American Diabetes Association (ADA) 72nd Scientific Sessions

June 8-12, 2012; Philadelphia, PA
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New Guidelines Focus on Patient-Centered Approach to Glycemic Management

Recent guidelines from the ADA and the European Association for the Study of Diabetes (EASD) regarding glycemic management in patients with type 2 diabetes were presented at the ADA meeting. During an oral presentation, Silvio E. Inzucchi, MD, Section of Endocrinology, Yale University School of Medicine, New Haven, CT, and colleagues presented the new position statement of the ADA and the EASD, titled Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach (Diabetes Care. 2012;35[6]:1364-1379).

An updated set of guidelines was needed due to contemporary information on the benefits and risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes, the withdrawal and restriction of others, and increasing calls for a move toward more patient-centered care. The point most stressed by Inzucchi about the recent guidelines was the need for individualization in diabetes treatment, since the achievement of any degree of glucose control requires active patient participation and commitment.

Patient-centered care is respectful of and responsive to individual patient preferences, needs, and values, and ensures that patient values guide all clinical decisions, according to Inzucchi and colleagues. When comparing the new guidelines to those from 2008, Inzucchi pointed out that the new guidelines are not as prescriptive and algorithmic, there is a harmonization of dual therapy options, and there is more of an acknowledgement of lifestyle changes in treatment.

The need to gauge a patient’s preferred level of involvement in his or her treatment is important, noted Inzucchi during the presentation. “In a chronic disease where lifestyle changes need to be made,” collaboration between the patient and the healthcare provider is necessary, according to Inzucchi.

In an attempt to manage hypoglycemia, the following elements should be considered: patient attitude and expected treatment efforts; risks potentially associated with hypoglycemia and other adverse events; disease duration; life expectancy; important comorbidities; established vascular complications; and resources and support systems. These elements should help during decision-making used to determine appropriate efforts to achieve glycemic targets. Using a scale to measure the severity of each element should help efforts to lower glycated hemoglobin levels. This scale should not be applied rigidly but rather used as a broad construct to help guide healthcare providers.

Additional considerations for treatment plans should include age, weight, sex/racial/ethnic/genetic differences, and comorbidities, including coronary artery disease, heart failure, chronic kidney disease, liver dysfunction, and hypoglycemia. Inzucchi believes that “comorbidities are not given proper attention. Patients want to a take a pill once a day and not think about their illness,” so the burden of treatment has to be considered in each individual.

In the position statement, a potential sequence of antihyperglycemic therapy is offered. Diet, exercise, and diabetes education remain the foundation for any type 2 diabetes treatment plan. Metformin is usually the optimal first-line drug suggested for treatment. After metformin, two-drug and three-drug combinations are suggested, but vary based on the patient. Many patients will then also require insulin therapy, alone or in combination with other agents, to maintain glucose control. Cardiovascular risk reduction must also be a major focus of treatment therapy.

Future research suggested by Inzucchi and colleagues was addressed, including the need for high-quality comparative-effectiveness research regarding glycemic control, costs, and outcomes that matter most to patients, such as quality of life and the avoidance of morbid and life-limiting complications, especially cardiovascular disease. In addition, pharmacogenetics may very well inform treatment decisions in the future, guiding the healthcare provider to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects. More clinical data are needed on how phenotype and other patients/disease characteristics should drive drug choices in the future.—Kerri Fitzgerald
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 Exenatide Once Weekly Is a Viable Alternative to Insulin Detemir for Glycemic Control

In patients with type 2 diabetes mellitus (T2DM), treatment with exenatide once weekly (EQW) injection is associated with a significantly higher likelihood of achieving target hemoglobin A_1C (HbA_1c) levels and weight loss, compared with insulin detemir treatment, reported Melanie Davies, MD, Department of Cardiovascular Sciences, Diabetes Research, Leicester General Hospital, United Kingdom, and colleagues, among other key findings, in an ADA poster session summarizing the findings of their multicenter, open-label, parallel-arm study. 

Treatments that improve hyperglycemia and body weight, while keeping the risk of hypoglycemia low, are more desirable in the treatment of T2DM than in treatments associated with weight gain, Davies and colleagues noted. In previous studies, EQW has shown to provide continuous glycemic control with improvements in body weight and no increased risk of hypoglycemia when not used with a concomitant sulfonylurea (SFU). Insulin detemir is considered the most weight-neutral and long-acting insulin currently available, and it is associated with fewer hypoglycemic events compared with other long-acting insulins.

