Combination injection improves glucose control for patients with type 2 diabetes

 A multinational clinical trial led by UT Southwestern Medical Center and others found that injection of a new long-acting insulin combined with another drug improves glucose control in patients with Type 2 diabetes and, additionally, is associated with weight loss.

The trial compared glucose control of participants receiving daily injections of either basal insulin glargine or IDegLira, which is a mixture of insulin degludec and liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist. Liraglutide stimulates cells in the pancreas to produce insulin. The study findings were published today in the Journal of the American Medical Association.

"Many patients who are on an oral agent and basal insulin are unfortunately not at goal glycemia. Treatment options for such patients are to either increase the basal insulin dose or to add additional shots of insulin at mealtimes. The downside of both of these approaches is weight gain and hypoglycemia (low blood sugar)," said the study's lead author, Dr. Ildiko Lingvay, Associate Professor of Internal Medicine and Clinical Sciences at UT Southwestern. In addition, taking multiple injections per day also increases the burden on the patient.

Currently, about two-third of patients with Type 2 diabetes who are treated with basal insulin are not in good glucose control, Dr. Lingvay said. 

"The clinical trial found that participants treated with the combination product had more improvement in their HbA1C (hemoglobin A1C) test than those treated with basal insulin alone, they had weight loss rather than weight gain, and they had many fewer episodes of hypoglycemia," she added.

The phase 3 trial, conducted from September 2013 to November 2014, enrolled 557 participants with uncontrolled Type 2 diabetes in 75 treatment centers located in 10 countries. At the time they enrolled, study participants were taking an oral diabetes medication, metformin, as well as basal insulin glargine. All remained on the oral medication. 

Participants were then randomly assigned to continue on insulin glargine - or to switch to daily injections of IDegLira. Those who were assigned to the insulin glargine group had their insulin dose sequentially increased as high as necessary to bring their glucose levels under control. For those taking IDegLira, dosage was also increased based on glucose readings, but there was a cap on the amount their dosage could be increased because of limits on liraglutide dosage. 

Participants who took the combination product saw their glucose levels drop faster. On average, the HbA1C blood sugar level for participants on IDegLira dropped from 8.4 to 6.6. On average, the HbA1C level for participants on insulin glargine dropped from 8.2 to 7.1. The HbA1C test indicates the average blood glucose level over a three-month period; participants with an HbA1C level below 7 are considered within normal range.

Those taking IDegLira lost an average of about 3 pounds compared with an average weight gain of nearly 4 pounds for the glargine group. Only 6.1 percent of participants on the combination product experienced confirmed episodes of nighttime hypoglycemia compared with 24.4 percent of the patients on the basal glargine. 

"The advantage of the combination product is that the treatment burden is the same as taking a basal insulin - one shot a day - but you are getting an additional product that works through a different mechanism and addresses different pathophysiologic defects of the disease. The liraglutide affects satiety and induces weight loss, while also stimulating insulin secretion. The combination product addresses more underlying abnormalities present in this disease," said Dr. Lingvay.

Insulin degludec, which was approved last fall by the Food and Drug Administration, is the longest-acting insulin currently available. 

"Patients on IDegLira did better overall, especially when factoring in weight loss and decreased hypoglycemia risk," said Dr. John Buse, Professor of Medicine at the University of North Carolina School of Medicine and senior author on the study.

Eylea outperforms Avastin for diabetic macular edema with moderate or worse vision loss

NIH-funded clinical trial shows Eylea, Avastin, and Lucentis perform similarly when vision loss is mild.

