Diabetes debates defy easy resolution

An ever-changing knowledge base without clear consensus makes diabetes management especially challenging.

The ever-changing nature of medical evidence and expert opinion (with no clear consensus, in some cases) was apparent at the American Diabetes Association's (ADA) 73rd Scientific Sessions.

Speakers at the meeting, held in Chicago in June, discussed a number of subjects that were assumed settled many years ago but are once again open for debate, including use of sulfonylureas, diabetes and osteoporosis, and concentrated insulin.

Sulfonylureas, pro and con

“There is no clear consensus on what to add to metformin when [hemoglobin] A1c [HbA1c] goals are not met,” Martin J. Abrahamson, MD, FACP, told ADA attendees during a debate on whether sulfonylureas should be the add-on therapy of choice when metformin and lifestyle changes have proven insufficient.

Dr. Abrahamson, who is an associate professor of medicine at Harvard and chief medical officer of the Joslin Diabetes Center in Boston, took the stage to support sulfonylureas' role as “effective, cheap and well-tolerated,” he said.

On average, sulfonylureas have been found to decrease HbA1c by 1.6% when added to metformin or a thiazolidine, and ADOPT (A Diabetes Outcome Progression Trial) found faster reductions in HbA1c with glyburide than rosiglitazone or metformin, Dr. Abrahamson reported.

The medical literature has also revealed sulfonylureas' greatest disadvantage, especially a concern with glyburide, he acknowledged. The drug class can cause hypoglycemia and definitely should not be used in patients at high risk for it.

“Glyburide is the one sulfonylurea that has been associated with more hypoglycemia than other sulfonylureas,” Dr. Abrahamson said. But results from the UKPDS (United Kingdom Prospective Diabetes Study) showed that insulin actually poses a higher risk of hypoglycemia, as well as indicating that sulfonylureas cause no increase in adverse cardiac events, he added.

Obviously, the same cannot be said for rosiglitazone, and the data are uncertain on sulfonylureas' other competitors. “We do not know the long-term cardiac safety of the two newer drug classes,” said Dr. Abrahamson, referring to dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists.

More long-term comparisons of the competing drug classes are needed, he said, and will presumably be provided by the recently launched GRADE (Glycemia Reduction Approaches in Diabetes) study. “Until there is more evidence, let's not throw the baby out. Let's not eliminate sulfonylureas from our therapeutic toolkit,” Dr. Abrahamson concluded.

Sulfonylureas don't have to be eliminated, but they should not be one of the first choices for adding to metformin, countered Saul Genuth, MD, FACP, a professor of endocrinology at Case Western Reserve University in Cleveland.

He cited the recent “Hypoglycemia and Diabetes” report from an ADA workgroup and The Endocrine Society, which states, “For patients with type 2 diabetes, sulfonylureas are the oral agents that pose the greatest risk for iatrogenic hypoglycemia, and substitution with other classes of oral agents or even glucagon-like peptide 1 analogues should be considered in the event of troublesome hypoglycemia.” Moreover, the addition of the alternative agents to metformin lowers HbA1c as effectively as the addition of sulfonylureas and with far less risk of hypoglycemia, he added.

Dr. Genuth said, “You shouldn't wait for troublesome hypoglycemia. You should make this change to prevent troublesome hypoglycemia.” He also pointed to sulfonylureas' interactions with other medications, including aspirin, allopurinol, warfarin, sulfonamides, trimethoprim, fibrates and monoamine oxidase inhibitors. “A lot of commonly used drugs interact adversely with sulfonylureas,” he said.

Sulfonylureas, because of their propensity to cause hypoglycemia, may also not be the best choice for cardiovascular safety, suggested Dr. Genuth. “There are now three studies showing a clear-cut association between cardiovascular events and mortality in patients with prior vulnerability to severe hypoglycemia, especially the aged,” he said. “One alternative, pioglitazone, appears likely to have beneficial effects on cardiovascular disease.”

It's indisputable that sulfonylureas are currently more affordable than the likely alternatives, but that could change, according to Dr. Genuth. “For hundreds of thousands and maybe millions [of patients] who can't afford these alternatives, we have an obligation. We should prevail on the pharmaceutical industry to bring those prices down,” he concluded.

Diabetes and the bones

To further complicate their treatment decisions, clinicians could dive into the counterintuitive data provided during the ADA session “Diabetes and the Bones.”

