American Diabetes Association 77th Scientific Sessions

Overweight Boys Who Lose Weight Can Avoid Type 2 Diabetes Later

MEN WHO WERE OVERWEIGHT during childhood but of normal weight as young adults have the same risk of type 2 diabetes (T2D) as men who were never overweight, according to a study presented at the ADA meeting.

“These findings suggest that adverse metabolic health consequences of being overweight in childhood may possibly be reversed,” lead study author Lise G. Bjerregaard, PhD, a postdoctoral research fellow in the Department of Clinical Epidemiology at Frederiksberg Hospital, in Copenhagen, Denmark, said. “We expected that overweight boys who reach normal weight by age 18 could reduce their risk of developing type 2 diabetes. However, we were excited to discover that achieving normal weight by young adulthood resulted in the same risk level as [in] men who had always been of normal weight.”

The study examined the links between overweight patterns, defined as the combination of weight status in childhood and young adulthood and a development of T2D later in life, to determine whether overweight boys who achieve a normal weight from age 7 to 18 years could reverse the negative impact of being overweight during childhood.

Researchers analyzed health data of 62,565 men in Denmark who had their weight and height measured at age 7 years and again at 17 to 26 years. In this cohort, 5.4% of the men were overweight in childhood and 8.2% were overweight in young adulthood, which showed that 40% of the men who were overweight in childhood were also overweight in young adulthood.

By age 30, 6710 men had T2D; however, those who had been overweight as boys but normalized their weight by their young adult years had a risk of T2D comparable to that of men who were never overweight (hazard ratio [HR] = 1.01 [0.87-1.16]).

Particularly concerning was the finding that men who were persistently overweight or became overweight as young adults had 3 times the risk of developing T2D, compared with non-overweight men who were overweight as children (HR = 2.88 [2.40, 3.44]) and (HR = 2.95 [2.53, 3.45]), respectively.

“Our results highlight the need for normalizing weight among overweight children before they reach adulthood,” Bjerregaard said. “Prevention and treatment interventions of overweight pediatric populations should be a priority in many countries around the world, especially where there are higher incidences of obese children and rising rates of type 2 diabetes.”

Results from inTandem1 and inTandem2 Show A1C Benefit

TWO PIVOTAL STUDIES on sotagliflozin— inTandem1 and inTandem2—were presented at the ADA meeting, yielding 24-week data that demonstrated key efficacy and safety results for the drug’s use in patients with type 1 diabetes (T1D).

As a First-in-Class, sotagliflozin (Lexicon Pharmaceuticals, Inc) is an oral dual inhibitor of sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). Both inTandem1 and inTandem2 showed that when used on top of optimized insulin, sotagliflozin 200 mg and 400 mg both reduced hemoglobin A1C (HbA1C), compared with placebo (P <.001 in both studies).

The drug was generally well tolerated, with a low rate of severe hypoglycemia seen in both studies. Severe hypoglycemia occurred less frequently on the sotagliflozin regimen than it did on placebo in 3 out of 4 arms. Also in both studies, the rate of diabetic ketoacidosis was low (0.4% to 3.1% over the 24 weeks); it was higher in patients who were on an insulin pump than it was in patients taking multiple-dose injections.

The inTandem1 study met its primary endpoint of change in A1C levels from baseline after the 24-week treatment period. Changes in A1C were 0.08% for placebo, 0.43% for the 200-mg dose, and 0.49% for the 400-mg dose. For patients treated with the 200-mg and 400-mg doses, the differences compared with placebo were 0.36% and 0.41%, respectively (P <.001 for both doses).

Secondary endpoints were also met in the 400-mg arm, with net benefit (defined as A1C <7.0% without an episode of severe hypoglycemia or diabetic ketoacidosis), weight, bolus insulin, and fasting plasma glucose, as well as 2 patient-reported outcomes, all being statistically significant. The secondary endpoints of net benefit and weight were also statistically significant in the 200-mg arm.

