cases of severe hypoglycemia in either group (see Table 1).

Because of its robust postpranadial effects, lixisenatide could complement basal insulin therapy in patients with type 2 diabetes therapy, said Julio Rosenstock, MD, lead investigator of a study in which the efficacy of lixidenatide in reducing the level of HbA1c was assessed in addition to treatment with insulin glargine and oral antidiabetic agents. The study demonstrated that when added to optimally titrated glargine and oral agents, lixisenatide significantly improved HbA1c and reduced postprandial glucose levels.

In the GetGoal-Duo 1 study, 446 patients with HbA1c >7% despite controlled FPG levels were randomly assigned to once-daily lixisenatide, 20 µg, or placebo for 24 weeks while continuing on insulin glargine, which had been titrated during a run-in phase to achieve FPG of 80 mg/dL to 100 mg/dL.

Levels of HbA1c decreased on average from 8.6% to 7.6% during the run-in period with insulin glargine. The addition of lixisenatide led to a further significant decrease in HbA1c to a mean value of 6.96%, compared with 7.3% in patients assigned to placebo (P<.0001), reported Dr Rosenstock, director of the Dallas Diabetes and Endocrine Center.

Significantly more patients assigned to lixisenatide achieved a target HbA1c <7.0% compared with placebo (56.3% vs 38.5%, respectively, P=.0001). Lixisenatide also significantly improved 2-hour postprandial glucose compared with placebo, after a standardized breakfast, with a mean difference of -3.16 mmol/L (P<.0001).

A third study presented here was GetGoal-L, a 24-week randomized, double-blind multicenter trial of 496 patients with type 2 diabetes insufficiently controlled on basal insulin with or without metformin. Patients were randomly assigned to add lixisenatide, 20 µg, or placebo.

The mean reduction in HbA1c, the primary end point, was 0.74% in the lixisenatide arm compared with 0.38% in the placebo arm (P=.0002); a significant decrease in 2-hour postprandial glucose after a standardized breakfast also occurred in the lixisenatide group versus placebo (5.54 mmol/L vs 1.72 mmol/L; P<.0001), said Matthew C. Riddle, MD, professor of medicine, Oregon Health & Science University, Portland.

Severe hypoglycemia occurred in 1.2% of patients treated with lixisenatide compared with none with placebo.

"Studies that document significant improvement in glycemic control, as well as safety, when this drug class [ie, GLP-1 receptor agonists] is combined with other antidiabetic regimens-in this case a thiazolidinedione or basal insulin-provide practitioners another effective tool to better manage type 2 diabetes." according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City.

The studies are supported by Sanofi.

Exenatide twice daily better than glimepiride once daily for maintaining glycemic control in metformin-treated type 2 diabetes

Exenatide twice daily is superior to glimepiride once daily for glycemic control in patients with type 2 diabetes whose blood glucose levels are inadequately controlled on metformin, according to data from an open-label randomized comparison.

In many countries, following the loss of glycemic control with metformin, the most frequently used second-line antidiabetes therapy is a sulfonylurea, said lead investigator Guntram Schernthaner, MD, in providing the impetus for the study.

The study was conducted in 1,029 adults with type 2 diabetes who developed suboptimal glycemic control, defined as a glycated hemoglobin (HbA1c) level of 6.5% to 9.0% despite stable and maximally tolerated doses of metformin. As add-on treatment, they were assigned in an open-label fashion to exenatide injected subcutaneously within 60 minutes before breakfast and evening meals, starting at 5 µg twice daily for 4 weeks and followed by 10 µg twice daily for the remaining study period; or glimepiride, 1 mg/day, immediately before breakfast.

The primary end point was treatment failure, defined as either of the following occurring after at least 6 months of treatment: HbA1c >7% at 2 consecutive visits 3 months apart on the maximally tolerated dose of antidiabetes agents, or an HbA1c level >9% at any visit on the maximally tolerated dose of antidiabetes agents.