Patients with type 2 diabetes tend to have higher than average body mass, and therefore, greater bone density, said Nelson Watts, MD, FACP, an endocrinologist with Cincinnati Mercy Health in Ohio. “But DXA [dual-energy X-ray absorptiometry] doesn't tell the whole story,” he said. “Patients with type 2 diabetes have an increased likelihood of breaking their bones.” The Women's Health Initiative found that diabetic patients were more likely to have every type of fracture measured except for forearm fractures, he reported.

The typical strategy for reducing diabetes complications—good glucose control—seems not to apply in bone health. “We have no evidence that bone health improves with intensive glucose control,” said Michael McClung, MD, FACP, an endocrinologist and founding director of the Oregon Osteoporosis Center in Portland, Ore. In fact, among patients taking insulin, better HbA1c levels have actually been associated with a greater risk of falls and fractures, perhaps due to hypoglycemia, Dr. Watts noted.

Among the other drug options, thiazolidines (TZDs) cause the most concern for skeletal health, according to Dr. McClung. Sulfonylureas have not been found to increase fracture risk, and metformin may even have a positive effect, but increased rates of extremity fractures (especially in women) and possible bone loss have been found with the TZD class.

That data should guide bone density screening decisions, according to E. Michael Lewiecki, MD, FACP, clinical assistant professor of medicine at the University of New Mexico and director of the New Mexico Clinical Research & Osteoporosis Center.

“Any adults over the age of 50 with diabetes, especially those taking TZDs, are potential candidates for a screening bone density test,” he said. If a patient's bone density result meets the criteria for osteoporosis, then preventive treatment is appropriate.

“The challenge to all of us is to identify those patients who do not have osteoporotic T-scores but are nonetheless at risk of fracture and candidates for treatment,” said Dr. Lewiecki. The most helpful resource for this task is the FRAX (Fracture Risk Assessment Tool). “I use FRAX every day,” he said.

However, among a number of other limitations (such as validity only between ages 40 and 90 and failure to differentiate between previous and never smoking or extent of steroid treatment), the FRAX has been found to underestimate fracture risk in diabetics, Dr. Lewiecki said. The International Society for Clinical Densitometry has been working to develop tools to further refine fracture prediction, he noted.

One particularly hard-to-evaluate group of diabetic patients includes those who have undergone bariatric surgery. Dramatic, worrisome drops in bone mineral density have been measured in patients who have recently undergone these procedures, said Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital in Boston.

“BPD [biliary pancreatic diversion] has by far the greatest degree of bone loss by DXA measurements, followed by Roux-en-Y, gastric sleeve, gastric banding,” said Dr. Yu.

However, it's not certain exactly how these measurements relate to actual fracture risk. “DXA may not be accurate in obesity and during weight loss,” she said. DXA

calculations rely on lean tissue to fat ratios that may be inaccurate in post-bariatric surgery patients.

Further research is needed to definitively answer these issues, but in the meantime, intensive vitamin D and calcium supplementation is key for patients who have had bariatric surgery, Dr. Yu advised. If treating patients orally, keep in mind that their ability to absorb supplements and medications (including bisphosphonates) may be decreased.

The same is true of diabetic patients with gastroparesis, Dr. Lewiecki noted. “If we start treatment, we probably want to monitor patients” with DXA or bone turnover markers, he advised.

Concentrated insulin

Close monitoring is also important to the effective use of concentrated insulin, according to Mary Korytkowski, MD, a professor of medicine and director of the Center for Diabetes and Endocrinology at the University of Pittsburgh.

U500 insulin, which contains 5 units of insulin per 0.01 mL, has been on the market for decades, but it's recently seen a dramatic uptick in use, almost doubling between 2008 and 2010. “It's very likely due to the increase in obesity associated with type 2 diabetes, with many patients now requiring higher insulin doses to achieve glycemic control,” Dr. Korytkowski said.

Two additional formulations of concentrated insulin—degludec U200 and glargine U300—are currently undergoing clinical trials and may eventually be available for clinical use. This makes it all the more important for patients and clinicians to know how to use these insulins safely.

“Any insulin is a high-alert medication; concentrated insulin is a very high-alert medication,” said Dr. Korytkowski. “There are stories of severe overdosing of insulin with U500 insulin because of improper education.”

Concentrated insulin is indicated for patients who require more than 200 units of insulin a day, or more than 2 units per kilogram of body weight per day. But the optimal dosing strategy is less well established, with clinicians adopting individualized approaches. “U500 can be used alone, or in combination with long- or intermediate- or with rapid-acting. It would be nice to have a prospective study comparing these different uses,” Dr. Korytkowski said.

Whichever way you use it, the key to safety is thorough patient and clinician education, she said.