American Diabetes Association

Thank you

The meeting has ended and I'm saying good-bye to beautiful San Francisco and it's cool breezes.

I am very grateful that I've had a chance to attend this meeting and to tell you about some of what happened here. I hope you've enjoyed reading the blog, and thank you very much for stopping by!

Anita

What it all means

Results of the three major clinical trials presented here in recent days have confirmed that in treating diabetes, one size doesn’t fit all.

A panel of diabetes experts Tuesday discussed the studies’ findings and what they mean for doctors and their patients. They agreed that while the studies found no benefit on heart disease risk from drastic efforts to lower blood glucose levels in patients with advanced type 2 diabetes, keeping blood glucose levels at or near the currently recommended ADA target has other benefits, particularly on reducing damage to the small vessels that causes kidney disease and eye damage.

The studies, ADVANCE, ACCORD and the VA Diabetes Trial, were reported during the ADA’s Scientific Sessions, which ended today.

“One of our messages needs to be that treating diabetes is a comprehensive treatment strategy that involves blood pressure and lipid control and aspirin therapy,’’ said Dr. M. Sue Kirkman, ADA’s vice president for clinical affairs. The ABCs of diabetes care – management of A1C, blood pressure and cholesterol – still apply, she said. “We have always talked about the individuality of glucose goals. Some may be candidates for lower goals, and some are candidates for higher.’’

As written now, ADA guidelines recommends lowering A1C to about 7%, a target which “has been shown to reduce microvascular and neuropathic (nerve) complications of diabetes and, possibly, macrovascular disease.’’

But now, the guidance “should be changed to say there is no evidence that reducing glycemic control benefits cardiovascular disease, because that is, in fact, what these data tell us,’’ a revision may be needed, said Dr. Robert Rizza of the Mayo Clinic, a former ADA president.

Panel members cautioned that the studies may not apply to people who don’t fit the profile of those involved in the clinical trials: mainly middle-aged or older people who have had type 2 diabetes for several years, are obese and, in many cases, have a history of heart disease.

“My feeling would be that in patients with advanced disease and age, we should accept somewhat higher (A1C) values,’’ as long as other factors, such as the risk of kidney disease, are taken into account, said Dr. Robert Sherwin of Yale University School of Medicine, also a former ADA president.

Dr. Rury Holman of Oxford University noted that these and other studies suggest that treating diabetes early is more effective and safer than starting treatment after the disease has progressed. “The message the community needs to receive is that the guideline goals are still the same,’’ he said, “but might be flexible in people with advanced disease.’’

Among considerations flagged in the new studies are the danger of hypoglycemia and the effect of weight gain associated with intensive glucose control, said Dr. Eberhard Standl, chair of the International Diabetes Federation. Another factor to consider is the speed at which study participants reduced their glucose levels, he said. “Those with the highest A1C at baseline had higher mortality,’’ so possibly a rapid drop or fluctuations in glucose levels take a toll.

He said long-term studies should be done to find answer to these and other questions. But at present, he sees no need to change the current A1C target for most patients. His advice, “take your time, but reach the (A1C) target and stay on it.’’

The panel, moderated by Dr. Harold Lebovitz, chair of the Scientific Sessions planning committee, agreed that diabetes treatment usually begins later than it should.

“The best way to deal with cardiovascular disease and diabetes is to prevent it,’’ said Dr. Sherwin, because damage begins before glucose levels rise to a point where diabetes is diagnosed. “We’re probably late intervening in the process and we probably need to treat people sooner.’’

One positive note, he said, is that in all three studies, the rate of heart attack, stroke and other cardiovascular problems was about a third less than researchers had predicted. Thanks in part to better control of high glucose levels, “there has been a major fall-off in complications of people with diabetes in the last decade.’’

Insights into new treatments

Every year the "Late-Breaking Trials" present some of the most exciting news at Scientific Sessions, and this year was no exception.

