What’s on the Horizon with Diabetes Research and Therapy?

(Editor’s Note: The items below are brief summaries of key presentations at the American Diabetic Association’s recent 74th Scientific Sessions, held June 13-17 in San Francisco.)

Like any large institution, the American Diabetes Association has its share of critics. However, say what you will about it, when the ADA holds its annual Scientific Sessions, they become the intense center of focus for almost everybody in the diabetes field.

 The sessions are where big pharma make important drug announcements; researchers publicize their latest findings; manufacturers introduce new or improved devices, and experts wrestle publicly with such issues as Obamacare’s eventual effects on diabetes treatment or how to deal with the estimated 80 million U.S. cases of pre-diabetes.  

 Major highlights included:

Growth in new cases of diabetes may be slowing down, according to Linda S. Geiss, MA, who reported that statisticians first noted a slowdown in the percentage growth of the disease in 2003 and 2008. Whether this is a long-range trend, given the rise in obesity levels nationally and the growth in the numbers of ethnic populations that have a greater predisposition to diabetes (such as blacks, Hispanics, and Pacific Islanders), she could not say.

 In a related presentation, Terri Lipman, Ph.D., CRNP, FAAN, reported that the incidences of type 1 diabetes recorded in the Philadelphia Pediatric Diabetes Registry, increased 17 percent from 2005 to 2009. While the most marked increase was in children under the age of 5, every age and ethnic/racial group in the registry had increased incidences of type 1.

 The ADA has revised its A1c target to 7.5% to apply across all pediatric age groups. Previously, recommended A1c targets were <8.5% for children under 6 years, <8.0% for children 6-12 years, and <7.5% for ages 13-19. The revised target comes in the wake of greater knowledge about hypoglycemic events, including their incidence among younger people and the availability of more sophisticated means for dealing with it.

Other Highlights:Devices: Bionic Pancreas, Closed Loop

Bionic Pancreas Outperforms Insulin Pumps in Type 1 Adolescents             

Boston-based researchers reported that the test of an “automated bihormonal bionic pancreas”* among 32 adolescents showed that the device improved the youngsters’ glycemic control without increasing incidences of hypoglycemia. The report is significant because one of the main concerns with machine control of insulin doses is possible overcompensation in correcting for high blood glucose levels, leading to hypoglycemia.

The young patients tested the device at a summer camp for five days followed by five days using an insulin pump. The patients had no restrictions placed on them regarding diet or exercise. Results of the comparison showed a mean plasma glucose level of 138 mg/dL among bionic pancreas users versus 157 mg/dL among insulin pump users. Mean frequency of treatments for hypoglycemia went from once per 0.8 days to once per 1.6 days.

Another interesting aspect of the summer camp experiment was that the bionic pancreas was initialized based on the patient’s weight. That was sufficient data for the system’s algorithm to kick in and adjust insulin and glucagon doses as necessary based on measurements made every five minutes. 

 Instruments used in the experiment included a fingerstick PG meter from HemoCue, a DexCom G4 Platinum CGM Sensor, and infusion set tubing and pump from Tandem Diabetes Care.

 (*A bionic pancreas uses continuous glucose monitoring and subcutaneous delivery of both fast-acting insulin to reduce high blood sugar and glucagon to raise it, based on measurements made at frequent intervals. Inclusion of a glucagon-dispensing capability makes the device different from previous attempts at automated blood sugar control.)

 Unsupervised Closed-Loop System Works Well Overnight for Type 1s

Cambridge University researchers told ADA attendees that adults with type 1 diabetes can benefit from unsupervised overnight use of a closed-loop insulin delivery system to avert or shorten hypoglycemic episodes. They tracked 24 adults with type 1 diabetes over four weeks using an automated insulin delivery system that used a predictive algorithm to deliver insulin with one group and a sensor-augmented pump delivery system with another group as a control.

They found that the closed-loop system, used between the hours of midnight and 7 a.m., produced glucose levels within the target range of 70 mg/dL to 144 mg/dL—”significantly greater” than with the sensor-activated system. Time spent above target was also significantly lower than with the sensor-augmented system.

The British scientists concluded that unsupervised in-home insulin delivery for up to four weeks with a closed-loop system is a viable treatment for type 1s. 

