BBI Executive Editor

The impact of diabetes on the American populace is big – mighty big. According to the American Diabetes Association (ADA; Alexandria, Virginia), which held its 65th annual scientific sessions here in mid-June, more than 18 million Americans now have diabetes, about 30% of them undiagnosed. That being the case, it is not surprising that the annual meeting of the ADA, the largest organization focused on the disease, is equally big. More than 2,000 papers were presented to an attendee audience totaling about 13,000 scientists, physicians and other healthcare professionals during the five-day gathering at the San Diego Conference Center.

One of the most intriguing sessions of this year’s conference – largely because of the unexpected nature of its subject at a meeting overwhelmingly weighted toward therapeutic management rather than medical devices – saw a variety of clinicians address the value of gastric bypass on diabetes patients. The case study-based session posed the question “Gastric Bypass: A Quick Cure for Diabetes?”

The most enthusiastic advocate of this strategy was Philip Schauer, MD, director of abdominal lap-aroscopic and gastric surgery at the Cleveland Clinic Foundation, who expressed a certain measure of amazement that the session even had made it onto the ADA program. He noted, for instance, that the Standard of Medical Care for Diabetes, which includes the association among its primary developers, “makes no mention of bariatric surgery.”

But, lo and behold, said Schauer, along came the February 2005 issue of the journal Diabetes Care with an article headlined “Who’d Have Thought It? A Surgical Treatment for Diabetes.” Discussing the existing standard of medical management (oral agents and insulin) of the disease, he declared: “We haven’t altered the natural history of this disease in 100 years.”

Schauer provided his audience with a run-through of the medical literature covering different types of gastric bypass surgery, noting in particular their success in bringing a “resolution” to diabetes among a significant proportion of obese patients who undergo such surgery. He cited a report by noted gastric surgeon W.J. Pories, MD, which appeared in The Annals of Surgery a decade ago, citing an 83% diabetes resolution rate for Type 2 diabetics who had undergone such surgery. Lamenting that “unfortunately, only surgeons saw that report,” Schauer implied that its effectiveness would have been enhanced had it appeared in a journal directed toward endocrinologists and other “diabeticians.” Another well-known surgeon, Harvey Sugarman, MD, found a nearly identical rate of resolution for Type 2 patients, although he reported that older patients had outcomes that were not quite as successful.

Schauer said that in his own experience, largely when affiliated with the University of Pittsburgh Medical Center prior to moving to his present post in Cleveland, he found that 82% of obese Type 2 diabetics who underwent gastric bypass reached resolution of the disease, while the blood glucose readings and other diabetes measurements for the remaining 18% were “much improved.” He said the study looked at the duration and severity of Type 2 diabetes in 191 patients. The weight loss experienced by those who underwent gastric bypass was “very good,” he said, adding that the results were “fairly durable over a five-year period.” As for A1c readings – the test that measures average blood glucose over a two- to three-month period – Schauer said that “dramatic decreases” in weight were recorded after surgery.

He noted that those patients who had “less severe disease at the time of surgery [also] had the most dramatic improvement,” as did those who had had Type 2 diabetes for a shorter time. The patients had an 84% reduction in the use of oral agents after having their surgery, with 30% of patients discontinuing all medications upon discharge from the hospital – “a pretty dramatic effect within days of surgery.” And, he said, “during five years, no patients got worse [insofar as level of blood glucose was concerned] and no patients developed diabetes.”

Schauer cited still another study, this one conducted by Italian researchers, which showed “significant improvements” in pre-diabetes or very early diabetes patients who underwent laparoscopic adjustable gastric banding surgery, with 55% resolution of diabetes at one year, 79% at two years and 84% at three years.

He also described the 10-year outcomes data from the Swedish Obesity Subject (SOS) study, which compared what Schauer termed “the most comprehensive medical management” to all forms of gastric bypass surgery. “There were significant differences at 10 years in weight loss, blood glucose, blood pressure and insulin use,” he said. All forms of surgical procedures together showed a 72% resolution of diabetes at 10 years, Schauer said. He also cited a bariatric surgery “meta analysis” reported in the Journal of the American Medical Association in late 2004, which showed a 76% resolution of diabetes and an 86% improvement in A1c readings.