A two-year clinical trial that compared three drugs for diabetic macular edema (DME) found that gains in vision were greater for participants receiving the drug Eylea (aflibercept) than for those receiving Avastin (bevacizumab), but only among participants starting treatment with 20/50 or worse vision.  Gains after two years were about the same for Eylea and Lucentis (ranibizumab), contrary to year-one results from the study, which showed Eylea with a clear advantage. The three drugs yielded similar gains in vision for patients with 20/32 or 20/40 vision at the start of treatment. The clinical trial was conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net), which is funded by the National Eye Institute, part of the National Institutes of Health.
“This rigorous trial confirms that Eylea, Avastin, and Lucentis are all effective treatments for diabetic macular edema,” said NEI Director Paul A. Sieving, M.D., Ph.D. “Eye care providers and patients can have confidence in all three drugs.”
Eylea, Avastin, and Lucentis are all widely used to treat DME, a consequence of diabetes that can cause blurring of central vision due to the leakage of fluid from abnormal blood vessels in the retina. The macula is the area of the retina used when looking straight ahead. The drugs are injected into the eye and work by inhibiting vascular endothelial growth factor (VEGF), a substance that can promote abnormal blood vessel growth and leakage. Although the drugs have a similar mode of action, they differ significantly in cost. Based on Medicare allowable charges, the per-injection costs of each drug at the doses used in this study were about $1850 for Eylea, about $60 for Avastin, and about $1200 for Lucentis.
DRCR.net investigators enrolled 660 people with DME at 89 clinical trial sites across the United States. When the study began, participants on average were 61 years old with 17 years of type 1 or type 2 diabetes. Only people with a visual acuity of 20/32 or worse were eligible to participate (to see clearly, a person with 20/32 vision would have to be 20 feet away from an object that a person with normal vision could see clearly at 32 feet). At enrollment, about half the participants had 20/32 to 20/40 vision. The other half had 20/50 or worse vision. In many states, a corrected visual acuity of 20/40 or better in at least one eye is required for a driver’s license that allows both day- and nighttime driving.
Each participant was assigned randomly to receive Eylea (2.0 milligrams/0.05 milliliter), Avastin (1.25 mg/0.05 mL), or Lucentis (0.3 mg/0.05 mL). Participants were evaluated monthly during the first year and every 4-16 weeks during the second year. Most participants received monthly injections during the first six months. Thereafter, participants received additional injections of assigned study drug until DME resolved or stabilized with no further vision improvement.  Subsequently, injections were resumed if DME worsened. Additionally, laser treatment was given if DME persisted without continual improvement after six months of injections. Laser treatment alone was the standard treatment for DME until widespread adoption of anti-VEGF drugs a few years ago.
Among participants with 20/40 or better vision at the trial’s start, all three drugs improved vision similarly on an eye chart. On average, participants’ vision improved from 20/40 vision to 20/25.
Among participants with 20/50 or worse vision at the trial’s start, visual acuity on average improved substantially in all three groups. At two years, Eylea participants were able to read about 3.5 additional lines on an eye chart; Lucentis participants were able to read about three additional lines, and Avastin participants improved about 2.5 lines, compared with visual acuity before treatment. Eylea outperformed Avastin at the one- and two-year time points. While Eylea outperformed Lucentis at the one-year time point, by the two-year time point gains in visual acuity were statistically no different. At the end of the trial, average visual acuity was 20/32 to 20/40 among participants in all three groups.
“The results of the DRCR Network’s comparison of Eylea, Avastin, and Lucentis will help doctors and their patients with diabetic macular edema choose the most appropriate therapy,” said John A. Wells, M.D., the lead author of the study and a retinal specialist at the Palmetto Retina Center, Columbia, South Carolina. “The study suggests there is little advantage of choosing Eylea or Lucentis over Avastin when a patient’s loss of visual acuity from macular edema is mild, meaning a visual acuity of 20/40 or better. However, patients with 20/50 or worse vision loss may benefit from Eylea, which over the course of the two-year study outperformed Lucentis and Avastin.”
The number of injections participants needed was about the same for all three treatment groups. Eylea, Avastin, and Lucentis participants on average required nine injections in the first year of the study and five in the second year.
The need for laser treatment varied among the three treatment groups. By two years, 41 percent of participants in the Eylea group received laser treatment to treat their macular edema, compared with 64 percent of participants in the Avastin group and 52 percent in the Lucentis group.
The risk of heart attack, stroke, or death from a cardiovascular condition or an unknown cause by end of the trial was higher among participants in the Lucentis group. Twelve percent of Lucentis participants had at least one event, compared with five percent of participants in the Eylea group and eight percent of participants in the Avastin group. This difference in cardiovascular rates has not been seen across all other studies, and therefore may be due to chance. Continued assessment of these serious cardiovascular events and their association with these drugs is important in future studies. Cardiovascular events such as heart attack and stroke are common complications of diabetes. The occurrence of eye complications, such as eye infections and inflammation, was similar for all three drugs.
Results of the study were published online today in Ophthalmology, the journal of the American Academy of Ophthalmology. Eylea and Lucentis were provided by drug manufacturers Regeneron and Genentech, respectively. Additional research funding for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, also a part of NIH.