Animas Predictive Controller Reduces Type 1 Hypoglycemia in Study

Animas Corp. said research on the feasibility of the predictive controller it has under development confirmed what dosing characteristics may work best to percent hypoglycemia. The predictive controller automatically delivers insulin doses in response to CGM readings in type 1s. Animas tested three settings for dosage—conservative, medium, and aggressive—to determine which levels worked best at preventing patients’ glucose readings from dropping below 70 mg/dL.

 The company began its test on 12 type 1 patients expecting the conservative dosage setting to work best, but found that medium and aggressive produced better results. Animas acknowledged that the small patient sampling and testing the predictive controller in a tightly monitored clinical setting means that more research is necessary before the device can come to market. 

Type 1 Diabetes: 

Immunotherapy

 Although NeoStem’s report on an immunotherapy approach to treating recent-onset type 1 is only in Phase 1 study, it echoes similar “autologous” approaches that are being tested in cancer treatment. The company’s T regulatory cell (Treg) therapy, called NBS-03D, extracts patients’ blood, infuses it with expanded Treg cells, and then reintroduces it into the patients. Because the Treg cells are derived from the patients’ own bodies, the therapy’s safety factor is considerably increased.

 In the 14 patients treated, C-peptide levels, which are an indicator of pancreatic beta cell function, continued steadily for a period of two years. NeoStem believes that with further testing, Treg therapy could become a significant tool for extending the vigor of beta cells in people with recently diagnosed type 1.

 Cholesterol as CVD Predictor in Type 1s

Swedish researchers report that by itself low-density lipoprotein (so-called “bad cholesterol”) is not a significant predictor for cardiovascular disease in type 1s. Instead, they found, after a study that involved almost 31,000 patients ranging in age from 18 to 79, that the ratio of high-density lipoprotein (so-called “good cholesterol”) to LDL was a better predictor of the onset of CVD in type 1 patients who are not taking lipid-lowering medications.

Two Reports on Beneficial Effects of Pancreas/Islet Cell Transplants

Two reports on the effects of whole pancreas and pancreatic islet cell transplantation indicate that the procedures have beneficial effects that were not noticed before the medical community had considerable experience with them.

 1. According to researchers at the University of Pisa in Italy, by itself pancreatic transplantation for type 1s appears to be safe and effective in terms of mortality, insulin independence, and improvement in overall metabolism. They studied 34 type 1 patients who had undergone pancreas transplants and found that 97 percent of them were still alive 10 years after the operation. Of the survivors, 64.7 percent still had functioning grafts. All of those were insulin independent, with a median fasting glucose of 96 mg/dL versus 230 mg/dL pre-transplant.

 The Italians conclude that pancreatic transplants are safe and meet their hoped-for goals, especially in light of advances in surgical and immune system suppression techniques. 

2. Canadian scientists said islet cell transplantation may have a beneficial effect on diabetic neuropathy. A Vancouver-based study followed 44 islet transplant patients who were given nerve conduction velocity tests of their motor and sensory nerves. Results showed that the estimated 85 percent of the patients who had neuropathy when they underwent transplant surgery showed statistically significant improvement in nerve conductivity in follow-up studies conducted over the years after the procedure.

 Inhaled Insulin Said Effective for Type 1s and 2s

 Ultra rapid-acting insulin, delivered via inhalation rather than by injection, has been found to be an effective, non-invasive post-prandial therapy according to two presentations at the ADA Sessions.

In the first, researchers who compared the effectiveness of MannKind Corp.’s Technosphere inhaled insulin versus injected insulin or oral diabetes medications for type 1 patients reported that insulin inhalation powder performed as effectively in reducing A1c’s as shots and pills. They also noted that inhalation produced fewer episodes of hypoglycemia. Drawbacks included temporary but reversible lessening of pulmonary function.

The second presentation covered the results of inhalable insulin use with insulin-naive type 2s whose oral medications were ineffective in helping them achieve improved A1c’s. Working with a group of type 2s with A1c’s ranging from >7.5% to <10%, twice as many patients undergoing inhaled insulin therapy, as opposed to placebo (38 percent versus 19 percent), saw their A1c’s drop to 7% or below.

(Note: Within days after the presentations at ADA, news came that  the FDA has approved MannKind Corp’s inhaled fast-acting insulin, under the brand name Afrezza.)

Type 2 Diabetes:

Inhaled Insulin Said Effective for Type 1s and 2s (See the item immediately above for this item’s complete text.)