Five late-breaking studies today report new drug approaches and insulin strategies to treat or slow the progression of diabetes:

• A study showed that when basal insulin alone is no longer enough, adding pramlintide (Symlin) instead of rapid-acting insulin gets more patients to target glucose levels without weight gain, and with a lower risk of hypoglycemia.

• The HEART2D study compared prandial insulin (a fast-acting insulin taken close to mealtime) versus basal insulin (long-acting insulin that is released slowly) on cardiovascular disease risks in 1,115 patients with type 2 diabetes who already had heart risk factors. They found no difference between the groups, showing post-meal glucose levels are not relevant in preventing heart attacks.

• The first proof that an anti-oxidant, anti-inflammatory agent can reduce the rate of progression to type 2 diabetes was reported in a clinical trial involving more than 6,000 people who have coronary artery disease. The study, ARISE (Aggressive Reduction of Inflammation Stops Events), was designed to see if the drug, now called AGI-1067 (succinobucol), had benefits when added to current therapies. Last year, researchers reported the drug reduced heart attack and cardiac death by 19%. Today they announced it brought about a 63% reduction in incidence of type 2 diabetes compared to placebo, and slowed the rate of progression to diabetes in people who had abnormal fasting glucose. In a poster presented this week, researchers reported in animal studies using AGI, the drug improves insulin sensitivity but unlike currently available TZDs, which do the same, the new one doesn’t cause weight gain.  A lot more  research will need to be done, however, before we can know whether this therapy is ready for widespread use in patients.

• Three diabetes drugs are known to help delay progression from impaired glucose tolerance (IGT) to type 2 diabetes. They are metformin, rosiglitizone (Avandia) and acarbose (Precose). Now, there’s a fourth: pioglitazone (Actos). In a study, 6.8% of patients taking a placebo developed diabetes compared to only 1.5% on pioglitazone. Pioglitazone reduced by 81% the conversion of IGT to type 2 diabetes, researchers said (The Diabetes Prevention Program, the gold standard of prevention trials, showed a 58% reduction through intensive lifestyle changes without medications). In addition, insulin sensitivity improved in the pioglitizone group, suggesting that the drug, one of the thiazoladinediones (TZDs), improved function of insulin-producing beta cells.

• A once-weekly version of exenatide, marketed as Byetta, produced the same glucose control and weight loss as the current twice-daily shots in a 30-week study involving 295 patients with type 2 diabetes. Both groups of patients lost nearly nine pounds during the study, but those who got once-a-week shots had greater improvements in long-term blood glucose levels measured by the A1C, and in fasting plasma glucose. Those improvements were sustained in a group of 120 patients who continued getting the weekly shots for 52 weeks. Lipid profiles, which measure blood fats such as cholesterol and triglycerides, improved in both groups after 30 weeks, but were even better in those who received the once-weekly version of exenatide.

What's your birth sign?

Astrology has nothing to do with diabetes, as far as we know, but the season in which a baby is born may play a role.

In a session today on Genetics and Emerging Epidemiology, Dr. Henry S. Kahn of the Centers for Disease Control and Prevention’s Division of Diabetes Translation and colleagues reported on a study in which they compared birth data on the more than 10,000 children with diabetes in the SEARCH for Diabetes in Youth Study. The children were born between 1982 and 2003.

Results were inconclusive for the 15% of those in the study who developed type 2 diabetes, but in the 85% of children who developed type 1 diabetes, there was a seasonal pattern in birth month that peaks in the spring and drops in the fall.

For instance, the researchers found babies born in May in the U.S. are 10% more likely to develop type 1 diabetes than those born in November. The finding was strongest among children born in the northern part of the U.S., Dr. Kahn said.

Why there would be seasonal differences is not known, he said, but it could relate to exposure to infectious agents, mother's diet or exposure to solar radiation, he said. Clarifying the role of environmental influences "could lead to interventions for reducing type 1 diabetes,'' he said.

