Archive for the Diabetes Clinical Trials

Do Anitdepressants Cause Diabetes?

written by Michael O’Leary

The headlines about anti-psychotic drugs tripling the risk of type 2 diabetes is bad enough, but coupled with a seven-fold increase in the number of kids being prescribed these anti-psychotic drugs leaves one to wonder.

What are we doing to our kids?

From 1993 to 2009 the number of kids aged 0 to 20 prescribed anti-psychotic drugs jumped 700 percent, according to a 2012 study published in Arch Gen Psychiatry.  By comparison, anti-psychotic drug prescriptions for adults increased 500 percent.

Now in a study published in the Aug. 21 journal JAMA Psychiatry the number of kids being diagnosed with type 2 diabetes was three times higher among kids on the anti-psychotic drugs compared to kids who were not on the drugs.

The anti-psychotic drugs included in the study are known by brand names Seroquel®, Abilify® and Risperdal® are approved to treat schizophrenia and bipolar disorder. Also included were patients taking antidepressants and psychostimulants such as Adderall® and Ritalin® including alternative ADHD drugs clonidine, guanfacine, and benzodiazepines.

Among those studied, most of the antipsychotic drugs used (87 percent) were of the newer generation, drugs. Risperidone (Risperdal) accounted for 37 percent, while quetiapine (Seroquel) and olanzapine (Zyprexa), each composed 20 percent of those studied.

Researchers at Vanderbilt University (including Dr. Wayne Ray – pictured below) analyzed existing data from the Tennessee Medicaid program and included 28,858 children and youth who recently began taking antipsychotic drugs. They were compared to 14,429 similar children and youth who were not taking antipsychotic drugs. Children who had already been diagnosed with diabetes, schizophrenia, or some other condition for which anti-psychotics are the generally recognized therapy were excluded from the analysis.

Dr. Wayne Ray at Vanderbilt University

They found that users of the antipsychotics had a 3-fold increased risk of type 2 diabetes, which showed up within the first year of taking the drugs. They also found that the risk increased with the cumulative dose, meaning the longer the children were given the anti-psychotics the higher the risk of type 2 diabetes.

When they looked just at older youth up to age 17 they found the anti-psychotic group had a 3.14-fold increased risk of type 2 diabetes, which was similar to the overall study.

The researchers noted that a limitation of the study is that it involved Medicaid patients, who are generally poor and that the incidence of type 2 diabetes may be elevated in this group due to economic, social and behavioral factors. It should be noted, however that 40 percent of Tennessee’s children are on Medicaid according to the authors.

The authors suggest that the study means physicians and parents should carefully consider the risk of type 2 diabetes as part of the discussion of risks and benefits of treating children with these anti-psychotic drugs.

Is Oral Insulin on the Way?

written by Michael O’Leary

Two companies announced clinical trials in the last three weeks aimed at bringing insulin taken by mouth to market.

Generex Biotechnology Corporation announced at the end of January results of a phase III clinical trial showing that its oral insulin spray Oral-lyn™ is as effective as subcutaneously injected regular insulin. The 12-week study conducted by an Indian licensee of Generex involved 209 men and women with type 2 diabetes at 14 clinics in India who did not have well controlled blood sugar levels with oral diabetic drugs.

While the Indian company that conducted the trial released few details of the study results, it advised the drug’s maker, Generex, that it had submitted the study results to Indian drug approval agencies and expected it to be approved this summer. The drug comes in an inhaler, much like asthma drugs, and is delivered in a metered spray through the mouth.

Last week Israeli company Oramed Pharmaceuticals reported that it is ready to launch a phase II clinical trial that it hopes will take it one step closer to putting its oral capsule on the market for people with type 2 diabetes.  The study will be conducted at 12 clinical sites in the U.S. and will enroll close to 150 people.

Scientists have been searching for a way to administer oral insulin for more than 100 years. The difficulty is that stomach acid breaks down the insulin making it unusable by the body, and the intestines block absorption of large molecules such as insulin. Inhaled insulin has been tried, but early versions met with an increased risk of lung cancer.