Acknowledging that gastric bypass procedures have risks, he said that endocrinologists and other diabetes practitioners “have to consider that in your strategy” of helping patients deal with the disease. Since surgical therapy “is not even on the map in your standard of treatment,” Schauer offered this suggestion: “Let’s get surgical treatment into the program of care as a possible means of resolving diabetes.”

That, he said, might help change the definition of diabetes as a disease for which there is not yet a cure. “Perhaps surgery is as close to a cure as we can possibly get,” said Schauer.

Responding to a question from the audience about gastric surgery being limited to those with a body mass index (BMI) of 35 or higher, he said; “Unfortunately, insurance carriers will only cover gastric bypass procedures for severely obese patients under those BMI guidelines.” He did predict, however, that that eventually would change, with those with lower BMIs becoming eligible for such insurance coverage.

After an endocrinologist urged Schauer to “talk with your [surgical] colleagues about increasing their follow-up and publication of outcomes” on bariatric surgery, he nodded his agreement. He said that the rapidly growing specialty – which has increased 10-fold in the past five years – needs more centers of excellence, and more gathering and publication of long-term outcomes.

To diabeticians who might refer their patients for gastric bypass surgery, he said, “make sure your surgeon is experienced and has a record of outcomes.”

Intensive control pays CVD dividends

Tight glucose control is widely known to lower cardiovascular disease (CVD) risk in Type 2 diabetics. Now, the same can be said for Type 1 diabetics, those who require daily intake of insulin via injection, inhalation or pumps. Results of a follow-up study to the landmark Diabetes Control and Complications Trial (DCCT), reported during a “Late-Breaking Clinical Trials” session at the ADA meeting, were characterized by the association’s top scientific official as “the biggest news story of this meeting.”

During a press conference held prior to the presentation of results of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, Richard Kahn, PhD, the association’s chief scientific and medical officer, said it was “remarkable to see this kind of substantial reduction [in CVD rates] after just six years of intensive therapy.” The EDIC research was a follow-up to the epic DCCT study, which compared intensive management of blood glucose to conventional control in 1,441 persons with Type 1 diabetes. DCCT and EDIC were funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (NIH; both Bethesda, Maryland).

The original study, which ran from 1983-1993, involved intensive treatment through at least three insulin injections a day, or via an insulin pump. “Intensive” meant keeping hemoglobin A1c (HbA1c) as close as possible to what is considered “normal” – 6% or less. The HbA1c blood test reflects a person’s average blood sugar over a two- to three-month period and is a key diagnostic used in determining both control and compliance by both Type 1 and Type 2 diabetics.

David Nathan, MD, of Massachusetts General Hospital (Boston), who co-chaired the DCCT/EDIC research group, noted that the original DCCT study focused on eye, nerve and kidney damage of Type 1 diabetes, finding that intensive glucose control “greatly reduced” such effects. A study of DCCT participants published in 2003 showed that tight control also lowers the risk of atherosclerosis.

The EDIC study focused on such cardiovascular events as angina, heart attack and stroke, with the most remarkable finding being the long-lasting benefit of such control. In a statement, EDIC chair Saul Geneth, MS, of Case Western Reserve University (Cleveland), said, “The longer we follow patients, the more we’re impressed by the lasting benefits of tight glucose control.” He said that the earlier such therapy begins and the longer it is maintained, “the better the chances of reducing the debilitating complications of diabetes.”

The results reported at the ADA late-breaking trials session indicate that the intensively treated patients among the roughly 1,375 persons who volunteered to continue in the study while continuing intensive therapy on their own have had less than half the number of CVD events – 46 vs. 98 – than the conventionally treated group.

Noting that the risk of heart disease is “about 10 times higher in people with Type 1 diabetes than in people without diabetes,” a proportion which he termed “much higher than in the Type 2 population.” Nathan added that tight control “is difficult to achieve and maintain, but its advantages are huge.”

He said that “the major message” of the EDIC study after some 6-1/2 years of follow-up “is that intensive therapy should be implemented in as many Type 1 patients as possible, and as early as possible.” Such patients, Nathan added, “get a remarkably durable benefit from intensive therapy – clearly, intensive therapy is important.” And that benefit is as substantial as it is long-lasting. “For every 10% lower A1c, patients get a 21% reduction in heart disease.”

