American Diabetes Association (ADA) 71st Scientific Sessions

 June 24-28, 2011; San Diego, CA

Posters
Hypoglycemia Risks, Costs Associated with Type 2 Diabetes Treatments

A retrospective analysis of claims data for 212,061 patients (56% male) with type 2 diabetes found that those who took sulfonylureas, insulin, or other oral antidiabetic agents (eg, meglitinide and alpha-glucosidase) had a higher 6-month risk of hypoglycemia than did patients taking metformin or thiazolidinediones. Use of dipeptidyl peptidase-4 inhibitors or exenatide did not increase the 6-month risk of hypoglycemia.

These and other findings were presented at the ADA meeting in a poster titled Hypoglycemia in Adult Versus Elderly Type 2 Diabetes Mellitus Patients: Risks, Costs, and Impact on Treatment Persistence. The authors noted that two prior studies have shown that patients who experience hypoglycemia while taking antidiabetic medication are less satisfied with their therapy and are therefore less likely to adhere to it than those who do not develop hypoglycemia, making treatment less effective.

In conducting the current study, investigators reviewed records for adults with type 2 diabetes mellitus stored in the Ingenix Impact database, which contains enrollment and demographic information and prescription drug claims for 45 US health plans. They found that those patients who experienced hypoglycemia during antidiabetic therapy racked up significantly higher annual drug and medical costs than patients who did not experience any hypoglycemic incidents ($14,031 vs $9007, respectively; P <.0001). An analysis of just the diabetes-related drug and medical claims showed that these were also significantly higher each year among patients experiencing hypoglycemia versus those who did not ($7012 vs $3265, respectively; P <.0001).

The authors analyzed data pertaining to a subset of 31,109 elderly patients (≥65 years of age) and found that this cohort had higher all-cause and diabetes-related annual costs and a greater risk of hypoglycemia compared with the cohort of individuals aged 18 to 65 years. The annual drug and medical costs for the elderly population totaled $20,264 for patients experiencing hypoglycemia versus $11,897 for those who did not develop the condition. The portion of annual costs related to diabetes totaled $11,829 in the hypoglycemia group versus $4190 in the group with no hypoglycemia.

In the study population overall, the following treatments were associated with significantly higher 6-month hypoglycemia risk (P <.0001 for each comparison): insulin (hazard ratio [HR], 2.10; 95% confidence interval [CI], 1.98-2.24); other oral antidiabetic agents (HR, 1.59; 95% CI, 1.46-1.74); sulfonylureas (HR, 1.56; 95% CI, 1.50-1.62); metformin (HR, 1.18; 95% CI, 1.13-1.23); and thiazolidinediones (HR, 1.09; 95% CI, 1.04-1.13).

In elderly patients, the following treatments were significantly associated with higher hypoglycemia risk in a 6-month interval (P <.0001 for each comparison): insulin (HR, 2.36; 95% CI, 2.04-2.74); other oral antidiabetic agents (HR, 1.86; 95% CI, 1.57-2.21); sulfonylureas (HR, 1.95; 95% CI, 1.78-2.14); and thiazolidinediones (HR, 1.22; 95% CI, 1.11-1.35).

Individuals eligible for study inclusion had at least two independent claims for type 2 diabetes and no claims for type 1 diabetes between January 1999 and September 2008. They were also required to have filled at least one prescription for an oral antidiabetic agent and to have been continuously enrolled in a medical and pharmacy benefits plan for 12 months after filling their first antidiabetic prescription. One-third of eligible patients were enrolled in a health maintenance organization, ~40% were enrolled in a point-of-service health plan, and 26.3% subscribed to a preferred provider organization.

The study did not directly compare data for elderly versus nonelderly patients. The authors hope to do this in the future.

This study was sponsored by Takeda Pharmaceuticals International, Inc.