Generex and Oramed have overcome these limitations by changing the delivery route of the insulin.

Oramed’s capsule overcomes the dual obstacles of stomach acid and molecule size with a special capsule coating that protects the insulin through the esophagus and stomach, and into the intestines. There the capsule breaks down and releases the insulin along with an absorption enhancer that transports the insulin protein across the intestinal membrane. Once across the membrane, the insulin travels through the blood directly to the liver where it is used like natural insulin.

In Generex’s case while it is sprayed into the mouth, it is not inhaled. Instead it is absorbed into the blood stream through the mucous membrane in the mouth.

A number of other companies with a variety of delivery strategies are all racing to get oral insulin tested and approved. Until recently most experts doubted an oral insulin could be achieved. Now, as Oramed CEO Nadav Kidron, said in an interview with Israeli magazine 21c, it is no longer a question of if, but when.

“When they initiated this project almost 30 years ago at Hadassah (University in Israel), trying to get insulin delivered orally looked almost impossible,” says Kidron. “Today it’s just a matter of time till it’s on the market.”


More Evidence for Surgery for Type 2 Diabetes?

Intensive lifestyle changes including diet and exercise were significantly more effective than standard counseling and medications for reversing type 2 diabetes, an ongoing federal study shows. But the success rate may add fuel to the debate for those advocating surgery as a more effective method of reversing the disease.

Funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Look AHEAD: Action for Health in Diabetes study began in 2001 and continues today, but is no longer recruiting participants. The researchers led by Edward Gregg, acting director, Division of Heart Disease and Stroke Prevention,

National Center for Chronic Disease Prevention and Health Promotion, at the CDC aimed to determine whether lifestyle changes can reverse type 2 diabetes and whether the effects  are sustained over time.

The 4,503 participants were 45 to 75 years old with an average age of 59 years. They had a median of five years since being diagnosed with diabetes, meaning half had been diagnosed more than five years prior to starting the trial and half had been diagnosed less than five years before. All had body mass index (BMI) scores that placed them in the obese category. Partial remission of diabetes was defined as meeting the criteria for prediabetes and complete remission was defined as having a nondiabetic blood sugar levels or a fasting blood sugar level of less than 126 mg/dL and HbA1c of less than 6.5 percent without medication.

The interim results, reported in the Dec. 19 Journal of the American Medical Associationshowed that 11.5 percent of the 2,241 people in the intensive lifestyle group achieved a partial reversal of their diabetes after one year, compared to 7.3 percent of 2,262 in the standard treatment group. Complete reversal of the disease occurred much less often, with only 1.3 percent of the intensive lifestyle group achieving a complete remission after one year and 0.7 percent after four years.

The differences between the two groups were sustained over four years, although the percentage of participants who achieved partial remission of type 2 diabetes declined each year with only 7.3 percent of the lifestyle group meeting the goal after four years.

In an editorial in the same issue Dr. David E. Arterburn of Group Health Research Institute, Seattle, and Dr. Patrick J. O’Connor of HealthPartners Institute for Education and Research in Minneapolis, pointed out that the partial reversal of the disease failed to translate into fewer heart attacks and strokes.

They noted that while other lifestyle trials have shown similarly disappointing results, the evidence is growing that weight-loss surgery may be more effective than either lifestyle treatments or medicines for reversing type 2 diabetes.

Good News For Potential Approval of Tresiba – A New Long-Acting Insulin

written by Michael O’Leary

Last week an FDA advisory panel recommended degludec, a once-daily injectable insulin, be approved by the FDA, but will require Novo Nordisk to conduct additional trials to assess the heart risk that may be posed by the drug.

As reported by Fierce Biotech, Reuters and others the outside panel of non-FDA medical experts recommended approval by an 8-4 vote, but unanimously voted to require additional studies to assess the heart risk.

In recommending approval, the panel looked at the combined study results of 16 clinical trials Novo has conducted involving more than 9,000 people with type 1 diabetes and those with type 2 diabetes who are no longer able to control their blood sugar levels with other medications alone.