In citing the “enormous reductions” in cardiovascular events reported by the EDIC study group, the ADA’s Kahn said: “All of this makes it a ‘wow’ event that will have people talking about these results in the hallways through the rest of this meeting.”

CVD risk markers aid in assessment

Various new markers of cardiovascular disease (CVD) risk are helping clinicians assess such risk in their patients. Their use is proving particularly important for CVD risk assessment in diabetic patients, according to reports presented at the ADA meeting.

During an ADA symposium that focused on non-traditional cardiovascular risk factors, Lewis Kuller, MD, professor of epidemiology at the University of Pittsburgh, said electron-beam computed tomography (EBCT) measurement of coronary artery calcium (CAC) is a valuable marker of sub-clinical atherosclerosis. Coronary calcium scores in diabetics increase markedly, he said, in those with impaired glucose tolerance, with a score above 100 serving as strong predictor of CVD risk. The higher the CAC score in diabetics, the higher the mortality risk, Kuller said, citing “a direct linear relationship” as a predictor of mortality. He noted that the rates of atherosclerosis rise with age.

Ronald Krauss, MD, director of atherosclerosis research at Children’s Hospital Oakland Research Institute (Oakland, California), cited low-density lipoprotein (LDL, the so-called “bad” cholesterol) as a risk factor for CVD, saying it had been slowly emerging in that role over the past two decades. He said that small LDL particles – LDL-3 or LDL-4, which also are the most common – are much more capable of inducing atherosclerosis than large- (LDL-1) or medium-sized (LDL-2) particles. He added that high levels of triglycerides have been shown to produce smaller LDL and high-density lipoprotein (LDL, or “good” cholesterol) particles.

Krauss cited studies showing that diabetics with a larger concentration of small LDL particles than larger particles have a risk of cardiovascular disease triple those without such concentration. Measuring LDL particles and reducing small particles with therapeutics can reduce the progression of coronary artery disease, he said.

The usefulness of C-reactive protein (CRP) as part of overall CVD risk assessment for patients was discussed by Christie Ballantyne, MD, director of the Center for Cardiovascular Disease Prevention at the Baylor College of Medicine (Houston). Noting that CRP is “the best-studied marker for CVD,” he said that increased levels of CRP are indicative of a doubled risk for stroke.

Study backs retinopathy screening

In another study whose results were reported during the late-breaking trials session, researchers said that diabetic retinopathy lesions were found in nearly 8% of pre-diabetic participants in the Diabetes Prevention Program, as well as in 12% of Type 2 diabetics who advanced to a diagnosis of diabetes during the DPP.

Richard Hamman, MD, professor and chairman of the department of preventive medicine and biometrics at the University of Colorado School of Medicine (Denver) and vice chairman of the DPP, said the study findings “suggest that retinopathy begins to show very early in diabetes.”

Noting that “certain retinopathy lesions are considered indicative of the presence of diabetes because they are the first retinal changes to develop in this disease,” he said the early study findings “suggest that changes in the eye may be starting earlier and at lower glucose levels than we previously thought.” Hamman said the eye changes found in pre-diabetics “may lead diabetes experts to reconsider the diagnostic thresholds used to define diabetes, which are based on levels of blood glucose.”

Massachusetts General’s Nathan, who chaired the DPP study, said the study findings were based on a small, random sample of study participants – about 12% of total trial participants. “These initial findings confirm what other studies have suggested,” he said. “The complications of diabetes may begin before diabetes is diagnosed, at least by current-day standards.” He said that an expanded study of the remaining DPP outcome study participants “might enable us to establish more appropriate diagnostic thresholds.”

Noting that the early findings “suggest that retinopathy begins to show very early in diabetes,” Hamman said: “A good retinal exam, as a patient transitions from pre-diabetes to diabetes, is important.” He added, “Some of these lesions are beginning to show at very low levels of pre-diabetes.” In order to slow the development of retinopathy, he said, “we have to start intensive [glucose control] therapy much earlier.”