 Comparison of Premixed Insulin Analogs and Long-Acting Insulin Analogs

A diabetes simulation model programmed from a US healthcare payer perspective found that patients with type 2 diabetes taking premixed insulin analogs were likely to have longer life expectancy and quality-adjusted life expectancy compared with those taking long-acting insulin analogs (LAIAs). The authors reported that the model associated premixed insulin analogs with higher lifetime and direct medical costs, calculating  incremental cost-effectiveness ratios per quality-adjusted life-year of $28,580 for the premixed insulin analog group as compared with $23,150 for the LAIA group.

Results were presented during a president’s poster session at the ADA meeting. The poster was titled Estimating the Long-Term Cost-Effectiveness of Premixed Insulin Analog Versus Long-Acting Insulin Analog in the United States.

The researchers noted that an earlier meta-analysis from the Agency for Healthcare Research and Quality had concluded premixed insulin analogs provide more glycemic control than LAIAs. The substantial cost for insulin, which a 2007 ADA report placed at approximately $3.7 billion annually, prompted the authors to compare the cost-effectiveness of insulin regimens. The drugs compared in the model were insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro), insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin lispro), and an LAIA regimen.

The model, which was validated, was used to simulate mortality risk and incidence of diabetes-related complications and assumed each patient took an average of 40 insulin units per day. The authors obtained insulin costs and direct medical costs from published sources and diabetes complication costs from a 2008 study. They also used published sources to establish baseline cohort characteristics. The population was 57.5% male, and the mean patient age was 62.8 years. Patients were assumed to have had diabetes for a mean of 12.0 years and had a mean glycated hemoglobin level of 8.6%.

The model calculated a mean life expectancy of 7.82 years for the LAIA group, 7.89 for the insulin lispro mix 75/25 group, and 7.91 years for the insulin pro mix 50/50 group. The mean quality-adjusted life expectancy was 4.93 years in the LAIA group, 5.00 in the insulin pro mix 75/25 group, and 5.01 years in the insulin pro mix 50/50 group. Direct costs associated with the groups were $40,128 (LAIA), $41,852 (insulin pro mix 75/25), and $41,848 (insulin pro mix 50/50).

The authors also applied incremental cost-effectiveness scatter plots and acceptability curves to the data. They found that with a willingness to pay $50,000 per quality-adjusted life-year gained, there was a 58.8% probability that insulin lispro mix 75/25 would be more cost-effective compared with LAIA and a 64.5% probability that insulin pro mix 50/50 would be more cost-effective compared with LAIA.

The authors acknowledged limitations to the study, including their decision not to include hypoglycemia incidence in the base-case analysis. They also noted that using a meta-analysis of short-term clinical trials to make long-term predictions might have confounded the findings. Despite these concerns, the authors pointed out that using a validated and published model ranks among the best and most accurate ways to project long-term cost-effectiveness for a given study population.

This study was sponsored by Eli Lilly and Co.

 Lifestyle Interventions Improve Glycemic Control for Patients with Type 2 Diabetes

In a randomized trial involving patients with type 2 diabetes, those subject to intensive dietary intervention through consultations with a dietician and nurse demonstrated significant improvement in glycemic control compared with those who received normal care. The addition of an exercise regimen to the dietary changes, however, was not associated with additional benefit in glycemic control.

Results of the multicenter, randomized, controlled Early ACTID (Activity in Type 2 Diabetes) trial were presented at the ADA meeting and simultaneously published online in The Lancet.

From December 2005 through September 2008, the investigators enrolled 593 residents of southwest England, aged 30 to 80 years, who had received a diagnosis of type 2 diabetes in the past 5 to 8 months. Exclusion criteria included a glycated hemoglobin A_1c (HbA_1c) level >10%, blood pressure >180/100 mm Hg, body mass index (BMI) <25 kg/m², and weight >180 kg.