Based at sites throughout the United Kingdom and Ireland, the study set out to compare EQW and insulin detemir (once or twice daily) with respect to glycemic control, body weight, cardiovascular outcomes, and overall tolerability and safety in 216 patients with T2DM whose conditions were inadequately controlled with oral antidiabetes drugs, namely metformin, with or without SFUs.

Participants were randomized into two groups: one arm received exenatide 2 mg once weekly administered by subcutaneous injection (n=111; mean age, 59 years; 64% male); and one arm received insulin detemir once daily or twice daily titrated to achieve fasting plasma glucose levels of ≤99 mg/dL (n=105; mean age, 58 years; 69% male). At the end of the 26-week follow-up period, Davies and colleagues found that 44.1% of EQW-treated patients compared with 11.4% of detemir-treated patients had achieved a target HbA_1C level of ≤7.0% and weight loss of ≥1.0 kg (P<.0001). The EQW-treated patients also had greater reductions in HbA_1C levels (-1.30±0.08% vs 0.88±0.08%, respectively; P<.0001) and in weight (-2.68±0.34 kg vs 0.8±0.36 kg, respectively; P<.0001) than detemir-treated patients.

Additionally, they reported that both treatments were associated with improvement in some markers of cardiovascular risk as well as with glycemic improvement accompanied by low incidence of hypoglycemia; however, more significant improvements to systolic blood pressure, plasminogen activator inhibitor-1 levels, and high-sensitivity C-reactive protein levels were observed in the EQW arm compared with the insulin detemir arm. The authors noted that gastrointestinal and injection-site–related adverse events, including constipation, vomiting, and injection-site pruritus, were more common in patients treated with EQW than with insulin detemir.

Davies and colleagues concluded, “EQW may represent an alternative treatment option to insulin detemir in patients with T2DM with inadequate glycemic control despite treatment with [oral antidiabetes drugs].”—Allison Musante
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Dapagliflozin Added to Sitagliptin Reduces Glycated Hemoglobin Levels

After 48 weeks of treatment, patients with type 2 diabetes who took dapagliflozin had significant reductions in hemoglobin A_1c (HbA_1c) compared with placebo as an add-on therapy to sitagliptin, according to a phase 3, multicenter, randomized, double-blind, placebo-controlled study. Results were presented in an ADA poster session.

Dapagliflozin is an oral selective sodium-glucose cotransporter 2 inhibitor. In January 2012, the US Food and Drug Administration (FDA) told the drug’s manufacturers (Bristol-Myers Squibb and AstraZeneca) that it needed more data before making a decision on its approval. In July 2011, an FDA advisory committee recommended that the drug not be approved, citing potential risks of breast and bladder cancer.

In this study, 447 adults were randomized in a 1:1 ratio to receive 10 mg per day of dapagliflozin (n=223) or placebo (n=224) plus 100 mg per day of sitagliptin with metformin or without metformin. The patients all had type 2 diabetes and were inadequately controlled by sitagliptin or sitagliptin plus placebo. They also had an HbA_1c between 7.0% and 10.0%. The study included a 24-week treatment period followed by a 24-week extension.

At 24 weeks, patients in the dapagliflozin plus sitagliptin with or without metformin group had a 0.48% decrease in HbA_1c from baseline compared with patients who took placebo plus sitagliptin with or without metformin (P<.0001). There was a greater effect in dapagliflozin added to sitagliptin compared with placebo added to sitagliptin (HbA_1c reduction of 0.56%; P<.0001). However, there was still a significant decrease of 0.40% when dapagliflozin was added to sitagliptin and metformin compared with placebo plus sitagliptin with metformin (P<.0001). The authors noted that the results remained consistent during the 24-week extension period.

After 48 weeks, 66.2% of patients taking dapagliflozin and 61.1% of patients taking placebo had more adverse events. The rates for more than one serious adverse event were also similar (6.7% vs 8.0%, respectively). Hypoglycemia was found in 5.3% of dapagliflozin patients and 6.2% of placebo patients.—Tim Casey
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Linagliptin Reduces Marker of Kidney Function Decline in Patients With Diabetes

Linagliptin (Tradjenta), an oral agent approved to treat type 2 diabetes mellitus (T2DM), reduced urinary albumin-to-creatinine ratios (UACRs) significantly over 24 weeks in patients with diabetic nephropathy, according to a study presented at the ADA meeting. Elevated albumin levels in the urine, or albuminuria, indicates worsening kidney and cardiac function in patients with T2DM. Diabetes is a leading cause of kidney failure, and investigators said that linagliptin’s ability to reduce albuminuria in patients suggests it has kidney-protective properties.