Emily Chew, MD, of the National Eye Institute, the NIH unit that funded the study, said, “These findings reinforce the recommendation that patients with newly diagnosed Type 2 diabetes should be screened for retinopathy.”

Early testing, intervention key to cutting costs

Among the reports at the ADA meeting was one addressed to the pre-diabetes population in the U.S., said to number 41 million. The association defines pre-diabetes as “a condition in which blood glucose levels are higher than normal, but not high enough for a diagnosis of diabetes,” adding that “it is often a precursor of diabetes.”

Gregory Nichols, PhD, senior research associate at the Kaiser Permanente Center for Health Research (Portland, Oregon), said at an ADA press conference that the use of early diagnostic testing and intervention “could lengthen lives and lower healthcare costs when pre-diabetes is spotted.” He said of such preventive medicine techniques: “Doctors should be testing people with elevated blood glucose regularly and checking for other health problems in those found to have pre-diabetes.”

Pre-diabetes also is called impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), depending on which test was used to detect it. The Kaiser Permanente study used IFG, for which the current cut-point for a starting diagnosis of pre-diabetes is 100 mg/dl. The cut-point for diagnosing actual diabetes is 126 mg/dl.

Prior to a change made in November 2003, the starting cut-point for pre-diabetes was 110 mg/dl. The change was made by an expert committee in order to identify more people who are at increased risk of developing Type 2 (or adult-onset) diabetes.

Nichols described in his presentation the findings of a nine-year study that looked at the healthcare costs of some 28,000 patients enrolled in Kaiser Permanente Northwest – comparing the costs of those with normal glucose levels with those with two different levels of elevated glucose, but still not yet diagnosed as being diabetic.

The two levels of elevated glucose utilized in the study included 100 mg/dl to 109 mg/dl, representing the current level for diagnosing pre-diabetes, and 110 mg/dl to 125 mg/dl, representing the previous level for such a diagnosis. The Kaiser Permanente researchers called those stage 1 and stage 2 of pre-diabetes. For study purposes, each pre-diabetes subject was matched to another Kaiser Permanente Northwest member of the same age and sex who had normal fasting blood glucose readings.

In all, 28,335 patients were identified as having two or more IFG blood tests during the nine-year period of the study. Those with diagnosed diabetes were excluded. All patients were followed until they: recorded a blood test qualifying them for a higher stage or were diagnosed with diabetes; terminated health plan participation; or reached the end of the study on Dec. 31, 2003. Annual costs across the two pre-diabetes groups and the normal glucose readings group were then compared.

“Annual healthcare costs for those with the highest pre-diabetes blood glucose levels were 31% above those with normal blood glucose levels,” Nichols said, noting that “many of the extra costs [are] due to cardiovascular disease [CVD],” including angina, heart attack, heart failure and stroke. Costs (adjusted for age and sex) averaged $4,357 annually for those with normal glucose levels, $4,580 for those with stage 1 pre-diabetes and $4,960 among those with stage 2 pre-diabetes. When those in the normal group who later progressed to pre-diabetes or diabetes were removed from the statistical group, the average healthcare costs for those with normal blood glucose fell to $3,799 annually, thus the 31% difference, Nichols said.

While the study did not specifically address the costs for those who progressed to diabetes, Nichols said at the press conference that their healthcare costs run “50% to 75% higher than for those with normal glucose.” Characterizing CVD as “expensive to treat but far less expensive to prevent,” he said that “early intervention in people with pre-diabetes is important to prevent or delay Type 2 diabetes and cardiovascular disease,” and, he added, “to reduce healthcare costs for the individual and the employer.”

He said that he and his research partner, Jonathan Brown, PhD, identified the allocation of healthcare costs by looking at Diagnosis-Related Group (DRG) codes. “We found a great prevalence of cardiovascular disease and obesity and therefore assume those are driving the costs.”

The ADA said research has shown that people who are identified early as being pre-diabetic can prevent – or at least delay – progression to the disease itself by up to just under 60% through lifestyle changes that include modest weight loss and regular exercise. Similar changes are of benefit in reducing cardiovascular disease risk.

Nichols put it emphatically: “Not only can you save money by preventing diabetes, but also by preventing patients from progressing to a higher pre-diabetes level.”