The medication was generally well tolerated, with treatment- emergent adverse events (AEs) occurring at rates of 67.5% for placebo, 67.3% for the 200-mg dose, and 71.0% for the 400-mg dose. Serious AEs occurred at rates of 3.4% for placebo, 3.8% for the 200-mg dose, and 6.9% for the 400-mg dose. Study discontinuation rates because of AEs were 1.5% for placebo, 1.1% for the 200-mg dose, and 3.8 for the 400-mg dose. No deaths were reported in the study.

The inTandem2 study yielded a reduction in A1C from baseline to 24 weeks of 0.03% for placebo (P = 0.54), 0.39% for the 200-mg dose (P <.001), and 0.37% for the 400-mg dose (P <.001). The mean differences for the 200- and 400-mg doses, compared with placebo, were 0.36% and 0.35%, respectively (P <.001 for both doses).

Also compared with placebo, both doses were statistically significant (P <.001) on the net benefit endpoint, A1C <7.0% without an episode of severe hypoglycemia or diabetic ketoacidosis.

As with inTandem1, the medication was generally well tolerated, with incidence rates of treatment-emergent AEs being 51.4% for placebo, 55.9% for the 200-mg dose, and 54.4% for the 400-mg dose. The incidence rate for serious AEs was 3.5% for the placebo and 4.2% for both the 200-mg and 400-mg doses.

The discontinuation rates because of AEs were 1.6% for the placebo, 1.9% for the 200-mg dose, and 3.0% for the 400-mg dose. Two deaths were reported in the placebo arm; no deaths were reported in either the 200-mg or 400-mg dose arms.

“There remains a need for oral therapeutic agents in addition to insulin to help improve quality of life in patients with type 1 diabetes by reducing the diabetes management burden, and sotagliflozin has that potential,” John Buse, MD, PhD, lead investigator of inTandem1 and a professor of medicine, chief of the Division of Endocrinology and Metabolism, director of the Diabetes Care Center, and executive associate dean for clinical research at the University of North Carolina School of Medicine, said in a news release announcing the results. “Sotagliflozin has demonstrated, in three phase 3 studies, the ability for patients to achieve glycemic goals with a safety profile that supports its utility in the type 1 diabetes community.”

“We are extremely pleased with the results achieved by sotagliflozin in its three phase 3 studies,” Lonnel Coats, Lexicon’s president and chief executive officer, said in the same news release. “We look forward to seeing the pooled continuous glucose monitoring data from inTandem1 and inTandem2, as well as data from secondary endpoints in inTandem2 in the third quarter.”

SGLT2 Inhibitors Associated with Lower Rates of Death, Hospitalization for Heart Failure in Patients with Type 2 Diabetes

THE RESULTS of an international study showing the benefits of sodium-glucose transporter-2 (SGLT2) inhibitors were presented at the ADA meeting. According to the CVD-REAL study, the benefits were conferred regardless of pre-existing cardiovascular disease (CVD) or which type of SGLT2 inhibitor was used.

The study analyzed 306,156 patients with type 2 diabetes (T2D) from 5 countries—Denmark, Norway, Sweden, the United Kingdom, and the United States&mdash;who were treated with SGLT2 inhibitors. Using clinical practice data, the researchers compared the rates of heart failure (HF) and death in patients with and without prior CVD to HF rates in new users of SGLT2 inhibitors and other glucose-lowering drugs (oGLD).

The data on HF and subsequent death rates were collected using medical records, medical claims, electronic health records, and national registers. Propensity scores were used to match patients treated with SGLT2 inhibitors and oGLD. The baseline characteristics were balanced between groups and analyzed 306,156 patients, totaling >150,000 person years (PY) (100,947 PY for SGLT2 inhibitors; 89,208 PY for oGLD) and 950 new HF events. The hazard ratios (HR) for HF, death, and the composite of death from HF were estimated by country and pooled as a weighted average.

An association between SGLT2 inhibitors and lower rates of death and hospitalization due to HF were seen in all 5 countries. Furthermore, the benefits of treatment with SGLT inhibitors were consistent regardless of the type of inhibitor used, which varied from country to country.