"Exenatide twice daily was superior in preventing glycemic deterioration," said Dr Schernthaner, head of the department of medicine, Rudolfstiftung Hospital, Vienna, Austria.

Exenatide twice daily was associated with lower HbA1c levels over follow-up as long as 54 months compared with glimepiride. Treatment failure occurred in 41% in the exenatide group versus 54% in the glimepiride group, a risk difference of 12.4% (P<.002). The hazard ratio for inadequate glycemic control was 25% lower with exenatide compared with glimepiride.

Exenatide met the criteria for non-inferiority and separately showed superiority over glimepiride as add-on treatment to metformin.

The median time to inadequate glycemic control was 180 weeks in the exenatide group and 142 weeks in the glimepiride group (P=.032). Forty-five percent of those assigned to exenatide achieved an HbA1c concentration <7% compared with 31% assigned to glimepiride (P<.0001).

Fasting plasma glucose concentration was significantly lower in the exenatide group at years 1 (P=.048), 2 (P=.004), and 3 (P<.001) compared with the glimepiride group. Glucose levels during oral glucose tolerance tests were also significantly lower with exenatide versus glimepiride at these time points (year 1: P<.001; year 2: P<.001; year 3: P<.0001).

Exenatide-treated patients experienced significantly greater weight loss over time. Those randomly assigned to exenatide lost 3.32 kg of body weight from baseline to last visit, compared with a gain of 1.15 kg in those randomly assigned to glimepiride (difference between groups: 4.47 kg; P<.0001).

The proportion of patients reporting hypoglycemia of any type was 36% in the exenatide group and 67% in the glimepiride group (P<.001); documented symptomatic hypoglycemia (blood glucose value <2.8 mmol/L) occurred in 7% of the exenatide group versus 12% of the glimepiride group (P =.002).

"The number of different treatment strategies for type 2 diabetes is immense and having evidence to support one pharmacotherapy intervention over another is vitally important," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "In this study exenatide appears to be as effective as a sulfonylurea drug for the treatment of type 2 diabetes [as measured by HbA1c results]. The fact that exenatide may also induce a measureable degree of weight loss is another positive effect."

The study was funded by Eli Lilly and Company and Amylin Pharmaceuticals.

Early initiation of insulin glargine is superior to sitagliptin following metformin failure in type 2 diabetes

The addition of insulin glargine early in the course of type 2 diabetes, as a second-line treatment after metformin, aids in achieving glycemic control. In a head-to-head randomized comparison with a dipeptidyl peptidase-4 inhibitor, the reduction in glycated hemoglobin A1c (HbA1c) was greater with insulin glargine than with sitagliptin.

"The results of this study support the option of introducing basal insulin (glargine) in patients with type 2 diabetes inadequately controlled by metformin, with the potential for long-term benefits arising from the achievement of optimum glycemic control early in the course of the disease," said the study's co-investigator Pablo J. Aschner, MD, MSc.

He continued, "Insulin glargine was 1.6 times more likely than sitagliptin to achieve HbA1c <7%, and 2.5 times more likely to achieve HbA1c <6.5%, with concurrently lower fasting and postprandial blood glucose."

The study was an open-label design in which 515 metformin-treated patients with type 2 diabetes with an HbA1c level of 7% to 11% were randomly assigned to insulin glargine, starting at 0.2 U/kg injected at dinner or bedtime, or sitagliptin, 100 mg/day. The dosage of insulin glargine was adjusted according to patients' self-monitored fasting plasma glucose concentration (FPG) to maintain FPG between 4.0 and 5.5 mmol/L. The insulin glargine daily dose increased up to 41.4 U at the end of the treatment period.

The adjusted mean reduction in HbA1c level in the modified intent-to-treat population at 24 weeks was 1.72% in the patients assigned to insulin glargine and 1.13% in those assigned to sitagliptin (P<.0001), with a final mean HbA1c concentration of 6.8% in the insulin glargine group versus 7.4% in the sitagliptin group.