Pilot study cites Guardian effectiveness

The Medtronic Diabetes (Northridge, California) unit of Medtronic (Minneapolis) said participants in a pilot study, whose results were reported over the weekend, used its Guardian RT continuous glucose monitoring system to make therapy decisions for improved diabetes management. The patients responded to glucose values displayed by the system, along with “high” and “low” alerts, following confirmatory fingerstick measurements. Dr. Dorothee Deiss, a diabetologist at the Charite Clinic (Berlin, Germany), reported during the ADA meeting that 94% – 15 of 16 – of the patients in the small study used the real-time glucose values and/or high or low glucose alerts to control glucose fluctuations.

Other findings during the 10-day study included 81% of the participants reporting greater satisfaction with their blood glucose control; 75% adjusting their insulin delivery based on Guardian RT data; 63% changing their diet as a result of that data; and 31% making “lifestyle changes” based on the insights they received from real-time continuous monitoring. No severe hypoglycemic (low blood sugar) or hyperglycemic (high blood sugar) events were reported by those taking part in the pilot study.

Deiss said the findings “suggest that the Guardian RT System has the potential to help diabetes patients make more informed treatment decisions, on a more proactive basis, compared to random fingerstick measurements that patients rely on today.” She said the clinic “noticed that patients using real-time readings have more confidence in managing their disease, particularly at night, which often is a critical time for patients who struggle from severe hypoglycemia.”

Medtronic said a randomized, controlled study is under way using the Guardian system, involving 162 patients in France, Germany, Israel, Italy, Slovenia, Sweden and the UK. Its goal is to achieve a reduction in A1c levels – A1c being a test that measures average blood sugar levels over a two- to three-month period - of 0.5% or more. The larger study, whose results were expected to be available later in the summer, also will evaluate the number and duration of high and low blood sugar fluctuations, average daily blood glucose, quality of life and the health economic impact associated with improved glycemic control.

The Guardian RT System uses a subcutaneous glucose sensor that records as many as 288 glucose readings a day. The sensor is a small electrode that is inserted under the skin and measures interstitial fluid, which is found between the body’s cells. Readings are relayed every five minutes to a monitor that displays the glucose value. Alarm thresholds can be pre-set to alert patients when glucose levels become too high or low. The system also allows patients to download information to a computer and print reports on their glucose patterns for discussion with their physicians.

(At the time of the ADA meeting, Medtronic’s supplemental premarket approval application for the device was under review by the FDA. It received approval in the early part of August.)

The company also noted that three other studies reported at the ADA gathering demonstrated the value of insulin pump therapy in lowering A1c levels in Type 1 diabetic pediatric patients.

In an international study of 1,041 Medtronic insulin pump users, children with Type 1 diabetes were studied in 30 centers in 17 countries. Children who used their insulin pump to deliver bolus dosages – extra insulin – had “significantly better” A1c levels. In addition, the A1c levels of those children in the study who had less than half their total daily insulin delivered as a baseline, or basal, rate were significantly better than those with a higher daily basal rate. Medtronic said that indicates that “patients were able to achieve better blood sugar control” by “fine-tuning” bolus and basal insulin delivery with an insulin pump.

A study involving 102 patients with a mean age of 12.4 years showed “sustained significant improvements in A1c levels for up to three years” using insulin pump therapy compared to levels prior to pump use. “At the final study evaluation,” said Medtronic, “75% of patients had a lower A1c level than they had prior beginning pump therapy.”

Another study followed 27 patients, ages 2 to 7, over a two-year period and found pump therapy a safe and effective alternative to twice-daily insulin injections. When comparing pump therapy to twice-a-day injections, said Medtronic, pump users had fewer sick days and reduced episodes of severe hypoglycemia. A1c levels also were improved after the switch to pump therapy, according to the company.

Symposium eyes vascular system effects

An ADA symposium featured research on diabetes’ effects on the vascular system. Rama Natarajan, Phd, professor in the department of diabetes at Beckman Research Institute of the City of Hope (Duarte, California), cited the “significant increases in cardiovascular disease (CVD)” impacted by the complications associated with diabetes. Reporting on research examining vascular dysfunction caused by diabetic complications that inhibit the thickening of artery walls, she said: “it’s very important to study the underlying mechanisms” of obesity, diabetes and CVD.