The panel was impressed by the effectiveness of the drug’s long-acting characteristics, which allow people to take it at a different time of the day should they miss their dose at their regular time, which is not the case with current drugs.

Panel member Dr. David Cook who is an associate professor of pediatrics at Johns Hopkins University School of Medicine told Reuters that current basal insulins don’t last 24-hours, and one that does give constant coverage for 24 hours would make a difference.

In one study designed to demonstrate the flexibility of degludec showed effectiveness comparable to Sanofi’s Lantus. As presented at the American Diabetes Association meeting in 2010 and reported by Diabetes In, dosing that allowed patients to go days without a shot using the flexible insulin degludec schedule wasn’t any less effective for glucose control than once-daily dosing. Both degludec and Lantus lowered A1c by 1.3 percent to an average of 7.2 percent.

The studies the panel evaluated were designed to test blood sugar control, but a small number of people experienced heart-related events, such as heat attacks or chest pain. There were not enough of these events for the panel to hold up the drug’s approval, but there was enough concern for them to recommend unanimously that studies be done to specifically look at heart risks.

Heart risks have been of greater concern with diabetes drugs since heart problems occurred with GlaxoSmithKline’s Avandia, which eventually caused the drug to be withdrawn from the market.

If approved, Novo intends to market degludec under the brand name Tresiba. The European Medicines Agency has already recommended approval and it has been approved for marketing in Japan.

Does Qsymia Help Lower HbA1c? New Results From CONQUER Study

written by Michael O’Leary

People with type 2 diabetes who participated in a study using a newly FDA-approved weight-loss drug reduced their blood sugar by an average of 0.4 percent compared to those in the trial who were taking a placebo.

The researchers reported the results of an analysis they did after the large weight-loss study was completed, and presented them at the European Association for the Study of Diabetes meeting last week in Berlin.

As reported by MedPage Today, the analysis looked at a subset of the 388 people with type 2 diabetes, who were among 2,486 overweight and obese people who took part in the CONQUER study. The 56-week study was designed to test the effectiveness of two doses of the weight-loss drug phetermine/topiramate (Qsymia – pronounced kyoo-sim-EE-uh), which the FDA approved last July.

The analysis of the diabetes patients showed that regardless of the dose they received, their HbA1c fell by an average of 0.4 percentage points compared to a reduction of only 0.1 percent in those who took the placebo. In addition, the average weight-loss for the type 2 diabetes participants was the same as for the nondiabetic participants who took either dose of the drug. Of those on the highest dose, 40 percent lost more than 10 percent their body weight. Of those on the lower dose, 27 percent lost that much weight and only 6 percent of those on placebo lost that much weight.

The researchers noted that the patients with type 2 diabetes in the study appeared to all be at an early stage of the disease with an average baseline HbA1c of 6.8 percent for those in the drug groups and 6.9 percent for those in the placebo group. More than half were not taking metformin. Blood pressure also improved in the drug groups but not by enough to rule out the possibility the lower blood pressure was due to chance.

The analysis did not say whether the data would allow them to determine whether it was the drug or the weight-loss that produced the drop in HbA1c. Nevertheless the researchers concluded that the findings suggest Qsymia may help type 2 diabetics lose weight and improve their HbA1c.

Side effects included constipation, paresthesia or tingling sensations in the skin, and insomnia. These affected less than 20 percent of the participants taking the drug.

Qsymia joins lorcaserin (Belviq®) in becoming the first FDA-approved drugs for weight loss since Xenical® was approved in 1999 and its over-the-counter version sold as Alli® was approved in 2007.

The CONQUER study and the type 2 diabetes analysis were funded by Vivus, the pharmaceutical company that makes Qsymia.



Is Weight Loss Surgery the Best Option to Prevent Type 2 Diabetes?

written by Michael O’Leary

In a study that could lead to changes in doctors’ recommendations about weight-loss surgery for people at risk for type 2 diabetes, researchers have shown that the procedure may be twice as effective in preventing the disease as lifestyle changes.