When compared with oGLD, the SGLT2 inhibitors were associated with 31% lower rates of HF in patients with existing CVD (HR, 0.69; 95% CI, 0.59-0.80), and 45% lower rates of HF in patients without existing CVD (HR, 0.55; 95% CI, 0.34-0.88).

Similar results were seen for death due to all causes and due to HF regardless of the patients’ history of cardiovascular disease. Notably, all the patients treated with SGLT2 inhibitors were less likely to have HF or subsequent death, compared with the oGLD patients.

“This study offers further evidence regarding the potential of SGLT2 inhibitors to improve outcomes in patients with diabetes,” Matthew A. Cavender, MD, MPH, assistant professor of medicine at the University of North Carolina School of Medicine, said in the results presentation. “While our results are striking in their similarity to a prior randomized study evaluating the benefit of SGLT2 inhibitors in patients with diabetes and known cardiovascular disease, these results go one step further to show that SGLT2 inhibition may benefit all patients with diabetes, regardless of whether they have known cardiovascular disease.”

Cavender addressed the possibility of a class effect in the results: “It’s also important to note that there was a significant difference in the particular SGLT2 inhibitor used in each country, suggesting that the benefits seen with SGLT2 inhibitors are likely to be a class effect. Previous research has shown that patients with diabetes have a 30% higher risk for heart failure when compared to patients without diabetes. These findings suggest that use of SGLT2 inhibitors may provide the opportunity to reduce the incidence of heart failure among patients with diabetes.”

Ongoing randomized clinical trials with SGLT2 inhibitors likely will provide considerably more information regarding its clinical effectiveness. The follow-up to this study, Cavender said, includes plans to further evaluate the effectiveness of SGLT2 inhibitors on other important clinical events, as well as to broaden the focus to evaluate the association between other drugs designed for use in patients with diabetes who have a history of cardiovascular events.

Investigational SGLT2 Inhibitor Meets Primary Endpoint in Phase 3 Studies

MERCK, IN PARTNERSHIP with Pfizer Inc, has announced that VERTIS MET and VERTIS SITA met their primary endpoints. Both trials are phase 3 studies of an oral sodium—glucose co-transporter (SGLT2) inhibitor, ertugliflozin, that is currently in development to help improve glycemic control in adult patients with type 2 diabetes (T2D).

Researchers will report that the tested daily doses, 5 mg and 15 mg, achieved statistically significant reductions in hemoglobin A1C when added to metformin or in initial co-administration with sitagliptin.

The results of these studies, along with 52-week extension data from 3 other studies in the VERTIS clinical development program of ertugliflozin, were presented the ADA meeting.

“We are pleased to share these new phase 3 data with the scientific community that support the product profile of ertugliflozin as add-on therapy to metformin or for first-line use when combined with sitagliptin,” Sam Engel, MD, associate vice president of Merck clinical research, cardiometabolic and women’s health, said in a joint news release from Merck and Pfizer. “These studies are important milestones on our journey to bring this medicine to adults with type 2 diabetes and the physicians who care for them.”

“These results, combined with findings from other studies in the VERTIS program, underscore the potential of ertugliflozin as an important therapeutic option for adults with type 2 diabetes to help improve their glycemic control,” added James Rusnak, MD, PhD, chief development officer, cardiovascular and metabolic diseases, for Pfizer Global Product Development. “As the global burden of diabetes continues to rise, we are committed to meeting patients’ needs with additional treatment options to help manage their condition.”

VERTIS MET, a 26-week study, evaluated the efficacy and safety of ertugliflozin taken in combination with metformin. It was compared with placebo and metformin in adult patients with uncontrolled T2D who take metformin monotherapy.

VERTIS SITA, which is also a 26-week study, compared the efficacy and safety of initial combination therapy of ertugliflozin and Merck’s dipeptidyl peptidase (DPP)-4 inhibitor, Januvia (sitagliptin), with placebo.