Some reports from Europe and the Southern Hemisphere have found a similar pattern, though others have not.

Earlier this week, Jaakko Tuomilehto of the University of Helsinki said that in Finland, there are fewer babies born in June and July who go on to develop type 1 diabetes, but no difference in incidence during the rest of the year.

A spin through the Exhibit Hall

Walking through the massive Moscone Convention Center here in San Francisco, it’s easy to forget where in the world you are. As big as the place is, it’s as crowded as a busy city street, and the voices around you are speaking a dozen different languages.

There are about 15,000 people from a dozen or more countries at the ADA’s 68th Scientific Sessions. Even the press room has been packed, more than I remember in previous years, and American journalists seem to be outnumbered by those from media outlets in France, Germany, Spain, Hong Kong, Poland, the Netherlands and elsewhere.

Downstairs in the cavernous, noisy, bustling Exhibit Hall, where companies that make pharmaceuticals and medical devices set up displays, members of Team Type 1, the cycling team made up of athletes with type 1 diabetes, demonstrate their riding skills on a stationary bike set up at the Abbott Freestyle Navigator booth. Last year, just their second year competing, the team won the Race Across America, which bills itself as “The World’s Toughest Bicycle Race.’’

Not only did Team Type 1 win the 24-hour relay race, but they also set a record, crossing the country in 5 1/2 days. Team member Matt Vogel, 32, a triathlete as well as a cyclist, has had diabetes for 18 years. “Two weeks after I was diagnosed, I thought, I have a choice,’’ he said. “Do I feel sorry for myself, or do I manage my diabetes and move on?’’ Clearly, he moved on. He and his teammates will set off again across American when the race starts Wednesday in Oceanside, Calif. You can follow the team’s progress and cheer them on at www.teamtype1.org.

Elsewhere in the Exhibit Hall companies display new products or designs for future devices to make living with diabetes easier. Examples:

• A luxurious Lincoln parked at the Medtronic booth displays a built-in car dashboard screen that integrates Medtronic’s continuous glucose monitoring system into the technology in the car. The touch screen, which looks like the built-in screens found in many newer car models, will accommodate a GPS system, radio and other standard features, but for wearers of Medtronic’s CGM system, it will receive information from the system’s transmitter and provide continuous updates on readings and trends. It’s still in the concept phase and Medtronic would have to partner with automakers to produce the technology.

• Tube-free insulin pumps. The OmniPod has two parts – the 1.2 ounce pod, worn on the arm or elsewhere on the body, and the personal diabetes manager that programs the pod with individual basal rates and bolus dosages. It still requires fingerstick glucose monitoring, but the company is working on developing its own CGM system. Meanwhile, companies that already have CGM systems are working to develop tube-free insulin pumps, so presumably, in a couple of year’s the complete systems, sans annoying tubes, will be available.

• A remote glucose monitor. This is another of Medtronic's concepts. It’s comparable to a baby monitor used by worried new parents, but would display all the information on an insulin pump, complete with an alarm, so parents can keep an eye on their little one’s glucose levels without standing over the bed all night.

• A new blood test, called GlycoMark, enhances the information provided by the A1C by measuring post-meal glucose levels. Dr. Eric Button of the University of North Carolina, scientific developer of the test, said the $10 test is licensed by the Food and Drug Administration as an adjunct for A1C testing, for people whose diabetes is moderately controlled (under 8.5%). “The advantage of this is that it can tell when there are elevated glucose levels, such as after meals – and we have agents to target that, like Byetta,’’ he said. The test can be used as often as every two weeks.

A new approach to treating type 2?

The ADA’s recommended first-line treatment for type 2 diabetes – lifestyle changes and metformin – doesn’t include drugs that could preserve all-important insulin-producing cells of the pancreas, and should be changed, Dr. Ralph DeFronzo of the University of Texas Health Sciences Center told scientists today at the ADA’s Scientific Sessions here in San Francisco.