In conducting the post-hoc analysis, researchers identified a subset of 227 patients from four phase 3 trials who had diabetic nephropathy at enrollment and were regularly taking an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) to slow the progression of renal impairment. The study included men and women primarily of white (70%) and Asian (26%) descent.

Patients were randomly assigned to 5 mg of linagliptin daily with or without another glucose-control agent (n=168) or to placebo (n=59) for 24 weeks. Patient and disease characteristics were well balanced between the cohorts, and the groups had similar proportions of patients with microalbuminuria and macroalbuminuria. Slightly more patients in the linagliptin group than in the placebo group had mild to moderate renal impairment at baseline (normal renal function, 47.0% vs 57.6%, respectively).

At 24 weeks, linagliptin was associated with a 33% reduction in baseline UACR, a difference of 29% compared with placebo (P=.0305). In a sensitivity analysis of data for 249 patients who took part in the trials but were not using ACEs or ARBs, investigators found a median 30% reduction in baseline UACR for patients treated with linagliptin compared with 16% for those given placebo. The effects of linagliptin on UACR were evident within 12 weeks of initiating therapy and were consistent across all racial subgroups.

Linagliptin also lowered patients’ levels of glycated hemoglobin (HbA_1C) and fasting plasma glucose at 24 weeks. Investigators found no correlation between degree of improvement in glycemic control and change in UACR, however, with patients whose HbA_1C levels declined by <0.1% experiencing a reduction in UACR similar to that for patients whose HbA_1C levels dropped by more than 0.64%. They said that this suggests linagliptin “may have kidney-protective properties beyond glucose-lowering effects.”

Patients in the placebo arm experienced a small drop in blood pressure levels, whereas blood pressure levels remained stable in the linagliptin arm. Kidney function was also stable in the linagliptin arm, which had a slightly lower composite rate of renal and urinary disorders at 24 weeks compared with the placebo group (5.1% vs 4.2%, respectively).

The rates of adverse events in the trials were low, overall, with hypoglycemia the only treatment-related adverse event observed in more than 2% of patients taking linagliptin. All 14.3% of patients in the linagliptin arm who experienced hypoglycemia had also been taking a sulfonylurea; none required medical assistance.

In a press release by the drug’s manufacturer, lead investigator Per-Henrik Groop, MD, DMSc, Division of Nephrology, Helsinki University Central Hospital, Finland, said, “This analysis is important because approximately 65% of patients living with T2DM are at risk of declining renal function, which can limit treatment options.” He added that, based on the results of the post hoc analysis, the research team planned to study the relationship between linagliptin and urine albumin levels further. “We recognize the importance of considering declining renal function when treating T2DM patients,” he said.

Diabetes-related kidney disease can progress even in patients with good glucose control. To monitor the risk of renal impairment in patients with T2DM, the ADA and the National Institutes of Health recommend testing urine albumin excretion levels and estimated glomerular filtration rate annually.—Garrett Melton
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Insulin Glargine has Neutral Effect on Cardiovascular Outcomes and Cancers

After more than 6 years of follow-up, a large, international, randomized trial found that daily injections of insulin glargine in patients with type 2 diabetes, or with a high risk of the disease, had a neutral effect on cancer, serious cardiovascular outcomes, and death compared with standard care. The drug also reduced the progression of diabetes.

Hertzel Gerstein, MD, the study’s principal investigator and a professor of medicine at McMaster University in Ontario, Canada, said that the researchers found no new side effects with insulin glargine. Common side effects of the medication are hypoglycemia and weight gain, both of which were cited in this study.

Results were presented during a symposium at the ADA meeting. The findings were simultaneously published online in the New England Journal of Medicine (N Engl J Med. 2012;367[4]:319-328). Gerstein said that the academic steering committee first analyzed the data and then shared the findings with Sanofi, the drug’s manufacturer. “It is very unlikely that the drug is either causing harm or benefit in these individuals,” Gerstein said. “There is a very clear neutral effect, which is important for patients to know.”

The ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial had two main objectives for high cardiovascular risk patients: (1) determining if administering insulin glargine once daily and adjusting the dose to target a normal fasting glucose level (≤95 mg/dL) reduces cardiovascular outcomes more than standard care; and (2) determining if adding omega-3 fatty acids to the regimen reduces cardiovascular death.