The VERTIS clinical development program comprises 9 phase 3 trials including approximately 12,600 adult patients with T2D. An ongoing cardiovascular (CV) outcomes trial of ertugliflozin, VERTIS CV, recently completed enrollment with approximately 8000 patients with T2D and established vascular disease. Its primary endpoint is to assess the noninferiority of ertugliflozin to placebo on the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. VERTIS CV was expanded in 2016 with prespecified secondary endpoints added to test for superiority on the composite of CV death and hospitalization for heart failure, as well as for superiority on CV death alone.

Marketing applications for ertugliflozin and 2 fixed-dose combination products (ertugliflozin/Januvia and ertugliflozin/metformin) are under review by the FDA and the European Medicines Agency. According to the partner companies, the Prescription Drug User Fee Act action date from the FDA for the 3 new drug applications will be in December 2017.

Severely Obese Children Have Dangerously Increased Risk of Type 2 Diabetes

A STUDY PRESENTED at the ADA meeting revealed that severely obese Native American children aged 5 to 9 years had 12 times the risk of developing type 2 diabetes (T2D) by age 20 as normal-weight youth in the same age range.

“We had previously found BMI [body mass index] in youth to be a strong predictor of type 2 diabetes, but we had not examined diabetes incidence rates in those with the severe degree of obesity that is prevalent today,” Madhumita Sinha, MD, MHSM, staff clinician at the Diabetes Epidemiology and Clinical Research Section of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, in Phoenix, Arizona, said. “We did not know if diabetes incidence rates among the obese plateaued among those with extremely high BMI. This study clearly shows that the risk of developing type 2 diabetes is associated with BMI, especially at very high extremes.”

The longitudinal study examined the risk of developing diabetes and other metabolic abnormalities in obese and severely obese Native American youths from the southwestern United States, a population at high risk of developing T2D. Incidence was studied in 2728 children without diabetes who were aged 5 to 9 years and a partially overlapping group of 4317 youths aged 10 to 17 years. They were followed up to age 45 or until the onset of T2D. Age- and sex-specific BMI percentiles were defined by the CDC’s 2000 growth charts.

Compared with nonobese 5- to 9-year-olds with a BMI in the middle of the distribution, children of the same age with a BMI at least 40% above the cutoff point defining obesity had 12 times the incidence rates of T2D by 20 years of age and 3 times the incidence by 45 years.

“Parents and healthcare providers should be aware of the future diabetes risk associated with obesity in youth, especially as more severe degrees of obesity become more prevalent,” Sinha concluded. “Results of our analysis emphasize the importance of developing effective means of preventing or treating obesity in youth, and additional risk factors for type 2 diabetes in youth should be explored for their interactions with severe obesity.”

LixiLan-L Phase 3 Study Results Show Lower A1C Levels

A NEW ANALYSIS has shown that insulin glargine 100 units/ mL and lixisenatide 33 mcg/mL in combination lowered hemoglobin A1C (HbA1C) levels by 1.09% to 2.41% after 30 weeks of treatment in a population of adult patients with type 2 diabetes (T2D) previously treated with 15 to 40 units of basal insulin daily.

The research was presented in a poster session at the ADA meeting. Among the post hoc analysis of data from the LixiLan-L phase 3 study is the finding that all subgroups treated with the insulin glargine/lixisenatide combination (Soliqua/Sanofi) achieved a mean A1C below 7% after the 30-week treatment period. The trial grouped the participants by A1C level at screening.

“Lowering elevated HbA1C is an important treatment goal in people with diabetes,” Riccardo Perfetti, vice president and head of Global Medical Affairs, Diabetes Division, for Sanofi, said in a news release distributed after the presentation. “This analysis demonstrated the substantial blood sugar—lowering effect that can be achieved with Soliqua 100/33 and its potential to help adults reach HbA1C levels below 7%, which is recommended as a treatment goal by bodies such as the American Diabetes Association for many adults with diabetes.”