The Swedish study in this week’s New England Journal of Medicine compared 1,658 obese patients who underwent weight-loss (bariatric) surgery with 1,771 obese people who underwent usual treatment including diet and exercise. None of the patients in either group had been diagnosed with type 2 diabetes at the start of the study.

All of the men in the two groups had a body-mass index (BMI) of 34 or more and the women had BMI of 38 or more. A normal BMI ranges from 19-25, and obesity is defined as a BMI of 30 or higher.

Bariatric surgery includes several different types of surgery, but all of them essentially reduce the volume of the stomach, which restricts the amount of food that can be consumed. In this study, among patients who underwent the bariatric surgery, 19 percent had the banding surgery, 69 percent had the vertical-banded gastroplasty and 12 percent had gastric bypass surgery.

The researchers then followed these patients for 15 years, and over that time 392 participants in the usual care group developed type 2 diabetes compared to 110 in the bariatric surgery group.

As reported by ABC News, lead author of the study Dr. Lena Carlsson of the University of Gothenburg, Sweden, wrote that the results show that surgery may be more effective for some people in preventing type 2 diabetes.

“Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons,” Carlsson wrote in the study.

While a single study is never enough to change clinical practice, this study offers enough compelling evidence to generate larger studies to see if these results hold up among bigger groups of people who are obese, but without type 2 diabetes. If it does it is possible that surgery might be recommended for more people to prevent them from developing the disease.

Some of the limitations of this study, are that 36.2 percent of the original participants dropped out of the study, and at the time of this analysis, nearly 31 percent had not been followed for the full 15 years.

It should also be noted that surgery does have risks, and in this study, the risk of death in the surgery group was two in 1,000 (0.2 percent) and 2.8 percent of the surgery group needed a second operation due to complications.


Dulaglutide Shows Evidence At Helping Manage Blood Pressure for Type 2 Diabetes

written by Michael O’Leary

People with type 2 diabetes may find that a new GLP-1 drug being tested in clinical trials may help to control both their blood sugar and their high blood pressure.

A large study was presented last week at the 27th American Society of Hypertension Scientific Meeting by Tulane University School of Medicine researchers. Led by Dr. Keith C. Ferdinand, the researchers found that the drug, dulaglutide being developed by Eli Lilly, lowered blood pressure by a significant amount compared to a placebo.

“Dulaglutide is currently in Phase III clinical trials, where it will continue to be evaluated on its efficacy to lower blood glucose levels, overall safety, weight effects and effects on cardiovascular outcomes,” said Gwen Krivi, Ph.D., vice president, product development, Lilly Diabetes. “We believe dulaglutide, if approved, can bring significant benefits to people with type 2 diabetes.”

Dulaglutide is a GLP-1 blocker, similar to Victoza and Bydureon. Like those two, dulaglutide is a once-weekly injection that works by stimulating the beta cells to release insulin only when blood sugar levels are high. The study results were announced in a Lilly press release.

In the study 755 adult patients averaging 56 years old were treated at 76 centers in seven countries. All patients had type 2 diabetes, with HbA1c level of 7 percent to 9.5 percent and were on a stable regimen of at least one oral blood sugar-lowering medication. Two-thirds of the 755 had a pre-existing diagnosis of high blood pressure, and to participate they had to be taking no more than three medications to lower their blood pressure.

The patients were randomly assigned to one of three treatment groups, one received dulaglutide at a dose of .75 mg, one group received dulaglutide at a dose of 1.5 mg, and the third group received a placebo.

The main objective of the study was to see the effect of the drug on blood pressure. After 16 weeks they found that the drug at the .75 mg dose lowered blood pressure by an average of 1.07 mm Hg at 16 weeks, which was not considered to be statistically significant, meaning the difference was so small they could not rule out the possibility that the reduction was due to chance.

At the higher 1.5 mg dose, however, patients lowered their blood pressure by an average of 2.8 mm Hg, which was a statistically significant amount. The difference remained after 26 weeks.