“This important study would not have happened without funding from the National Institutes of Health and the cooperation of two competing companies,” said Adam R. Glassman, M.S., principal investigator of the DRCR.Net Coordinating Center at the Jaeb Center for Health Research.

The U.S. Food and Drug Administration has approved a new treatment certain diabetic foot ulcers

The U.S. Food and Drug Administration has approved a new indication for the Integra Omnigraft Dermal Regeneration Matrix (Omnigraft) to treat certain diabetic foot ulcers. The matrix device, which is made of silicone, cow collagen, and shark cartilage, is placed over the ulcer and provides an environment for new skin and tissue to regenerate and heal the wound. 

An estimated 29 million people in the United States have been diagnosed with diabetes, according to the Centers for Disease Control and Prevention, and about 25 percent of them will experience a foot ulcer during their lifetime. Chronic diabetic foot ulcers are associated with tissue and bone infections and result in 50,000 amputations each year.

“We are excited to see a new innovation in diabetes care with the potential to improve the number of foot ulcers that heal,” said William Maisel, M.D., M.P.H., acting director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health. “Healing of these painful and debilitating ulcers is essential for patients to resume walking and other daily activities.” 

The FDA first approved Integra Dermal Regeneration Template (which the company now also calls Omnigraft) in 1996 for the treatment of life threatening burn injuries when the use of a patient’s own skin for a graft was not possible.  In 2002, Integra Dermal Regeneration Template was approved for a new indication to treat patients undergoing reconstructive surgery for burn scars when they cannot have skin grafts. Now, Omnigraft is approved to treat certain diabetic foot ulcers that last for longer than six weeks and do not involve exposure of the joint capsule, tendon or bone, when used in conjunction with standard diabetic ulcer care. 

Omnigraft’s new indication is based on a clinical study that demonstrated that the matrix device improved ulcer healing compared to standard diabetic foot ulcer care, which includes cleaning and covering the wound with a surgical bandage and keeping weight off of the foot with the ulcer. In the study, 51 percent of patients treated with Omnigraft had healed ulcers after 16 weeks compared to 32 percent of patients treated with standard diabetic foot ulcer care alone. 

Adverse events observed in the clinical trial included infections, increased pain, swelling, nausea, and new or worsening ulcers.

Omnigraft shouldnot be used in patients with allergies to cow (bovine) collagen or chondroitin (cartilage from any source) since serious allergic reactions may occur. Omnigraft should also not be used on infected wounds.

Omnigraft is manufactured by Integra LifeSciences Corporation of Plainsboro, New Jersey.

New treatment options, better hope of preventing vision loss from diabetes

There is some good news for people with eye complications from diabetes. A network of researchers supported by the National Eye Institute (NEI) found that the drug Lucentis (ranibizumab) can be highly effective for treating proliferative diabetic retinopathy, an eye disease that can occur as a complication of diabetes. The researchers, part of the Diabetic Retinopathy Clinical Research Network, say this is the first major advance in therapy in 40 years.

Diabetic retinopathy is the leading cause of vision loss and blindness among working-age Americans. An advanced stage, called proliferative diabetic retinopathy, occurs when abnormal blood vessels grow near the retina, the light-sensitive tissue at the back of the eye. These new vessels can leak blood, which can obscure vision and damage the retina. Lucentis is one of several drugs called VEGF inhibitors that can block this process.