The LixiLan-L trial compared the effectiveness of the combination of insulin glargine 100 units/mL and lixisenatide 33 mcg/mL with insulin glargine 100 units/mL alone in 736 adults with T2D that was not adequately controlled at screening.

These patients were on a regimen of 15 u to 40 u of basal insulin daily, alone or combined with 1 or 2 oral anti-diabetic agents. The primary outcome—a statistically significant reduction in A1C, compared with insulin glargine 100 units/mL&mdash;was previously reported by Sanofi in September 2015. For this study, patients were split into 3 categories based on A1C at screening: ≤8%, >8% to ≤9%, and >9%. Data were evaluated for the 660 patients who completed the 30-week study period. The least squares mean reduction in A1C for the insulin glargine 100 units/mL and lixisenatide 33 mcg/mL treatment group were 1.09%, 1.44%, and 2.41%, respectively, after 30 weeks. The mean A1C observed for each subgroup was <7% with insulin glargine 100 units/mL and lixisenatide 33 mcg/mL alone (7.22%, 7.42%, and 7.66%, respectively), and reductions in A1C were also greater in this group across all defined categories versus insulin glargine 100 units/mL alone (P <.0001 for all comparisons).

Teens with Type 1 Diabetes Can Text Improved Glycemic Control

TEENAGERS WITH TYPE 1 diabetes (T1D) maintained or improved their hemoglobin A1C (HbA1C) levels byfrequently using a receive-and-respond text messaging system, according to a new study presented at the ADA meeting.

The system was implemented as the teens prepared to transition from pediatric to adult care. A successful transition is largely predicted by how effectively teens maintain their A1C levels during adolescence. The study evaluated the effectiveness of text messaging to help teens manage and maintain glycemic control. The messaging system sent reminders to check blood glucose and required the teens to reply with their results. The 12-month, randomized, controlled trial enrolled 301 teenagers with T1D at 2 clinical sites in the United States.

The participants’ average age was 15 years, their average duration of living with T1D was 6.5 years, and their average baseline A1C was 8.5%. Gender was evenly split, and ethnic minorities composed 22% of the sample. In the entire cohort, 63% used insulin pumps.

To compare the teens who received texting intervention with teens who received a problem-solving intervention and teens who received standard care, the participants were randomized to 1 of 4 groups.

The 74 teens in the text messaging (TM) group received daily reminders to check their blood glucose and send the results to investigators by reply text. These teens started the study by receiving and replying to 1 text per day on weekends, gradually increasing to 4 text exchanges per day. Another 74 teens were randomized to the problem-solving (PS) group and received 5 self-care modules emphasizing increased monitoring of blood glucose and dosing with insulin at mealtimes. The third group, made up 77 teens, received both the text message and problem-solving interventions (TM + PS). The fourth group of 76 teens received no intervention.

According to the study results, which used a multivariate mixed linear model, the frequency with which the teens responded to texts significantly predicted their A1C levels (P <.003), while the problem-solving intervention did not have a similar impact, indicating that the text reminders could potentially preserve and improve teens’ glycemic control.

Further, during the study period, the teens who replied to most of the texts demonstrated the best glycemic control. These teens, in both the TM and TM + PS groups, exhibited a response rate of 68% to 100%, and, after 1 year, their average A1C levels were 8.1%.

“It is important to recognize the challenges faced by teens with type 1 diabetes as they navigate increasing independence in self-care,” noted lead study author Lori Laffel, MD, MPH, chief of the Pediatric, Adolescent and Young Adult Section and senior investigator/co-head of the Section on Clinical, Behavioral, and Outcomes Research at Joslin Diabetes Center and a professor of pediatrics at Harvard Medical School.

The researchers plan to evaluate the durability of the texting intervention on glycemic control in teens with T1D over the next 6 to 12 months. “Given the current landscape of cellphone use among teens, it is fitting to evaluate the potential impact of text message reminders aimed at assisting teens and young adults with their diabetes self-management as they transition from pediatric to adult diabetes care,” Laffel said.