A target HbA1c level <7% was achieved by significantly more patients randomly assigned to insulin glargine versus sitagliptin at week 11 (P<.0002), week 14 (P<.0001), and at the last available visit in which HbA1c was collected on treatment, at which time 68% of insulin glargine users and 42% of sitagliptin users achieved this target (P<.0001).

The adjusted mean difference in self-monitored FPG between the 2 groups was 2.3 mmol/L (41 mg/dL) in favor of insulin glargine (8.2 mmol/L with sitalgiptin vs 5.8 mmol/L with insulin glargine; P<.0001).

"As expected, the estimated rate of hypoglycemia per patient-year was 8 times higher with glargine, but the risk of severe events, although also 3 times higher, was not significantly different from that with sitagliptin," said Dr Aschner, professor of medicine, endocrinology unit, Javeriana University, Bogotá, Columbia.

The rates of hypoglycemia were 46% with insulin glargine compared with 13% for sitagliptin. Symptomatic hypoglycemia occurred more often in the insulin glargine recipients, severe symptomatic hypoglycemia was rare in either group (1% of the insulin glargine group and <1% in the sitagliptin group). "The risk of severe nocturnal hypoglycemia was the same for the 2 groups [<1% in each]," he said.

Body weight declined by a mean of 1.08 kg from baseline in the sitagliptin whereas it increased by a mean of 0.44 kg in the insulin glargine group, for an adjusted mean difference of 1.51 kg (P<.0001).

There were no new safety signals observed with insulin glargine in the study, said Dr Aschner.

"Insulin glargine, being used as a first-line therapy in type 2 diabetes, is becoming a popular treatment strategy," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "This actually makes good sense because insulin glargine [Lantus] is being used as a basal insulin equivalent for those patients who are unable to manufacture adequate amounts of basal insulin on their own. This study demonstrates the effectiveness of insulin glargine compared to sitagliptin in patients with type 2 diabetes."

This study was funded by Sanofi.

SGLT2 inhibitors have potent HbA1c-lowering effect in metformin/sulfonylurea failure

The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin produced significantly greater reductions in glycated hemoglobin (HbA1c) levels compared with glimepiride and sitagliptin in separate phase 3 studies of patients with type 2 diabetes on background oral antidiabetic drugs.

Both studies were supported by Janssen Research and Development, LLC, Raritan, N.J.

The sustained glucose control and low occurrence of hypoglycemia with canagliflozin compared with glimepiride over 52 weeks are promising, and suggest that the SGLT2 class of agents may be a valuable treatment option, said William T. Cefalu, MD, lead investigator of one of the studies, and chief of the Joint Program on Diabetes, Endocrinology and Metabolism of the Pennington Biomedical Research Center and Louisiana State University, Baton Rouge.

Once-daily canagliflozin, 100 mg or 300 mg, was compared with glimepiride in a double-blind, randomized, 52-week trial of 1,450 adults with type 2 diabetes inadequately controlled on maximal doses of metformin. Glimepiride was given at a starting dose of 1 mg/day and was uptitrated throughout the study period to a maximum of 6 mg/day or 8 mg/day. The mean dose of glimepiride achieved was 5.6 mg/day.

At week 52, HbA1c was significantly lower than at baseline with both doses of canagliflozin and with glimepiride. Both dosages of canagliflozin demonstrated non-inferiority to glimepiride in HbA1c lowering, as the upper limit of the 95% confidence interval (CI) was less than the pre-specified margin of 0.3%.

The 300-mg dosage of cangliflozin lowered HbA1c by 0.93% from baseline, which was significantly better than the 0.81% decline in HbA1c with glimepiride (difference in change between groups, –0.12%; 95% CI, –0.22% to –0.02%). (The change in HbA1c from baseline with the 100-mg dosage of canagliflozin was -0.82%.)

Glycemic rescue therapy with pioglitazone was required in 10.6% of glimepiride-treated patients versus 6.6% of those receiving canagliflozin, 100 mg/day, and 4.9% receiving canagliflozin, 300 mg/day.