In the new study, Lucentis was compared to scatter laser therapy (or panretinal photocoagulation), which has been the standard treatment for proliferative diabetic retinopathy since the 1970s. Although laser therapy is effective in improving central vision, it can cause decreased night and side vision. The study found that Lucentis produced more improvement in central vision and little change in side vision when compared to laser therapy.

An injection into the eye might sound scary, but it's one of the most common procedures performed by ophthalmologists. VEGF inhibitors have been used for several years to treat diabetic macular edema, a swelling of the retina that can occur as blood leaks around it. The new study suggests that VEGF drugs may even help prevent macular edema. Study participants who were treated with Lucentis were less likely to develop macular edema than those treated with laser therapy.

As better treatments for diabetic retinopathy emerge, it's important to remember that an early diagnosis is the first step to getting treatment and saving your sight. If you have diabetes, you should get a comprehensive dilated eye exam at least once a year. Diabetic retinopathy often has no symptoms in its early stages. But an eye care professional can detect it before symptoms occur. And with early detection and appropriate treatment, the risk of severe vision loss from the disease can be reduced by 95 percent.

"Only about half of all people with diabetes get an annual comprehensive dilated eye exam, which is essential for detecting diabetic eye disease early, when it is most treatable," said NEI Director Paul A. Sieving, M.D., Ph.D.

Keeping diabetes under control is also key to preventing vision loss. If you have diabetes, NEI's National Eye Health Education Program recommends these important steps to keep your health on TRACK:

• Take your medications as prescribed by your doctor.

• Reach and maintain a healthy weight.

• Add physical activity to your daily routine.

• Control your ABC's -- A1C, blood pressure, and cholesterol levels.

• Kick the smoking habit.

Diabetes expert warns Paleo Diet is dangerous and increases weight gain

UNIVERSITY OF MELBOURNE

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IMAGE: THE MICE INVOLVED IN THE STUDY WERE FED A SPECIAL DIET. THOSE ON A DIET MIMICKING THE PALEO DIET GAINED WEIGHT. view more 

CREDIT: THE UNIVERSITY OF MELBOURNE.

A new study has revealed following a low-carbohydrate, high-fat diet for just eight weeks can lead to rapid weight gain and health complications.

The surprise finding, detailed in a paper in Nature journal Nutrition and Diabetes, has prompted University of Melbourne researchers to issue a warning about putting faith in so-called fad diets with little or no scientific evidence.

Lead author, Associate Prof Sof Andrikopoulos says this type of diet, exemplified in many forms of the popular Paleo diet, is not recommended - particularly for people who are already overweight and lead sedentary lifestyles.

He says mass media hype around these diets, particularly driven by celebrity chefs, celebrity weight-loss stories in the tabloid media and reality TV shows, are leading to more people trying fad diets backed by little evidence. In people with pre-diabetes or diabetes, the low-carb, high-fat (LCHF) diet could be particularly risky, he said. 

"Low-carbohydrate, high-fat diets are becoming more popular, but there is no scientific evidence that these diets work. In fact, if you put an inactive individual on this type of diet, the chances are that person will gain weight," Assoc Prof Andrikopoulos, President of the Australian Diabetes Society, said.

"There is a very important public health message here. You need to be very careful with fad diets, always seek professional advice for weight management and always aim for diets backed by evidence." 

Researchers at the University of Melbourne's originally sought to test whether high-fat and low-carbohydrate foods would benefit the health of people with pre-diabetes.

They took two groups of overweight mice with pre-diabetes symptoms and put one group on the LCHF diet. The other group ate their normal diet. The mice were switched from a three per cent fat diet to a 60 per cent fat diet. Their carbs were reduced to only 20 per cent. 

After eight weeks, the group on the LCHF gained more weight, their glucose intolerance worsened, and their insulin levels rose. The paleo diet group gained 15 per cent of their body weight. Their fat mass doubled from 2 per cent to almost 4 per cent.

"To put that in perspective, for a 100 kilogram person, that's the equivalent of 15 kilograms in two months. That's extreme weight gain," Assoc Prof Andrikopoulos said. 