The trial included 12,537 patients who had new or recently diagnosed diabetes or impaired fasting glucose/impaired glucose tolerance plus additional risk factors for cardiovascular disease. They were recruited from 573 sites in 40 countries, representing every continent with the exception of Antarctica. Mean age was 63.5 years, and 35% of patients were women. Of the patients, 82% had prior diabetes for a mean of 5.4 years and 6% had new diabetes detected when they were randomized.

The rates of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes in the two groups were similar: 2.94 per 100 person-years in the insulin glargine group compared with 2.85 per 100 person-years in the standard care group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.94-1.11; P=.63). There was also no statistically significant difference in the rates of those three events plus revascularization or hospitalization for heart failure: 5.52 per 100 person-years compared with 5.28 per 100 person-years (HR, 1.04; 95% CI, 0.97-1.11; P=.27). In addition, there was no difference in mortality (HR, 0.98; 95% CI, 0.90-1.08; P=.70) or cancer (HR, 1.00; 95% CI, 0.88-1.13; P=.97).

The authors also noted side effects associated with the drug. In the insulin glargine group, 57% of patients had at least one episode of hypoglycemia compared with 25% in the standard group (P<.001). In addition, 6% of patients in the insulin glargine group had at least one episode of severe hypoglycemia compared with 2% in the standard group (P<.001). The insulin glargine group gained a median of 3.5 pounds during the trial compared with a loss of 1 pound for the standard group (P<.001).
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Omega-3 Fatty Acids Analysis

Jackie Bosch, MSc, McMaster University, presented the analysis of the same patient population who received a 1-g capsule of omega-3 fatty acids or placebo on a daily basis for more than 6 years. She said that adding the omega-3 fatty acids did not reduce cardiovascular outcomes in people with disglycemia and other cardiovascular risk factors.

The study found that compared with placebo, omega-3 fatty acids had a neutral effect on cardiovascular death and other serious outcomes, but they lowered triglyceride levels. Patients who took omega-3 fatty acids tolerated them well, and 88% adhered to the treatment until the study’s completion.

Of the patients taking omega-3 fatty acids, 9.1% died from a cardiovascular cause compared with 9.3% of patients in the placebo group (HR, 0.98; 95% CI, 0.87-1.10; P=.72). The results were similar for the composite of myocardial infarction, stroke, and cardiovascular death: 16.5% in the omega-3 fatty acids group and 16.3% in the placebo group (HR, 1.01; 95% CI, 0.93-1.10; P=.81).—Tim Casey

The study was funded by Sanofi.
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Dual Screening for IFG and Elevated HbA_1c May More Accurately Predict Diabetes in Older Adults

Impaired fasting glucose (IFG) is defined by the American Academy of Family Physicians as glucose levels of 100 mg/dL to 125 mg/dL in fasting patients; these levels are above normal, but below the level that is diagnostic for diabetes. Therefore, persons with IFG are an important target group for the primary prevention of diabetes. Similarly, a high level of hemoglobin A_1c (HbA_1c), a biomarker of cumulative glycemic exposure, is suspected to predict type 2 diabetes and other cardiovascular diseases.

During a poster session at the ADA meeting, Kasia J. Lipska, MD, Section of Endocrinology, Yale University School of Medicine, New Haven, CT, and colleagues set out to determine which measure—IFG or elevated HbA_1c—is more strongly associated with incident diabetes in older adults. The results of their study demonstrated that older adults with IFG or elevated HbA_1c are at similarly increased risk—about seven times more likely—of developing diabetes over 7 years compared with those with normal glucose metabolism. Additionally, older adults with both IFG and high HbA_1c are at a markedly increased risk—about 20 times more likely—of developing diabetes.

At year 1, data was taken from the Health, Aging, and Body Composition Study for 3075 well-functioning adults without diabetes. Baseline values of IFG and HbA_1c were measured at year 4, using modern methods, which narrowed the cohort down to 1790 participants without diabetes (mean age, 76.5±2.9 years; 46.5% men; 67.1% white). Participants were divided into the following groups: normal IFG (defined as 100 mg/dL-125 mg/dL) and elevated HbA_1c (defined as 5.7%-6.4%), per current definitions from the ADA; normal glycemic function (fasting plasma glucose [FPG] <100 mg/dL and HbA_1c <5.7%); IFG only; elevated HbA_1c only; and combined IFG and elevated HbA_1c.