The rates of documented hypoglycemia were 34.2% with glimepiride, 5.6% with the 100-mg dosage of canagliflozin, and 4.9% with the 300-mg dosage of canagliflozin.

Mean body weight reductions were 4.7% and 4.2% with the 300-mg and 100-mg dosages of canagliflozin, respectively; whereas patients randomly assigned to glimepiride had a mean gain of 1.0% of body weight.

Genital mycotic infections and urinary tract infections occurred in a greater proportion of patients assigned to canagliflozin compared with glimepiride (Table 2) but led to few study discontinuations, according to Dr Cefalu.

In a second randomized, double-blind 52-week study, canagliflozin, 300 mg/day, was compared with sitagliptin, 100 mg/day, in 755 patients with type 2 diabetes inadequately controlled with metformin and a sulfonylurea (mean baseline HbA1c: 8.1%).

The mean change from baseline in HbA1c was –1.03% in those randomly assigned to canagliflozin and –0.66% in patients randomly assigned to sitagliptin. The difference of 0.37% was statistically significant (95% CI, –0.50% to –0.25%) as measured by the last observation carried forward. Some 47.6% of canagliflozin recipients achieved a final HbA1c <7.0% versus. 35.3% of sitagliptin recipients.

Gential mycotic infections occurred more often in the canagliflozin group compared with the sitagliptin group but the rate of urinary tract infection was similar between the 2 groups (sitagliptin, 5.6%; canagliflozin, 4.0%) (see Table 2).

Late-phase clinical trials of other SGLT2 inhibitors under development were also presented.

■ An extension of 24-week study demonstrated a sustained reduction in HbA1c level with dapagliflozin over the long term (up to 104 weeks in patients with type 2 diabetes with poor glycemic control despite high doses of insulin). Other clinical trials showed that dapagliflozin does not adversely impact cardiovascular safety while improving glycemic control in patients with type 2 diabetes and cardiovascular disease or hypertension, and also displays no renal toxicity.

■ Empagliflozin showed sustained reductions in average HbA1c levels for up to 90 weeks in a study of 659 patients with type 2 diabetes.

"The effect that canagliflozin has on glycosylated hemoglobin [HgA1c] may be greater than the effect that either glimepiride or sitagliptin has on HgA1c," according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "This means that canagliflozin may offer a more pronounced pharmacologic impact on diabetes control than either glimepiride or sitagliptin. Canagliflozin may also be better tolerated than glimepiride as clinical studies indicate that the drug may cause fewer incidences of hypoglycemia than glimepiride."

The dapagliflozin studies are sponsored by Bristol-Myers Squibb and AstraZeneca. The empagliflozin study is funded by Boehringer Ingelheim Pharma GmbH & Co.

Carfilzomib: A second-generation proteasome inhibitor for the treatment of multiple myeloma

Although multiple myeloma (MM) only accounts for 1% of overall cancers, it is the second most prevalent blood cancer after non-Hodgkin lymphoma. The American Cancer Society has estimated that in 2012, 21,700 new cases of MM will be diagnosed in the United States, including 12,190 cases in men and 9,500 cases in women, and MM will cause an estimated 10,710 deaths.1

Despite the fact that MM is not considered curable with current approaches, treatment has improved dramatically during the past decade. In the past few years, treatment of MM has evolved rapidly with the introduction of new drugs such as thalidomide, lenalidomide, and bortezomib. The 5-year survival rate reported in the Surveillance Epidemiology and End Results database increased from 25% in 1975 to 34% in 2003, owing to the availability of newer and more effective treatment options.2

Protein degradation pathway is one of the emerging targets in the treatment of several cancers, including MM. The ubiquitin-proteasome pathway plays a major role in the maintenance of protein homeostasis and the degradation of many proteins involved in cell cycle, proliferation, and apoptosis. Proteasome inhibition in malignant cells leads to accumulation of target proteins followed by induction of cell death.3 After demonstrating single-agent efficacy in the treatment of relapsed and refractory disease, bortezomib was the first proteasome inhibitor approved for the treatment of MM. However, bortezomib therapy has several limitations, as adverse effects include painful peripheral neuropathy (PN), thrombocytopenia, and emergence of secondary resistance.