Patients were randomized at a 2:5:5 ratio to the following interventions: normal care, which included standard dietary and exercise advice at randomization and again at the conclusion of the study, with reviews by a physician and nurse at baseline, 6 months, and 12 months; intensive diet, consisting of a 1-hour consultation with a dietician at randomization and a 30-minute session every 3 months, along with nine 30-minute consultations with a nurse during the study; and intensive diet plus exercise, which required the patient to take a brisk, 30-minute walk on at least
5 days of each week, tracked by a pedometer and diaried. During the 12-month period, patients assigned to the diet cohort or the diet-plus-exercise group consulted with a dietician for an additional 2 hours and with a nurse for an additional 4.5 hours compared with the patients who were randomized to receive normal care.

The arms were well balanced in terms of baseline demographics. Approximately 65% of patients were men and the vast majority (95%) were white. The approximate mean age of the patients was 60 years.

At 12-month follow-up, patients in the diet group and the diet-plus-exercise group had significantly improved HbA_1c levels compared with patients in the normal care group (P = .005 and
P = .027, respectively). The mean HbA_1c level increased by 0.09% in the normal care group, decreased by 0.09% in the diet group, and decreased by 0.04% in the diet-plus-exercise group. No statistically significant difference was observed, however, in HbA_1c change between the diet and diet-plus-exercise groups (P = .43).

In addition, none of the groups differed significantly in mean systolic or diastolic blood pressure readings or in mean levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Compared with patients in the normal care group, persons assigned to the diet group and the diet-plus-exercise group demonstrated significant weight loss (P <.0001 for both comparisons) and a significant decline in BMI
(P <.0001 for both comparisons).

Robert C. Andrews, MB, ChB, PhD, was the study’s lead author, and he offered possible explanations for why exercise did not contribute to better patient outcomes. He said the authors might have selected the wrong activity and perhaps the exercise regimen should have included aerobic and anaerobic activities. He also hypothesized that people who exercise are not as strict with their dietary intake. He wondered whether, if instead of focusing solely on increasing the patients’ activity levels, the researchers should have concentrated more on decreasing the amount of time that the patients spent being sedentary.

Despite finding no additional benefit from adding exercise to dietary changes, Dr. Andrews said, “We should concentrate on exercise and diet.” The message, he added, was not that exercise should be avoided.

 Linagliptin in Type 2 Diabetes Patients with Hyperglycemia

A pooled analysis of three phase 3, placebo-controlled, randomized trials found that patients with type 2 diabetes and poor glycemic control who took linagliptin for
24 weeks had a statistically significant reduction in glycated hemoglobin A_1c (HbA_1c) levels compared with patients given placebo. In addition, the rate of adverse events was nearly identical between the groups. Results were presented at the ADA meeting in a poster titled Efficacy and Safety of Linagliptin in People With Type 2 Diabetes and Poor Glycemic Control. The authors said that although many patients with type 2 diabetes who have poor glycemic control are treated with medications or receive education about the disease, a significant number of patients fail to meet their target levels.

Linagliptin is the first once-daily dipeptidyl peptidase-4 inhibitor that is excreted primarily through bile and the gut. Several previous studies have confirmed the drug’s safety and effectiveness when administered alone or added to treatment with metformin with or without a sulfonylurea.

For this meta-analysis, the authors included three trials that had enrolled a cumulative 2258 patients, but only considered data for the 396 patients with a baseline HbA_1c level ≥9.0%. The trials had evaluated linagliptin as monotherapy or added to metformin or to a combination of metformin and a sulfonylurea.

Baseline characteristics for the 396 patients were similar between the groups. Approximately 41% of the patients were men, and the average age was around 56 years. Patients had a mean body mass index of approximately 29.0 kg/m², and their mean HbA_1c level was 9.4%. More than half the patients (57%) had received a diagnosis of type 2 diabetes >5 years earlier. On average, patients had been treated with at least 2 oral antidiabetic agents.