Both doses of dulaglutide produced a significant reduction in blood sugar levels compared to placebo at both 16-weeks and 26-weeks. The lower dose produced a nonsignificant increase in average heart rate of 1.6 beats per minute, while the bigger dose produced a significant average increase in heart rate of 2.84 beats per minute.

Side effects reported included diarrhea, nausea and vomiting, which is similar to other GLP-1 agonist drugs.

Four of the authors of the study work for Eli Lilly, and lead author Ferdinand disclosed relationships with AstraZeneca, Novartis, Pfizer, Forest, Daiichi-Sankyo, and Takeda.

Does Naturopathy Help Diabetes?

Would you go to a naturopathic doctor if it would help you lower your HbA1c? A new joint study by researchers at the Group Health Research Institute and Bastyr University Research Institute has found that such an approach might help people with poorly controlled type 2 diabetes lower their blood sugar by twice as much as similar patients treated with conventional therapy alone.

More and more researchers from mainstream medicine are looking at combining conventional therapy with naturopathic care into what they call integrated therapies. Group Health Research Institute is the research arm of the 600,000 member Group-Health Co-op, a managed care health insurer in the Pacific Northwest affiliated with Kaiser Permanente of California. Bastyr University is a fully accredited naturopathic medical school that is a leader in natural health education.

The research team led by Bastyr’s Ryan Bradley, ND, MPH, director of the Center for Diabetes and Cardiovascular Wellness at Bastyr, found that patients with type 2 diabetes gained several benefits from the integrated therapy compared to patients treated with conventional therapy alone.

“The news is encouraging for those fighting the disease,” Bradley said in a press release. “Patients involved in the study cited the benefits of trying different approaches to find the best ways to minimize the effects of type 2 diabetes. In many ways, that strategy mirrors our partnership with Group Health in this research study—working together to discover the best possible solutions.”

In the study, 40 type 2 diabetes participants with an average HbA1c between 7.5 percent and 9.5 percent were counseled on diet, exercise and glucose monitoring by four naturopathic physicians in addition to conventional diabetes care from their medical doctors, including prescription medicines. In addition, many participants received stress management care and dietary supplements.

These 40 patients were compared to the medical records of a group of 329 Group Health patients with type 2 diabetes who received only conventional care. The results were published April 18, 2012, in the online journal BMC Complementary and Alternative Medicine.

At the end of six months and an average of 4 visits to their  naturopathic doctors, the researchers found that those in the integrated care group had dropped their blood sugar by an average of  1.0 percent compared to an average .05 percent decrease for those treated with conventional care. The difference persisted for 12 months following the study start, but was not as great and was no longer statistically significant at 12 months.

Changes in total cholesterol and blood pressure were not statistically different between the two groups, meaning the differences were not large enough to rule out the possibility that the differences were due to chance.

Nevertheless Bradley says the difference in blood sugar control were significant enough to warrant a larger comparison trial involving patients randomly assigned to each of the two treatment groups. Such a trial would be able to determine if the benefits shown in this study were due to the naturopathic counseling or whether the patients in the integrated care group were more motivated to control their blood sugar than their conventionally treated counterparts.

Will Albiglutide Be Approved?

British pharmaceutical company GlaxoSmithKline announced this week that it was ready to submit its once-weekly drug for controlling blood sugar for approval. The announcement came following the results of a series of clinical trials, called HARMONY, that have shown effectiveness without wowing investors.

As reported by MedPage Today and the Wall Street Journal, the trial results for HARMONY 6, released April 3, showed that albiglutide reduced HbA1c levels by .82 percent compared to a .66 percent reduction for patients taking insulin before meals.

In addition the patients taking albiglutide lost an average of 1.6 pounds compared to the insulin treated patients who gained 1.8 pounds. Side effects were nausea that occurred in 13 percent of those taking albiglutide compared to 2.1 percent of those taking insulin, and vomiting occurring in 7 percent of the albiglutide compared to 1.4 percent of the insulin group.