Carfilzomib (PR-171, Kyprolis) is a second-generation proteasome inhibitor being evaluated for treatment of relapsed and/or refractory MM as well as for first-line therapy in patients with newly diagnosed disease. In July 2012, FDA granted accelerated approval to carfilzomib for the treatment of patients with multiple myeloma who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. The approval was based on an open-label, single-arm, phase 2b trial evaluating 266 heavily pretreated patients. Carfilzomib is being evaluated in 2 pivotal phase 3 trials, Carfilzomib for Advanced Refractory Multiple Myeloma European Study (FOCUS) and Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma (ASPIRE).


The 26S proteasome complex is made up of a proteolytic core particle, the 20S proteasome, and two 19S regulatory complexes. The 20S proteasome has 3 distinct proteolytic activities harbored by β subunits: caspase-like (β1 subunit), trypsin-like (β2 subunit), and chymotrypsin-like (β5 subunit). Carfilzomib is a modified peptide related to the natural, potent, and selective proteasome inhibitor epoxomicin. It comprises a short peptide portion that binds to the substrate binding pocket of the proteasome and an epoxybutane pharmacophore that interacts with the catalytic NH2-terminal threonine residue of the enzyme inhibiting its activity (Figure 1). Carfilzomib primarily targets the chymotrypsin-like (β5) subunit; however, inhibition of the other 2 subunits probably is required for antitumor activity. The covalent adduct formed by the carfilzomib-enzyme complex is irreversible, unlike the slowly reversible adducts formed by bortezomib. Induction of messenger ribonucleic acid transcription and de novo synthesis is the primary pathway for the recovery of proteasome activity.4,5

Carfilzomib is a highly selective inhibitor of chymotrypsin-like (β5) subunit activity of the 20S proteasome and has minimal cross-reactivity with other protease classes. It induces dose- and time-dependent inhibition in vitro and in vivo.6 Proteasome inhibitions results in the accumulation of polyubiquitinated proteins and induction of apoptosis through activation of both the intrinsic and extrinsic caspases' pathways. Carfilzomib induces apoptosis and growth cell cycle arrest in a variety of hematologic and solid tumor cell lines, including MM, acute myeloid leukemia, Burkitt lymphoma, Waldenstrom macroglobulinemia, pancreatic cancer, and lung cancer.7-9

Activity of carfilzomib is enhanced with coadministration of histone deacetylase inhibitors. Vorinostat increases the activity of carfilzomib in diffuse large B-cell lymphoma cells resistant or sensitive to bortezomib via increased mitochondrial injury, caspase activation, apoptosis through Jun NH2-terminal kinase, and p38 mitogen-associated protein kinase activation.10,11

Treatment with carfilzomib can overcome primary and secondary resistance to bortezomib and several chemotherapeutic agents in cell lines and in patient-derived clinical samples.12 However, carfilzomib resistance in cell lines, likely caused by P glycoprotein upregulation and multi-drug resistance-related efflux pumps, has been observed. Resistance can be overcome in vitro with the addition of the P-glycoprotein inhibitor verapamil, or by addition of peptide analogs lacking the pharmacophore.13


Preclinical pharmacokinetic (PK) properties of carfilzomib were evaluated in rats and monkeys. After a single intravenously administered dose, the drug was rapidly eliminated from plasma, with a terminal half-life in rats and monkeys of 15 and 7.2 minutes, respectively. Prolonged dose-dependent inhibition of proteasome activities was observed in all tissues except the brain, an indication that the drug does not cross the blood-brain barrier.14