The 396 patients had been randomized to receive 5 mg of linagliptin (n = 287) or placebo (n = 101) daily, which was administered alone or combined with the other specified agents, for 24 weeks. At the time of the final analysis, data were missing for 7 patients in the linagliptin group and 1 in the placebo group. After 24 weeks of treatment, HbA_1c levels decreased a mean of 1.2% for patients treated with linagliptin versus a mean decrease of 0.4% in those assigned to placebo (P <.0001).

These results were similar to the findings of each individual trial. The monotherapy trial showed an adjusted mean decrease in HbA_1c levels of 0.9% for the linagliptin group versus an adjusted mean increase of 0.2% in the placebo arm (P = .0005).

In the metformin add-on trial, patients in the linagliptin group had an adjusted mean decrease of 1.0% in HbA_1c levels compared with an adjusted mean decrease of 0.2% in the placebo cohort (P = .0062). In the metformin plus sulfonylurea add-on trial, HbA_1c levels decreased an adjusted mean of 1.2% in the linagliptin arm compared with 0.4% in the placebo group (P <.0001).

The pooled analysis of all 396 patients showed 61.9% of patients taking linagliptin had an adverse event compared with 62.7% of patients given placebo. In the linagliptin group, 3.1% of patients had a serious adverse event compared with 4.9% of patients in the placebo arm. The incidence of hypoglycemia was 8.8% in the linagliptin group versus 4.9% in the placebo group.

The majority of hypoglycemia incidents in the linagliptin group (25 of 26) involved patients who were taking the drug with metformin and a sulfonylurea. The authors advised caution for patients using linagliptin with a sulfonylurea.

This study was supported by Boehringer Ingelheim.

Substituting Liraglutide for Sitagliptin Is Effective in Patients with Type 2 Diabetes

A randomized trial that switched patients with type 2 diabetes from sitagliptin to liraglutide observed improved glycemic control and weight loss after 26 weeks. In addition, the percentage of patients achieving the ADA’s target glycated hemoglobin A_1c (HbA_1c) level of <7% increased from 30% to 50%. Both drugs are approved by the FDA as treatments for type 2 diabetes. Trial data were presented at the ADA meeting in a poster titled Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide Further Improves Glycemic Control and Weight Loss in Patients With Type 2 Diabetes.

The 26-week study was an extension of a 52-week randomized, parallel-group, open-label trial that had compared 1.2- and 1.8-mg doses of liraglutide with a 100-mg dose of sitagliptin in patients with type 2 diabetes. The oral drugs were administered daily in combination with metformin. The liraglutide groups experienced a significantly greater reduction in levels of HbA_1c and fasting plasma glucose and lost significantly more weight.

Eligible persons were 18 to 80 years of age, with an HbA_1c level between 7.5% and 10.0%. Their body mass index had to be ≤45 kg/m² and they had to have been taking at least 1500 mg of metformin daily for ≥3 months.

A total of 436 patients completed the initial 52-week trial, and 419 continued on to the 26-week extension phase. In total, 381 persons completed all 78 weeks of the study.

In the extension phase, patients who had been in the sitagliptin group were switched to a 1.2- or 1.8-mg dose of liraglutide. Patients who switched to the 1.2 mg-dose of liraglutide experienced a mean decrease of 0.24% in HbA_1c levels (P = .006), while patients who switched to 1.8 mg of liraglutide had a mean decrease of 0.45% (P = .0001).

Of the patients who switched to 1.2-mg liraglutide for the study’s extension phase, 29.5% had achieved an HbA_1c level <7% at the end of the main phase. This increased to 49.2% of patients at the conclusion of the extension study. The fasting plasma glucose level for this contingent of patients decreased a mean of 0.84 mmol/L from week 52 to week 78 (P = .0004)

Among patients who switched to 1.8 mg of liraglutide, 29.5% had an HbA_1c level <7% at 52 weeks versus 50% of patients at 78 weeks. Fasting plasma glucose levels fell a mean of 1.42 mmol/L from
week 52 to week 78 for those who switched to 1.8 mg of liraglutide (P < .0001).