Dr. DeFronzo is the recipient of this year's Banting Medal, ADA's highest award for scientific achievement. In his award lecture, he said that at the time of diagnosis, most type 2 patients have already lost 80% of their pancreatic beta cells, and would benefit from newer classes of drugs that have been shown to reduce beta cell loss, the thiazolidenediones (TZDs) such as Actos or Avandia, and drugs that affect gut hormones, such as exenatide (Byetta).

By delaying the start of these newer (and more expensive) therapies, there is the risk of further loss of beta cell function, Dr. DeFronzo said.

The damage of diabetes begins well before blood glucose levels rise to the point where diabetes is diagnosed, he said. Studies show about 10% of people with IGT, impaired glucose tolerance, already have diabetic eye damage, even though they have "pre-diabetes", not diabetes.

“I have serious concerns about the phrase ‘pre-diabetes,’’’ he said. “Prevention of beta cell damage must begin early.’’

He said studies to be presented later in the meeting will show that TZDs can slow or prevent progression from impaired glucose tolerance to full-blown type 2 diabetes
Research in recent years has shed light on many body systems that play a role in diabetes, from the gut to the brain, he said. “It’s clear type 2 diabetes will require multiple drugs in combination to correct multiple pathophysiological defects.’’

Treatment should start early and should not be based only on targeting A1C, which measures glucose levels over two or three months, he said. There is an “additive effect’’ of combining drugs such as metformin with an insulin-sensitizing TZD, he said, but most doctors put newly diagnosed patients on a program of diet and exercise, metformin, and perhaps a sulfonylurea. “This should be a major concern for all of us here,’’ he said. Instead, he recommends a combination of “lifestyle modification plus triple therapy from the beginning,’’ including a TZD plus metformin and exenatide, along with an A1C target of under 6%, considerably lower than the current ADA recommendation of 7%.

His novel approach might raise some eyebrows, Dr. DeFronzo acknowledges, but he said all new ideas face the same kind of skepticism: “When it’s new, of course, it isn’t so. And when it’s proven, of course, it isn’t new’’

Hypoglycemia and heart attacks

Researchers with the VA Diabetes Trial, one of three major studies out this week designed to see if tight glucose control reduces heart disease, reported today that the strongest predictor of heart attack or stroke was not high blood glucose, but the opposite: very low blood glucose.

Study participants who had hypoglycemia severe enough to cause impaired consciousness within the last three months were also at highest risk for cardiovascular death or death from any cause, said Dr. Carlos Abraira, professor of medicine at the Miami VA Medical Center, and a co-chair of the VA study.

In findings that add to those of the ACCORD and ADVANCE trials being reported here this week at the ADA’s Scientific Sessions, researchers with the 7 ½-year VA trial said their study suggests that the benefits of tight glucose control may be greater if started at the time of diagnosis.

“If you treat patients intensively early in the disease, there is a benefit,’’ said Dr. William C. Duckworth, co-chair of the study and director of research at the Carl T. Hayden VA Medical Center in Phoenix, Ariz. “If you wait 15 years (before starting), the benefit goes away, and may even be detrimental.’’

The three studies – ACCORD, ADVANCE and the VA trial – each looked at somewhat different populations and used different strategies to lower blood glucose, but none found any significant improvement in cardiovascular risk as a result of tight glucose control. ADVANCE reported a strong benefit in reducing kidney disease and a trend toward improvement in heart risk, though not statistically significant; ACCORD found a negative effect of tight glucose control on heart risk, resulting in excess deaths that prompted a halt to part of the study earlier this year. The significant risk of hypoglycemia was not noted in ACCORD or ADVANCE.