The PK parameters of carfilzomib were also evaluated in an open-label, multicenter phase 1 study enrolling 29 patients with refractory or relapsed hematologic malignancies, including MM.15 Carfilzomib was given as an intravenous push every day for 5 consecutive days in 14-day cycles, and the dose administered ranged from 1.2 mg/m2 to 20 mg/m2. The mean maximum concentration for the maximum tolerated dose in this study, 15 mg/m2 , was 325.9 ng/mL, time to maximum concentration was 5.8 minutes, area under the curve was 9728 ng·hr/mL, and elimination half-life was 28.9 minutes (Table 1). The volume of distribution at steady state was 942 L, an indication of wide tissue distribution, and clearance was 7054 mL/min, higher than liver blood flow, which suggests multiple clearance pathways.15 The major metabolites observed in both preclinical and clinical studies were from peptide and epoxide hydrolysis, with oxidative metabolites representing greater than 0.1% of the total dose. Carfilzomib exposure is unlikely to be affected by hepatic impairment due to its extrahepatic metabolism.14

The PK profile of carfilzomib does not seem to be affected by renal impairment. The PK parameters in patients with mild renal impairment (creatinine clearance, 50–79 mL/min); moderate renal impairment (creatinine clearance, 30–49 mL/min); and severe renal impairment (creatinine clearance, <30 mL/min) were similar to those in patients with normal renal function.16


Carfilzomib is under evaluation for use in treatment of MM and some solid tumors. The NDA for carfilzomib for treatment of patients with relapsed or refractory MM was supported by efficacy data from 526 patients enrolled in 4 phase 2 studies and safety data from 768 patients enrolled in phase 1 and phase 2 studies.

The pivotal study, PX-171-003A1, was an open-label, single-arm, phase 2b study, in which carfilzomib showed significant, durable responses in patients with relapsed or refractory MM who were previously treated with at least 2 therapies (bortezomib and either thalidomide or lenalidomide; and an alkylator and/or anthracycline).17–19 Carfilzomib was administered intravenously at 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for 12 cycles. After cycle 1, the dose was increased to 27 mg/m2. The trial included 266 patients, of which 257 had responses evaluated. These patients were heavily pretreated: the mean number of prior therapies was 5.4, 74% of patients had been treated with autologous transplantation, and the majority of patients (95%) were judged refractory to their most recent therapy. An independent review committee assessed responses based on the International Myeloma Working Group criteria. The overall response rate (ORR) was 24% with median duration of response (DOR) of 7.4 months (95% confidence interval [CI], 6.2–10.3). Cytogenetic studies were available for 229 patients, and 71 of the 229 had at least one cytogenetic abnormality.18 Patients with unfavorable cytogenetic characteristics had an ORR of 28% and DOR of 7 months (95% CI, 4–10).18 The median overall survival rate was 15.5 months (95% CI, 12.7–19.0).18 The clinical benefit response (ORR + minimal response) was 36%.17 The drug was well tolerated, and hematologic adverse events were the most common complications. Grade 3 or higher adverse events were thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%).17 Seventy-seven percent of patients with baseline grade 1 or 2 PN tolerated therapy without worsening of symptoms or decreased response (ORR, 24%).17 Less than 1% of patients had new-onset grade 3 or higher PN.17,19

The second open-label, multicenter, phase 2 study, PX-171-004, enrolled less heavily pretreated patients compared with PX-171-003A1.20 One hundred twenty-nine bortezomib-naïve and 35 bortezomib-treated patients with relapsed or refractory MM were enrolled. Patients had to have been treated with 1 to 3 regimens previously. Cohort 1 (n=59) was administered carfilzomib 20 mg/m2 intravenously on days 1, 2, 8, 9, 15, 16 of a 28-day cycle. Cohort 2 (n=70) was administered carfilzomib 20 mg/m2 intravenously for cycle 1, which was escalated to 27 mg/m2 for all subsequent cycles, for 12 cycles. An independent review committee assessed responses based on the International Myeloma Working Group criteria. The ORR in cohort 1 was 42.4%, and the ORR in cohort 2 was 52.2%. The median DOR in cohort 1 was 13.1 months and was not reached in cohort 2. The median time to progression was 8.3 months in cohort 1 and was not reached in cohort 2. Complete response was achieved in 2 patients (3.4%) in cohort 1 and 1 patient (1.5%) in cohort 2. Clinical benefit response rates were 59.3% and 64.2% in cohorts 1 and 2, respectively. As in PX-171-003A1, grade 3 toxicities were mostly hematologic and included lymphopenia (16.3%), anemia (14.7%), neutropenia (13.2%), thrombocytopenia (13.2%), and pneumonia (12.4%). The most common adverse events overall were fatigue (62.0%), nausea (48.8%), anemia (41.9%), dyspnea (38.8%), cough (34.1%), and pyrexia (34.1%). The overall incidence of treatment-emergent PN was 17.1% (1 patient with grade 3 PN; no patients with grade 4 PN).20