An FPG test can determine whether a patient has IFG. The test requires a person to fast overnight and measure blood glucose the following morning. A normal FPG is <100 mg/dL, whereas persons suspected of prediabetes have an FPG level between 100 mg/dL and 125 mg/dL. Patients with diabetes have an FPG level of >126 mg/dL.

Among the 1790 participants, 7.9% (n=141) developed diabetes over the 7-year follow-up period. A diagnosis of diabetes was based on annual self-report, use of antihyperglycemic medicines, or any FPG ≥126 mg/dL. Logistic regression analyses were adjusted for age, sex, and race.

Lipska and colleagues determined that IFG and elevated HbA_1c levels similarly increase the likelihood of developing diabetes mellitus over 7 years by more than 8-fold compared with normal glycemic parameters. Furthermore, the authors concluded, “Combined use of the FPG and HbA_1c for screening purposes identifies a group of older adults at very high risk for future diabetes.”

Despite these results, the authors acknowledged several limitations of the study. The analyses did not take into account death or loss to follow-up; however, sensitivity analyses excluding those individuals yielded similar results. Additionally, a relatively small number of diabetes diagnoses (n=141) precluded systematic subgroup analyses. The authors also noted that cost-effectiveness of this dual screening strategy should be an area of future study.—Allison Musante
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Knowledge of Age-Related Complications in Type 1 Diabetes Patients Could Lead to Improved Treatment

There is a lack of understanding of the characteristics of older adults with type 1 diabetes and the complications that they experience with age. Heightened awareness of the efficacy and safety of current approaches to treatment and serious acute complications of type 1 diabetes could yield better approaches to treatment in individuals as they age, explained Ruth S. Weinstock, MD, PhD, Division of Endocrinology, Diabetes, and Metabolism, Upstate University Hospital, Syracuse, NY, and colleagues during an ADA poster session.

The researchers presented a data analysis gleaned from the T1D Exchange Clinic Registry. The analysis included 5546 participants between the ages of 31 and 93 years who had type 1 diabetes for 1 year or longer, from 39 endocrinology centers across the United States. The participants included 639 adults aged ≥65 years, 1907 adults aged 50 to 65 years, and 3000 adults aged 31 to 50 years. Information regarding participants’ complications, medications, body mass index, and hemoglobin A_1c (HbA_1c) levels was gleaned from medical records; use of insulin pumps and sensors were reported by participants in a questionnaire and then confirmed by medical records. The prevalence of complications was assessed by age and diabetes duration.

Among the study’s key findings was that the presence of macrovascular complications increased with greater disease duration and age. Coronary artery disease or myocardial infarction was present in 26% of adults aged ≥65 years and in 12% of adults aged 50 to 65 years. The majority of adults ≥65 years were also taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (72%), statins (73%), and aspirin (79%). These patients had a mean HbA_1c level of 7.4%, and only 8% used continuous glucose
monitoring.

In all age groups, the presence of severe hypoglycemia increased significantly with longer durations of type 1 diabetes. In adults aged ≥65 years, severe hypoglycemia was present in 21% of patients ≥40 years, in 16% of those with the disease for 20 to 40 years, and in 7% of those with type 1 diabetes for <20 years. At least one severe episode of hypoglycemia resulting in seizure or coma in the previous 12 months was recorded in 16% of adults aged ≥65 years.

Diabetic peripheral neuropathy, a microvascular complication of diabetes, was most commonly reported in adults aged ≥65 years with the disease for ≥40 years (43%), followed by adults aged 50 to 65 years with type 1 diabetes for ≥40 years (30%).

Despite the high prevalence of diabetic retinopathy, the researchers found that a significant proportion of adults with type 1 diabetes had not been treated for diabetic retinopathy in either eye. Adults aged ≥65 years with type 1 diabetes for ≥40 years were most likely to have been treated for retinopathy (54%) compared with 32% of adults aged ≥65 years with the disease for 20 to 40 years.

The authors concluded that a large proportion of adults with type 1 diabetes do not have clinically significant renal disease or macrovascular disease, despite decades of living with the disease; however, “better approaches are needed to prevent severe hypoglycemia and chronic diabetes-related microvascular and macrovascular complications in adults with type 1 diabetes.”—Allison Musante

The T1D Exchange Clinic Registry and Statistical Resource Center are supported by the Leona M. and Harry B. Helmsley Charitable Trust.