Ultra rapid-acting insulin, delivered via inhalation rather than by injection, has been found to be an effective, non-invasive post-prandial therapy according to two presentations at the ADA Sessions.

 Type 2 Drug Studies

Government requirements for how researchers can set up studies for type 2 drugs for pediatric patients are making it “virtually impossible” to test the effectiveness and safety of drugs in the research pipeline, said William V. Tamborlane, MD, Yale School of Medicine. As a result, many studies have not been able to achieve full enrollment, in some cases even when the enrollment period has been extended several years. As an example, he cited mandated eligibility criteria for studies involving metformin which only 6.9 percent of the patients enrolled in the Pediatric Diabetes Consortium’s type 2 database could meet.

After Gestational Diabetes, Breastfeeding Lowers Later Type 2 Risk

Women who experience gestational diabetes during pregnancy can significantly lower their chances of developing type 2 diabetes by engaging in “intensive, extended” breastfeeding, according to a report from Kaiser Permanente Northern California.  After adjusting for such factors as BMI, race/ethnicity, and treatment during gestational diabetes, Kaiser researchers found that women who exclusively breastfed (no formula feedings) six to nine weeks after giving birth lowered their risk of developing type 2 within the next two years by 61 percent. (A group that combined breast and bottle feeding had a 40 percent reduced risk.)

Incretins Not a Greater Risk Factor for Acute Pancreatitis in Type 2s

Based on animal studies, there have been long-standing concerns about a possible relationship between incretin drug use among type 2s and increased incidences of acute pancreatitis. Results of a Danish meta-analysis show that although patients who suffer acute pancreatitis are 40 percent more likely to be users of glucose-lowering drugs, no specific drugs used to treat type 2 diabetes can be associated with an increased risk for the condition.

 The meta-analysis included studies that involved 12,868 people who had been admitted to hospitals as first-time patients with acute pancreatitis.

 Data Say Insulin Degludec/Liraglutide Combo Works Well in Type 2s 

Novo Nordisk’s combination of insulin degludec and liraglutide, called IDegLira, works better than each drug separately in reducing A1c’s in type 2s. British researchers reported that a 52-week Phase 3a study of 1,311 type 2s whose oral medications were not controlling their blood sugar levels showed IDegLira users dropped their A1c’s 1.8% compared to 1.4% for insulin degludec users and 1.2% for liraglutide users.

Overall, IDegLira, 78.2 percent of IDegLira users achieved A1c’s of 7% or lower versus 62.5 percent for insulin degludec users and 56.5 percent for liraglutide users. IDegLira users also had a 37 percent lower rate of hypoglycemia than insulin degludec users.

Lilly’s Basal Insulin Peglispro for Type 2s Acts Differently From Glargine                                    

Eli Lilly and Company announced that new data on the performance of its basal insulin peglispro (BIL) shows less activity in fat and muscle than with insulin glargine. The company said BIL, which “works in a fundamentally different way” than insulin glargine, is more like human insulin than other artificial insulins. In a head-to-head comparison of the two insulins’ effects, aimed at suppressing glucose production in the liver, Lilly researchers noted that BIL showed less presence in peripheral tissues than glargine, a finding that replicated similar results in animals.

 BIL currently is in Phase 3 development.

Obesity:

Two Bariatric Surgery Studies:

Italian researchers reported that their study of 527 patients who had received laproscopic adjustable gastric banding (LAGB) over a six-year period enjoyed a reduced risk of cardiovascular disease and type 2 diabetes. The Milan-based researchers suggested that follow-up studies should look at other bariatric surgical techniques such as gastric bypass and sleeve gastrectomy to see if they have similar preventative effects on type 2.

 A Swedish study of glycemic variations in type 2 patients who had undergone gastric bypass surgery frequently experienced dangerous states of hypoglycemia as they recovered. Researchers at the University of Uppsala used continuous glucose monitoring on 15 gastric bypass patients (12 of them women with a mean BMI of 33). They observed that in a 24-hour period, the patients averaged 42 minutes at blood glucose levels of under 59.4 mg/dL, and 21 minutes at levels under 50 mg/dL. The group averaged 2.3 hypoglycemic episodes per 24-hour period. The researchers said that only 36 percent of bypass patients were aware that they were having hypoglycemic episodes, making the use of CGM even more crucial in post-operative care. 

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