Carfilzomib showed promising activity in the first-line setting in combination with lenalidomide and low-dose dexamethasone (CRd) in patients with newly diagnosed MM in a phase 1/2 trial.21 Patients had to have measureable disease and be symptomatic. Grade 3/4 neuropathy at baseline excluded enrollment in the study. Patients received CRd every 28 days for a maximum of 8 cycles until disease progression, or until they experienced unacceptable toxicity. After 8 cycles, patients received maintenance CRd for a total of 24 cycles followed by off-protocol single-agent lenalidomide. Carfilzomib was given at 20, 27, or 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 and on days 1, 2, 15, 16 after cycle 8. Lenalidomide 25 mg was given on days 1 through 21. Weekly doses of dexamethasone 40 mg were administered during cycles 1 through 4 and 20 mg from cycle 5 onward. After cycle 4, patients who were eligible for stem cell transplantation were able to undergo cell collection and then proceed with transplantation or resume CRd treatment. The trial included 53 patients from 4 sites. The median treatment duration was 12 cycles, and a single patient discontinued treatment during induction for CRd toxicity. Sixty-two percent of patients achieved near-complete response (nCR), and 98% of patients had at least partial response (PR). Thirty-six patients received 8 or more cycles with nCR rate of 78%. The 24-month progression-free survival estimate was 92% during a median 13-month follow up. A 20% dose-limiting toxicity (DLT) cutoff was used to determine the maximum tolerable dose. The probability of a DLT shows a trend of increasing with increasing dose: 5.9% at 20 mg/m2 , 8.1% at 27 mg/m2 , and 12% at 36 mg/m2. During phase 2, the 36 mg/m2 carfilzomib dose was used, as the 20% DLT probability was not achieved. Grade 3/4 adverse events during cycles 1 through 8 included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%). Twenty-three percent of patients experienced grade 1/2 PN. During maintenance CRd, the most common toxicities were lymphopenia (30%), leucopenia (26%), and fatigue (25%).21

The safety and PK of carfilzomib were also evaluated in patients with relapsed and refractory MM and baseline renal impairment, including patients receiving hemodialysis (see PK discussion).

Carfilzomib is under evaluation in 2 phase 3 trials. The ASPIRE trial analyzes the safety and efficacy of carfilzomib for treatment of MM relapse in combination with lenalidomide and CRd versus lenalidomide and CRd alone. The primary end point is progression-free survival. The FOCUS trial assesses the role of single-agent carfilzomib compared with corticosteroid agent with or without oral cyclophosphamide in relapsed and refractory MM for European approval of carfilzomib. The primary end point is overall survival.


Carfilzomib is generally well tolerated, and treatment-related adverse events are mainly low grade in severity. Safety data are available from 526 patients enrolled in all phase 2 trials and 266 patients enrolled in phase 3 trials. Progression of disease was the most common cause of death (33 of 792 patients; 4%). Less than 2% of patients died due to cardiac, hepatic, or pulmonary causes. The most common serious adverse events in patients enrolled in phase 2 trials were cardiac disorders (8%), respiratory disorders (7%), and hepatobiliary disorders (<1%). The most common serious adverse events in patients enrolled in phase 3 trials were infections and infestations (7%), cardiac disorders (4%) and respiratory disorders (4%). Common adverse events noted in the phase 2 trials (>20%) were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia, headache, upper respiratory tract infection, cough, lymphemia, blood creatinine increase, peripheral edema, vomiting, neutropenia, constipation, and back pain. Grade 3 or higher adverse events were mostly hematologic and included thrombocytopenia, anemia, and lymphopenia. The most common reasons patients discontinued therapy in phase 2 trials were cardiac disorders (6%) and respiratory disorders (4%). PN, a dose-limiting adverse event with bortezomib, was minimally noted with carfilzomib. Grade 3 PN occurred in less than 1% of patients, and no patients had dose adjustments or discontinuation due to PN. Patients with baseline PN tolerated therapy well without worsening of symptoms.18–21


