I left the American Diabetes Association Annual Meeting at its end yesterday and am still mulling over what I learned. It was big, reportedly 16,000 – mostly health care providers – and seemingly the largest faction of foreigners ever. Perhaps because of Florida’s proximity to Latin America, many booths had sections in Spanish. (I’ve since learned that 10.4 percent of all Hispanics/Latinos in the US (ages 20 years or older) have diagnosed type 2 diabetes.) I spent time with old friends, wandered the commercial sales floor, read hundreds of posters, and even rode the new Harry Potter ride at a theme park – but mostly I attended the Scientific Sessions. These sessions can be tedious, but the discipline of presenting a summary of scientific developments often brings out the best in many speakers. Their enthusiastic points of view enable me to understand data very quickly as opposed to just reading the literature. With up to eight sessions in parallel, I focused on type 1 diabetes and transplantation, my special areas of interest.
The ACCORD study continues to generate controversy. This study, with eight study groups and over 10,000 patients (at 77 centers), essentially asked whether taking type 2 diabetics from normal to intensive therapy in combination with enhanced lipid reduction therapy or enhanced hypertension therapy would reduce vascular events. The good news is that strokes were reduced significantly, so work on your blood sugars, type 2’s. But that is pretty much the end of the good news. Although the enhanced therapies reduced the number of heart attacks, death by heart attack actually went up. In short, you were less likely to have a heart attack, but if you did more likely to die. Last year the safety committee’s decision to suspend intensive control because of the excess death made waves. The controversy continues, apparently on two issues. Why did the safety committee suspend intensive controls when the excess deaths were not statistically significant? Some argued that if the study had continued to the end the question would be answered. But the safety committee has not made public its reasons and is not required to. The other question is: did tight control cause death by heart attack?
Dr. Gerstein, a main author of the study, says that tight control did not do it. He said that it is impossible to find any reason for the excess death in the study data. In particular, on the question of tight control, the correlation of glycated hemoglobin with death was too weak for blood sugars to explain the excess deaths. But he did offer an interesting clue. It appears that, within the intensive control group, the patients whose glycated hemoglobin responded least to the intensive therapy were the most likely to die. To put it simply, if your Lantus dose went up and your glycated hemoglobin did not change, you were susceptible to death by heart attack. As a man managing type 1 diabetes I suggest that more insulin and the same average means more blood glucose oscillations. Most of the patients were using Lantus, and a bigger dose might well cause a lot of overnight hypoglycemia. So the excursions from normal could be bigger but the average (measured by glycated hemoglobin) is the same. In plain language, maybe overnight low blood sugar makes heart attacks more likely to be fatal.
This hypothesis would be answered by examining the blood sugars of the intensively treated diabetics along side their glycated hemoglobin. But imagine this: there was no systematic measurement of blood sugars in the ACCORD study. So in a major diabetes study they did not measure blood sugar, only glycated hemoglobin. I find that an astonishing oversight in the design. We now know that stability of blood glucose’s is as important as the average level. I hereby prohibit the use of glycated hemoglobin in future diabetes clinical trials! So because of a badly designed trial the important clinical question of intensive control for type 2 diabetics has been muddied. Your tax dollars at work.
I went over to the Dexcom booth to meet Dr. Price, their medical director. As a new and happy user of the Dexcom device for Continuous Glucose Monitoring, I wanted to discuss using Dexcom as part of our large animal studies of the Islet Sheet. We had a nice chat and he promised to look into the feasibility. As a bonus, I met Apurv Kamath who actually manages the algorithm that estimates blood sugar from the sensor and calibration data. I asked him some pretty geeky questions about how the algorithm works.
The old insulin pump versus multiple daily injections controversy rolls along. This is an issue I think of as, The Engineers versus The Medical Practitioners. Engineers think of diabetics as machines with faulty parts. Medical Practitioners think of us as fallible humans who need help. (When said to a member of the Engineer Tribe that people won’t actually do something he was proposing, he responded, “That’s not my problem.”) Both groups have a point. There are a lot of people who will benefit from the pump compared with MDI. I may not be one — it seems that my overnight needs perfectly match what Levemir delivers. Choice of insulin delivery method continues to be based on many factors, including individual preference and efficacy.
The genetics of type 1 diabetes has made progress, although nothing of therapeutic relevance has been discovered. Researchers are beginning to sort out different subtypes of type 1 seemingly differentiated by the pattern of beta cell destruction. The most common form is lobular destruction, where large zones of beta cells are completely destroyed, but a few remain in edge areas.
Islet transplantation with immunosuppressant drugs continues its snail-like advance. Drug therapies are getting a bit better, especially the addition of exenatide-like hormones that stimulate islet function. And it is clear that the residual transplanted islet functions even when insulin injections are required. The residual function is good for the islet recipients. But the trade-off between improved glycemia and side effects of immune suppression drugs leaves conventional islet transplantation clinically marginal.
A controversy as old as my diabetes (30 years) is the cause of type 2 diabetes. Every ADA meeting produces more proposals supported by muddy data. It is beginning to look like real progress is being made, at least for the most common cause of type 2 diabetes in the US. Experimental animals can be made diabetic with high fat diets, and high fat diets are probably the biggest single problem in the US population. Several researchers led by Professor Bergman of USC are finding that, in essence, fat cells are as important as islets in regulating metabolism. Who knew? I was taught that adipocytes were completely passive, taking up and releasing fat under hormonal orders. It turns out that the release of Free Fatty Acids by adipocytes controls how much glucose the liver releases, and glucose output by the liver is the most important component in fasting blood sugar in type 2 diabetics. A lot of the evidence presented was new to me. Look for this line of inquiry to produce new therapeutic approaches in the coming years.
Advocates of the artificial pancreas continue their hard work. Using Continous Glucose Monitoring (CGM) to help the people control the pump is the first step. The next is sensor assisted pump therapy and finally … the fully closed loop. The big study to date showed the CGM helps, but only adult diabetics, not adolescents. An interesting study atom at Joslin showed that CGM works best in diabetics who (1) react to CGM data with problem solving, not emotion; (2) use patterns as well s recent data to improve insulin therapy and (3) have spousal support. Some diabetics discontinue the sensor when their spouse made cyborg jokes. The STAR 3 study showed the CGM sensor augmentation shows insulin pump therapy is better then multiply injection therapy without sensor augmentation. However, I remain unconvinced that the fully closed look system will ever be safe and effective.
I attended all the sessions devoted to new sources of islet tissue, nanotechnology, and encapsulation. Not much has changed since the International Pancreas and Islet Transplant Association meeting last October. I learned a lot I did not know about Colin Weber’s encapsulation work ar Emory and Cherie Stabler’s matrix and nanoencapslation work at Miami. Colin showed some advanced work with his microencapsulated islets in Miami. For reasons he could not identify. the fasting blood sugars were low and postprandial high.
Originally posted at Diabetes24-7.com.
For more on the ADA Scientific Sessions read Karmel Allison’s report.