The company’s press release did not provide details about the trials, such as how many people were enrolled, or how long people were taking the drugs. And the results have not yet been published in medical journals. Nevertheless the results coupled with results of other HARMONY trials were sufficient to convince Glaxo that it could be successful in seeking approval to market the drug.

Albiglutide is similar to Victoza and Bydureon, in that it binds the glucagon-like peptide, or GLP-1, which stimulates the release of insulin when glucose levels become too high. Normally when food is eaten, GLP-1 is released into the blood by the intestine. It’s two main effects, according to, are to slow the absorption of food in the intestine, and to stimulate the pancreas to boost insulin production.

But GLP-1 is like a catalyst, it works just long enough to trigger a reaction before it is broken down by another enzyme. GLP-1 agonists like Albiglutide or Victoza bind to GLP-1 in such a way as to protect it from being broken down, thus extending the length of time it remains effective in stimulating production of insulin.

According to MedPage Today, last November Glaxo released preliminary results from another trial in the HARMONY series, which found that albiglutide effectively reduced HbA1c, but was not as effective as liraglutide (Victoza).

As a result of these findings, The Wall Street Journal says investors are unimpressed with albiglutide, predicting sales might range from $250 million $750 million, which is considered modest by pharmaceutical industry standards.

Novo Nordisk’s Victoza led the introduction of GLP-1 agonists into the market with twice-daily injections. That was followed by Lyxumia from Sanofi and Byetta from Amylin and Lilly, which recently won approval for its once-a-week injection formulation named Bydureon.

Dapagliflozin maintains HbA1c control as companies seek to bolster case for approval

written by Michael O’Leary

Adding dapagliflozin to glimepiride (Amaryl®) maintained reductions of blood sugar levels over nearly six months, in an extension of a study that had already shown that the combination of type-2 diabetes drugs was better than either drug alone.

The Polish study, extended to add data to the case for FDA approval of dapagliflozin by AstraZeneca and Bristol-Myers Squibb, was presented at the Diabetes Federation World Diabetes Congress in Dubai, United Arab Emirates this past week.

Led by Dr. Krzysztof Strojek, of Silesian Medical University in Katowice, Poland, the study originally was a 24-week trial that enrolled 592 adults with type 2 diabetes and an HbA1c between 7 percent and 10 percent at the start of the study.

After 24 weeks, the results showed that 46.6 percent of patients in the combination group had an HbA1c level of 7 percent or less compared with 35.2 percent with metformin alone and 31.7 percent with dapagliflozin 10 mg alone. In addition, the patients in the dapagliflozin groups achieved an average weight loss of seven pounds.

Last July, however, an FDA advisory committee voted against recommending approval of the drug due to concerns that it could increase risk of cancer and cause liver injury. There have been nine breast cancers and nine bladder cancers among 5,478 patients in previous studies among the dapagliflozin groups compared to only 1 breast and bladder cancers among the 3,156 patients assigned to comparison groups.

Following that vote, the drug companies extended this study another 24 weeks. A total of 546 patients stayed on with the study, and after the entire 48 weeks the results as reported by MedPage Today showed that the reduction in blood sugar over the first 24 weeks were sustained over the following 24 weeks.

Side effects also remained similar to those reported earlier with the most common including: inflammation of the nasal passages, back pain, upper respiratory tract infection, bronchitis, cough, urinary tract infection, imbalances in fats in the blood, high blood pressure, joint pain, diarrhea, genital infections, and upset stomach. These were experienced by at least 3 percent of the patients in each of the groups given dapagliflozin.

Dapagliflozin works with a more comprehensive mode of action than DPP-4 (Onglyza®, Januvia®) and GLP-1 (BYETTA®) by slowing or blocking absorption of glucose in the kidneys so that sugar is excreted in the urine.

AstraZeneca and Bristol-Myers Squib funded the Polish study, and Dr. Strojek has been paid by the companies for speaking about the drug at conferences. The other authors on the study are all employed by the companies.