Carfilzomib is excreted primarily as inactive metabolites derived from peptide and epoxide hydrolysis, and it has no reported drug interactions.22 Although carfilzomib has been shown to be a moderate cytochrome P (CYP)3A4 inhibitor in vitro, it had no effect on the the PK of midazolam, a CYP3A probe, in a drug interaction study conducted in cancer patients.

In vitro studies using human hepatocytes have also shown that carfilzomib does not induce CYP3A4 and 1A2. These studies indicate that carfilzomib is unlikely to have any interactions or clinically relevant effects on the disposition of drugs metabolized by the CYP enzyme system.14


Carfilzomib is administered intravenously at 20 mg/m2 over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 in cycle 1, with escalation to 27 mg/m2 in subsequent cycles as tolerated every 28 days. The dose should be based on patient's actual body surface area at baseline up to a maximum of 2.2 m2. The dose should be recalculated for a weight change of ≥ 20% and treatment may be continued until disease progression or unacceptable toxicity. Infusion-related reactions or "first-dose effect" have been reported in early clinical trials. To reduce these reactions, which include shortness of breath, hypotension, and angina during or shortly after the infusion, dexamethasone (4 mg orally or intravenously) should be administered before each dose administration in the first 2 cycles and thereafter, if infusion reaction symptoms develop or reappear. Fluids, 250 to 500 mL, should also be administered intravenously before and after each dose in cycle 1 and as needed in subsequent cycles to reduce the risk of renal toxicity and tumor lysis syndrome. No dose adjustment is recommended based on age, sex, race, or baseline renal impairment. While carfilzomib exposure is unlikely to be affected by hepatic impairment due to its extrahepatic metabolism, patients with ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN were excluded from the clinical trials and specific dosing recommendations for these patients are not available.

Dose modification guidelines for hematologic and non-hematologic toxicity during treatment are included in the drug product information.


Carfilzomib demonstrated significant activity in relapsed and/or refractory myeloma, and it has one of the highest single-agent response rates (up to 52% in patients who had never received bortezomib) and longest durations of responses observed in this patient population. However, data on its impact on progression-free survival or overall survival are currently not available.

Carfilzomib may offer patients several advantages over bortezomib. It has greater target specificity, which may lead to better tolerability. PN, a DLT with bortezomib, which probably is attributable to nonproteasomal targets, was infrequently seen in carfilzomib's clinical studies, even in patients with baseline neuropathy. Carfilzomib also has activity against bortezomib-resistant MM cell lines from patients with clinical bortezomib resistance.23 Table 2 lists some of the differences between the 2 drugs.24,25

Carfilzomib will be an effective treatment option in patients who are either intolerant or resistant to bortezomib. Ongoing clinical trials will further define its role in the first-line setting, its safety and efficacy in patients with other malignancies, and early markers for best myeloma response.26 These studies will also determine whether the activity seen in the pivotal phase study was enhanced by the addition of low dose dexamethasone, an active agent in MM at higher doses, to prevent infusion-related toxicities.

Carfilzomib joined bortezomib as the only FDA-approved proteasome inhibitors. However, the market may soon be crowded with several other inhibitors in various stages of clinical development, including orally active agents. Efficacy, resistance data, adverse-effect profile, and patient convenience should be evaluated carefully before a formulary agent is chosen.

Mr Kuznar is a medical journalist based in Cleveland.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

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