"This level of weight gain will increase blood pressure and increase your risk of anxiety and depression and may cause bone issues and arthritis. For someone who is already overweight, this diet would only further increase blood sugar and insulin levels and could actually pre-dispose them to diabetes. 

"We are told to eat zero carbs and lots of fat on the Paleo diet. Our model tried to mimic that, but we didn't see any improvements in weight or symptoms. In fact, they got worse. The bottom line is it's not good to eat too much fat."

Prof Andrikopoulos says the Mediterranean diet is the best for people with pre-diabetes or diabetes. 

"It's backed by evidence and is a low-refined sugar diet with healthy oils and fats from fish and extra virgin olive oil, legumes and protein."

Diabetics who use verapamil have lower glucose levels

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A new University of Alabama at Birmingham research paper published in the journal Diabetes Research and Clinical Practice shows for the first time that there is an association of verapamil use and lower fasting glucose levels in humans with diabetes. It is a promising finding at UAB, where the Comprehensive Diabetes Center is currently conducting a first-of-its-kind, JDRF-funded clinical trial using verapamil, a drug that researchers in the School of Medicine have shown completely reverses the disease in mice models.

Yulia Khodneva M.D., Ph.D., a research associate and postdoctoral scholar in UAB's Division of Preventive Medicine and junior member of the Comprehensive Diabetes Center, examined the association of calcium channel blockers and verapamil use with fasting serum glucose among almost 5,000 adults with diabetes who were part of the REGARDS study. The Reasons for Geographic and Racial Differences in Stroke project, sponsored by the National Institutes of Health, is a national study focusing on learning more about the factors that increase a person's risk of having cardiovascular disease.

The sample of diabetic adults included 1,484 calcium channel blocker users, of whom 174 were verapamil users. The findings showed that calcium channel blocker users had 5 mg/dL lower serum glucose compared to non-users. Verapamil users had on average 10 mg/dL lower serum glucose compared to calcium channel blocker non-users. And the numbers showed a substantially greater difference among insulin users who also took verapamil. Verapamil users who took insulin in combination with oral medication had a 24 mg/dL lower serum glucose, and verapamil users who took insulin alone to manage their diabetes showed a 37 mg/dL lower serum glucose.

"This is a cross-sectional observational study unlike the current prospective randomized UAB verapamil clinical trial, so we can't infer causal relationship between using verapamil and lower glucose levels; but we can say there is an association with lower glucose levels, and that is absolutely encouraging," Khodneva said.

Khodneva says the findings in the final subgroup, which used insulin alone and included participants who had mostly Type 1 or severe Type 2 diabetes, were quite striking.

"The change in glucose for that group compared to those not taking verapamil -- 37 mg/dL -- is almost four times higher than when you look at the whole sample of diabetic adults," Khodneva said. "That made us think that verapamil is predominantly active for participants who have Type 1 diabetes or those with Type 2 diabetes who have really damaged beta cells. There seems to be something that works on the structural level, especially for those who have stronger beta-cell damage."

"Dr. Khodneva has done a tremendous job analyzing these large data sets and discovering for the first time that verapamil use is associated with lower glucose levels in patients with diabetes," said Anath Shalev, M.D., director of UAB's Comprehensive Diabetes Center and principal investigator of the verapamil clinical trial. "Strikingly, the observed difference in glucose levels is comparable to an approximately 1 percent reduction in HbA1C and to what would be expected from the addition of an approved diabetes drug. Moreover, the large difference in glucose levels especially in the groups taking insulin is consistent with our underlying hypothesis that verapamil promotes functional beta-cell mass."

UAB announced its verapamil clinical trial in November 2014 and began enrolling patients in January 2015. The first results that will assess verapamil's effectiveness on Type 1 diabetes are still approximately 18 months away.

The trial is testing an approach different from any current diabetes treatment by focusing on promoting pancreatic beta cells, which produce insulin the body needs to control blood sugar. UAB scientists have proved through years of research that high blood sugar causes the body to overproduce a protein called TXNIP, which is increased within the beta cells in response to diabetes, but had never previously been known to be important in beta-cell biology. Too much TXNIP in the pancreatic beta cells leads to their death and thwarts the body's efforts to produce insulin, thereby contributing to the progression of diabetes.