The VA trial, conducted at 20 Veterans’ Affairs Medical Centers around the U.S., involved 1,791 veterans with type 2 diabetes, 97% of them male. Their average age was 60, and their health was poorer, compared to patients in the two previously reported studies: 40% of them entered the study with a history of heart attack, stroke, bypass surgery or other heart conditions, 80% had high blood pressure, more than half had high cholesterol or other lipid abnormalities, and nearly all were obese. They started out with an average A1C of 9.5%. The ADA recommends a target of 7% on the A1C, a measurement of blood sugar control over two or three months.

All study participants received treatment for high blood pressure and lipids, and all saw improvements. In addition, those given standard glucose-lowering treatments, such as oral medications and insulin, dropped to 8.4% A1C. Those given more intensive treatment, including more insulin and medications aimed at reducing blood sugar levels further, reached 6.9% within six months. Both groups maintained these A1C levels for the six years of their involvement in the study.

Another potentially significant finding of the study is that there was no association between rosiglitizone (Avandia) and heart attack, said statistician Thomas Moritz of Hines VA Hospital, Hines, Ill. He said most patients in the study were taking the drug, and “in every type of analysis we did, the frequency and dose of rosiglitizone was higher in people who did not have the (cardiovascular) event, which would suggest rosiglitizone did not harm our patients.’’

There was a slightly higher rate of cardiovascular death in the group receiving intensive treatment, said Dr. Duckworth, but it was not statistically significant, and overall, there were far fewer heart problems than had been expected. The predicted number of heart attacks and strokes in the study had been 650-700, but there were actually only 263 in the standard-treatment group and 231 in the intensive-treatment group. Dr. Duckworth attributes that to good basic medical care, including control of blood pressure, cholesterol and triglycerides.

The trial’s results will help guide doctors treating diabetes. “It will make our approach simpler, in that we have a better idea of what to focus on,’’ said Dr. Duckworth. “There should be a huge emphasis on early intensive treatment and a large emphasis on reducing hypoglycemia.’’

Costly screening not routinely needed

Adults who are diagnosed with diabetes are at much higher risk for heart attack than people without diabetes, but in some cases, they lack the ability to detect the most common of warning signs: chest pain.

Chest pain, or angina, is caused by a reduction in flow of blood to the heart, called ischemia, and it’s a signal of heart attack. People who have diabetic nerve damage may not be able to feel angina, and doctors call this condition silent ischemia.

Some studies have indicated silent ischemia is common in type 2 diabetes, even as high as 60%, and doctors have been unsure whether they should routinely run expensive screening tests on their patients.

Now they have an answer. In a study involving more than 1,100 people with type 2 diabetes and no symptoms of heart disease, half received the screening test (adenosine stress myocardial perfusion imaging, or MPI) and half did not. Researchers found 22% of those screened had silent ischemia, “a far lower percentage than expected,’’ said Dr. Frans J. Wackers of Yale University School of Medicine, who led the Detection of Ischemia in Asymptomatic Diabetics study.

Study participants were on average 61 years old and had diabetes for about 8 years. They were generally overweight and only half were able to exercise. Sixty percent had two or more risk factors for heart disease.

But over the course of the study, both groups – those who got the screening and those who did not – did pretty well, and there was no difference in outcome between the groups. The rate of cardiac events was half a percent per year, and 7% in both groups had bypass surgery. Interestingly, Dr. Wackers says, during the study the percentage of patients who were given treatments such as aspirin, statins for lowering cholesterol, and blood pressure-lowering drugs rose from 40% to 75%. He suspects this treatment explains why everyone did so well.

His conclusion: The situation is not as bad as had been feared, and there's no benefit in expensive routine screening of patients who don't have cardiac symptoms. "The risk in these patients is really very low,'' he says, but people with type 2 diabetes should be followed closely, given standard clinical care and followed up with diagnostic testing and treatment as needed.

The doughnut hole dilemma

Patients who get drug benefits under Medicare Part D can look forward to $2,250 in drug benefits (increased to $2,500 in 2007), and after that they enter a land of no coverage that stretches on until they've paid for the next $3,600 worth of medicines out of their own pockets.