During a lecture on “Development of the Metabolic Syndrome in Type 1 Diabetes,” John Brunnell, MD, professor of medicine at the University of Washington (Seattle), said that nearly one-quarter of the U.S. population has metabolic syndrome, which, along with hyperlipidemia, “are major contributors to diabetes and are associated with premature coronary disease.” Citing such factors as genetics-based weight gains, he said that “intensive” diabetic therapy can have a “profound” effect on weight control. Noting that obesity “is at the heart of these problems,” he said that exercise is the key to the lifestyle changes that are central to treatment.

Also during the symposium:

Vincent Hascall, PhD, professor of biology at the Cleveland Clinic Foundation and Case Western Reserve University (both Cleveland), described molecular and cellular events that affect the CD44 membrane, marking the beginning of diabetic nephropathy.

Christopher Glass, MD, PhD, professor of medicine at the University of California-San Diego, discussed peroxisome proliferator-activated receptors, saying that PPAR “is primarily a negative regulator of macrophage gene expression. The macrophage may be a signal target of insulin sensitivity.”

Posters report on monitoring, sensing research

A variety of posters on glucose monitoring and sensing were featured during the ADA sessions. One poster featured research into use of continuous glucose monitoring in detecting hypoglycemic episodes. The study followed 24 Type 1 diabetic patients on insulin pump therapy. Tissue glucose was measured with a continuous glucose monitoring system from Medtronic Diabetes, using sensors from Roche Diagnostics (Indianapolis). Venous (blood) glucose was measured at least hourly by an Accu-Chek Compact system. During hypoglycemic (low blood sugar) episodes, blood glucose was measured twice, with mean venous readings compared with mean tissue readings. The research showed that tissue glucose monitoring is “comparable” to venous blood glucose measurements in hypoglycemic situations.

The researchers did note that in some cases, higher tissue glucose values might be observed, and said further studies should be conducted in order to evaluate whether higher warning levels are necessary on continuous glucose monitoring systems in order to adequately detect hypoglycermic episodes.

Another poster described an analysis of the effectiveness of alerts in the Guardian continuous glucose monitoring system from Medtronic Diabetes. A total of 71 persons were followed, randomly divided into control and alert groups. Hypoglycemia and hyperglycemia alerts were set at 70 mg/dl and 250 mg/dl, respectively. Researcher Lu Wang’s study indicated that, when fingerstick glucose measurements were taken, the system confirmed that blood glucose readings were within acceptable range 87% of the time.

The system identified five hours per day of glycemic risk among the Type 1 patients in the study and also detected 2.5 times as many nighttime hypoglycemia episodes than use of a conventional meter alone. The patients with the Guardian alarm turned on took one additional meter glucose reading in the hyperglycemic or hypoglycemic ranges per day. Wang said the alarm feature “provides valuable guidance for patients to take meter glucose readings. By properly adjusting the alarm threshold, the risk of missing an acute hypoglycemia or hyperglycemia can be greatly reduced, [although] at the cost of more false alarms.”

Another poster reported on a study of maintaining effective glucose control using the OneTouch UltraSmart System from LifeScan (Milpitas, California), a Johnson & Johnson (New Brunswick, New Jersey) company. The UltraSmart System is an integrated glucose meter and electronic logbook The study, which involved comparison with conventional glucose meters and paper logbooks, showed a greater reduction in A1c (a test that determines average blood glucose over a two- to three-month period) levels by those in the OneTouch UltraSmart arm, although both the test and control groups showed improvements in those readings.

Self-monitoring of blood glucose increased over the 16 weeks of the study in the UltraSmart group, and researchers said the “significant lowering” of A1c readings in the test group may have been accounted for by that increase, along with the “enhanced pattern recognition and record-keeping” made possible with the electronic logbook feature.

Another poster cited increased frequency of self-monitoring as being responsible for improved A1c readings in non-insulin users. The researchers noted that with insulin-taking patients, a high blood glucose reading “is the cue for the patient to take insulin,” but that for non-insulin-taking patients, “there is no similar recourse.” This, they said, “would lead one to believe that the effect, if any, would be smaller for non-insulin-users."