But UAB scientists have also uncovered that verapamil, which is widely used to treat high blood pressure, irregular heartbeat and migraine headaches, can lower TXNIP levels by decreasing calcium concentration in the beta cells -- to the point that, when mouse models with established diabetes and blood sugars above 300 milligrams per deciliter were treated with verapamil, the disease was eradicated.

'Beiging' white fat cells to fight diabetes

Researchers are getting closer to learning how to turn white fat cells into brown fat cells, in a process called "beiging," to bring down blood sugar levels and fight diabetes. The team, led by Joseph Baur, PhD, an assistant professor of Physiology in the Perelman School of Medicine at the University of Pennsylvania published their findings this month in the journal Diabetes.

"Beiging of white fat could be harnessed to fight diabetes by burning excess calories to cause a decrease in blood sugar," Baur said. "Our work suggests that activation of the mTOR pathway plays a critical role in this process." Induction of beige fat cells is considered a promising strategy to combat obesity because of this cell type's ability to metabolize glucose and lipids, dissipating the resulting energy as heat.

Brown and white fat cells, or adipocytes, play different roles in the body. While white adipocytes store energy as large fat droplets, brown adipocytes contain smaller fat droplets and are specialized to burn fat to produce heat. To do this brown adipocytes are packed with the powerhouses called mitochondria that contain iron, which gives them their brown color. In fact, babies are born with brown fat along the upper back and shoulders to keep warm.

In adult humans, the recent discovery of brown fat "depots" is also associated with lower body weight. Brown-like fat cells, called beige adipocytes, also appear within white fat deposits in response to cold and other signals. The energy balance within the body is influenced by brown and beige adipocytes, which are stimulated into action by cold temperatures and other signals to burn fat and carbohydrates.

The primary tool used in these studies was rapamycin, a drug that inhibits the protein mTOR (mechanistic target of rapamycin), which can be found in two distinct protein complexes. It was first discovered as a byproduct of Streptomycin hygroscopicus, a bacterium found in a soil sample from Easter Island, an island also known as Rapa Nui, hence the name. Rapamycin is currently used as an immunosuppressant in organ transplant, but has recently attracted attention when it was discovered to extend lifespan in mice.

Interestingly, in 2012, Baur's lab discovered that rapamycin also causes insulin resistance due to its ability to inhibit both arms of the mTOR signaling pathway controlled by the protein complexes mTORC1 and mTORC2. They showed in an animal model that these two arms could, in principle, be separated to dissect which pathway controls longevity versus endocrine effects.

In terms of physiology, mTOR signaling is involved in the control of blood sugar and cholesterol levels, and its inhibition increases the risk of diabetes. While previous studies suggested that mTORC1 inhibition would promote beiging of white fat cells, Baur's present work supports the notion that mTORC1 activity is actually required for cold-induced beiging of white fat cells. If activating mTORC1 directly can bring about the same result, then this approach could potentially be applied to combat diabetes.

In the Diabetes study, the team shows that rapamycin blocks the ability of cold or drugs that activate a specific neurotransmitter pathway to induce the appearance of beige fat cells. Accordingly, rapamycin-treated mice are cold-intolerant and fail to maintain body temperature and weight when moved to a colder environment.

The findings demonstrate a positive role for mTORC1 in the recruitment of beige fat cells to white fat depots, which could explain some of the negative metabolic effects of mTOR inhibition.

"Our study highlights the complex interconnection between mTOR signaling and metabolism," said first author Cassie Tran, PhD, a postdoctoral fellow in the Baur lab. "It will be critical in moving forward to determine the specific targets downstream of mTOR that are causing the negative metabolic effects in order to create better drugs and one day drugs that might also extend heathspan. The discovery of a critical signaling pathway for beige-fat formation also suggests the opportunity to target this pathway to therapeutically increase the number of heat-producing cells in obese or diabetic patients."