In a study sponsored by Novo Nordisk and presented as a poster this morning at the ADA's Scientific Sessions, researchers analyzed how that coverage gap, known as "the doughnut hole,'' affected people with diabetes who take insulin. Using prescription data representing half of all retail drug dispensing activity in the U.S. in 2006, they found that of the more than 40,000 -- 12% of all Medicare beneficiaries -- who entered the doughnut hole, almost half (49%) were able to remain on the same diabetes medications they had been taking, but 24% dropped at least one treatment, 16% discontinued all treatments and 13% began a new treatment.

But that might not be as worrying as it seems, says Christopher Conner, senior manager for health economics at Novo Nordisk, one of the study authors. The research provides a snapshot in time, rather than a full picture, he says. Patients who "discontinued all treatments'' may well have started newer treatments or switched to generics, he says, and would have been counted in more than one category. While it's likely some patients stop taking needed drugs because of cost, there may be others who had no prescription drug coverage at all until Medicare Part B was enacted in 2006, he says. "How many patients dropped all medications and didn't start new ones, we don't know,'' he says. "This study is a jumping off point for further investigation.'' He says a larger study has been done by the Centers for Medicare and Medicaid Services and will be published later this year.

A1C = eAG

If you've ever tried to explain what an A1C score means to someone who wouldn't know glycated hemoglobin from hash browns, you'll be glad to know there's a new, simpler way to talk about blood glucose levels. Instead of A1C percentages, doctors will soon start reporting to patients their eAG, or "estimated average glucose'' level.

In the last couple of years, a new international standard of the A1C test has been developed that is more precise in measuring those glycated hemoglobins. But the new test results in a "normal range'' for A1C that is 1.5 to 2% lower than the range everyone has become used to. For instance, what we call a 7% A1C would be reported as a 5% A1C with the new standard. Confused? Yes, that's what diabetes experts thought would happen. So a team of researchers in the U.S. conducted a study to define the mathematical relationship between the A1C and average glucose measurements reported in the same units everybody is familiar with from daily fingerstick monitoring -- milligrams per deciliter, or mg/dl. Diabetes experts have long assumed the A1C expressed two- to three-month average blood sugar levels, but the studies had not been done to prove it, until now.

  In a press briefing today and a paper published on line in Diabetes Care, David Nathan of Harvard Medical School and colleagues report that a study involving 507 people who tested their blood sugars through continuous glucose monitoring along with fingerstick testing showed the A1C matches estimated average glucose (eAG) in both type 1 and type 2 patients.

The researchers provided a chart for comparison:
A1C of 6% equals eAG of 126 mg/dl
A1C of 6.5% equals eAG of 140
A1C of 7% equals eAG of 154
A1C of 7.5% equals eAG of 169
A1C of 8% equals eAG of 183
A1C of 8.5% equals eAG of 197
A1C of 9% equals eAG of 212
A1C of 9.5% equals eAG of 226
A1C of 10% equals eAG of 240

As it turns out, it looks likely that labs will continue to report an A1C value as we now know it, along with the new "lower" value based on the new test.  But ADA and others will begin promoting the use of the term eAG and asking labs to report that value as well. Already, ADA has posted an online calculator at www.diabetes.org/AG so anyone can make the conversion from A1C to eAG at the click of a mouse. "The whole idea of this is to simplify clinical practice and education,'' says Dr. Robert Heine, a co-author of the paper. Labs may report three numbers to physicians, but "at the end of the day, one number will be reported to patients,'' he says, and it will be a number they will easily understand. With an eAG, "patients can relate what they are doing at home to what we're doing in the chemistry lab,'' he says. An accompanying editorial in Diabetes Care says the term A1C "with its current units and normal range will not vanish or change,'' but "we now have a new term that will likely be easier to explain to patients and to convey more meaning and importance to glucose control.''