Both groups experienced a statistically significant decrease in mean body weight. Patients who switched to 1.2 mg of liraglutide lost a mean of 1.64 kg (P <.0001), and those who switched to 1.8 mg of liraglutide lost a mean of 2.48 kg (P <.0001).

Patient satisfaction was assessed by comparing Diabetes Treatment Satisfaction Questionnaire scores from week 52 to week 78. The scores increased from a mean of 31.9 to 33.3 for patients who switched to 1.2 mg of liraglutide and from 30.9 to 31.7 for patients who switched to 1.8 mg of liraglutide, which was not significant.

Serious adverse events occurred in 6.0% of patients who switched to 1.2 mg of liraglutide and 2.9% of patients who switched to 1.8 mg of the drug. Gastrointestinal disorders were the most common adverse event, occurring in >30% of patients.

This study was supported by Novo Nordisk.

 Adding Exenatide to Glucose-Lowering Regimens Reduces Heart Failure Risk

A retrospective analysis of data from an electronic medical records database found that adding twice-daily injections of exenatide to a glucose-lowering regimen for patients with type 2 diabetes was associated with a reduced risk of heart failure. Results of the analysis were presented at the ADA meeting in a poster titled The Risk of Heart Failure among Patients Receiving Exenatide Versus Other Glucose-Lowering Medications for Type 2 Diabetes: A Matched Retrospective Cohort Analysis of the GE Healthcare Electronic Medical Record Database.

In 2005, exenatide became the first glucagon-like, peptide-1 receptor to receive FDA approval as a treatment for patients with type 2 diabetes. Exenatide is not recommended to be used as a replacement for insulin therapy nor is it intended to be  used with insulin, according to a news release from the manufacturers of the antidiabetic drug (Amylin Pharmaceuticals and Eli Lilly and Co).

Study investigators analyzed data obtained from the national Medical Quality Improvement Consortium, which consists of more than 14,000 healthcare providers that use GE Healthcare’s Centricity electronic medical records system. They identified 778,408 patients with a diagnosis of type 2 diabetes who had received glucose-lowering treatment (ie, exenatide, insulin, and/or another therapy) between January 2005 and September 2010.

The authors randomly matched the patients who took exenatide 1:1 with those who had not taken the drug, pairing them based on sex, age (according to 10-year spans), follow-up time available, and thiazolidinedione use. Patients were considered to have experienced heart failure if they had documented evidence of having had elevated concentrations (>100 pg/mL) of brain natriuretic peptide in addition to a clinical diagnosis of heart failure.

In an analysis of 50,330 patients, with disease severity adjusted according to the weighted Charlson Comorbidity Index (CCI), those who took exenatide with insulin and another antidiabetic therapy were 57% less likely to develop heart failure than those who took insulin and another antidiabetic therapy, but who had not used exenatide (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.35-0.53). When not adjusting for disease severity according to the weighted CCI, the OR dropped to 0.41 (95% CI, 0.34-0.51).

In an analysis of 53,446 patients, again after adjusting for disease severity using the weighted CCI, those individuals who received exenatide and other noninsulin therapies were 31% less likely to develop heart failure compared with those who took other noninsulin therapies but had not taken exenatide (OR, 0.69; 95% CI, 0.44-1.07). The unadjusted OR and 95% CI were identical to the adjusted findings.

When combining data for all the patients (n = 103,776) with type 2 diabetes, the patients who took exenatide were 54% less likely to develop heart failure compared with those who had not received exenatide (OR, 0.46; 95% CI, 0.38-0.56). The authors noted that the results of the study were “consistent with the positive effects of exenatide on cardiovascular risk factors observed in the clinical development program for exenatide and in clinical practice.” 

This analysis was funded by Amylin Pharmaceuticals, Inc, and Eli Lilly and Co.