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Evidence-Based Diabetes Management July 2014

Can Early Use of Insulin, GLP-1 Halt Diabetes Progression?

Mary K. Caffrey
ADA 74th Scientific Sessions
For years, the standard for treating type 2 diabetes mellitus (T2DM) has been step therapy. Newly diagnosed patients are told to make change in their diets and to exercise more. Then, most start metformin. If T2DM progresses, doctors add drugs from among the dozen other classes, either alone but typically in combination. Insulin is added last, after a slow progression of deteriorating beta cell function and, perhaps, complications such as retinopathy or kidney disease.

But what if treatment for newly diagnosed T2DM looked more like care in cancer? What if insulin came first, for just a few weeks, and the decline in beta cell function could be arrested or even reversed? What if the “maintenance” therapy, after the short intervention with insulin, was not metformin but 1 of the newer, more powerful drugs approved in recent years?

On June 13, 2014, experts at the 74th Scientific Sessions of the American Diabetes Association (ADA) said this concept holds promise, even though the panelists had to hold back discussing results from several trials involving glucagon-like peptide (GLP-1) agonists in combination with insulin, which were presented late in the conference. While the results varied depending on the precise drug combination involved, more than 1 trial reported glycated hemoglobin (A1C) levels falling from above 8% to below 6.5% in groups of patients after they received GLP-1/insulin combo therapy. (Results for xultophy, the injectable mixture of Novo Nordisk’s long-acting insulin Tresiba and its GLP-1 agonist Victoza, were described in 1 report as “the most talked about” in San Francisco.)1

The session, “Initial Treatment of Type 2 Diabetes—New and Not-So-New Ideas,” held at the Moscone Center in San Francisco, California, began with Sunder Mudaliar, MD, of the Center for Metabolic Research at the University of California at San Diego. Mudaliar gave an overview of the concept of glucolipotoxicity. The theory emerged in a 1985 paper by Roger H. Unger, MD, and Scott Grundy, MD, PhD, who wrote that severe hyperglycemia can irreversibly damage beta cells, but halting it could, in turn, stop the progression and perhaps restore function.2

More recently, Mudaliar said, the work of Vincent Poitout, DVM, PhD, on glucolipotoxicity examined the relationship between glucose and fatty acids. Poitout states that when levels are chronically elevated, they harm beta-cell function in the pancreas; over time, this leads to reduced insulin secretion.3

Glucose and fatty acids, “are bad actors when they act together,” Mudalair said. While needed at some level in the diet for fuel, they become toxic in high concentrations, and they do damage when those concentrations remain high over long periods. He reviewed multiple studies that showed how an intense period of hyperglycemia can have detrimental effects. To halt glucolipotoxcity, Ravi Retnakaran, MD, an endocrinologist from the University of Toronto and Mount Sinai Hospital of Toronto, has studied giving T2DM patients short courses of insulin for periods of 4 to 8 weeks. This must be done early in the cycle of the disease; as diabetes progresses he said, the loss of beta cell function is so severe that it cannot be restored. Trying insulin early, Retnakaran said, raises the possibility of halting the decline, even though, “We usually don’t think about reversible and irreversible factors of beta cell function.”

Retnakaran’s work has compared insulin delivery through a pump and through injections.4 In 2013, he co-authored a meta-analysis of studies involving early use of insulin, which found 66.2% of patients achieved a drug-free “remission,” after 3 months, although the effect was not sustained long-term after insulin stopped.5 The quest now is to find a maintenance therapy that can help the patient retain this improvement. Retnakaran’s 2010 pilot study with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin showed that therapy did not achieve the desired effect.

Why the GLP-1 class? The GLP-1 receptor is the gene expressed in pancreatic beta cells. Drugs in this class copy the process of natural incretins by helping trigger the release of insulin after meals, thus restoring blood sugar levels. Because of their link to the feeling of saiety after eating, these drugs also have the effect of contributing to weight loss,6,7 which Richard E. Pratley, MD, said makes them particularly attractive to patients.

Pratley, of the Florida Diabetes Center in Orlando, further discussed early use of GLP-1 therapy, reviewing various benefits of this class relative to metformin. It’s an ideal early monotherapy, he said, for patients who are metformin intolerant, who are overweight or obese, who are at risk of hypoglycemia, and who have “no barrier to injection.” (After the session, Retnakaran discussed the issue of patients’ fear of needles in his insulin studies; he said that when patients know that insulin treatment will not be forever, their objection to injection typically fades.)

Lawrence S. Phillips, MD, of Emory University in Atlanta, discussed “pattern care,” which involves early combination therapy. Thanks to trials involving the newer classes of drugs, researchers have the ability to look at groups of patients who followed a regimen for a period of time and then stopped. Across several studies Phillips presented, the patients who were treated early and then stopped did see progression in their diabetes, but it never “caught up” to control group patients. This suggests the value of early intervention, he said, because the “legacy effect” lasts well beyond the period when the drug is taken.

It’s important, he said, to get patients to their A1C goal at least once during their treatment, because of studies that show the more often this happens, the slower the progression of the disease. “If we screen patients every 2 to 3 years, we can find patients when they have prediabetes,” he said. Treating these patients with better diet, exercise and perhaps therapy can help keep A1C levels down. Instead of targets such ADA’s level of 7% or the 6.5% advocated by the American Academy of Clinical Endocrinologists, Phillips advocates targeting a level between 5.5% and 5.7%. “If we keep the A1C at 5.5, we preserve beta cells, and fewer complications develop later.

1. Wolf A, Liu N, Brown A. Conference Pearls: Advances for type 2 diabetes at the American Diabetes Association 74th Scientific Sessions. diaTribe. Published June 30, 2014. Accessed July 9, 2014.

2. Unger RH, Grundy S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function. Diabetologia. 1985;28(3):119-121.

3. Poitout V. Glucoliptoxicity of the pancreatic beta-cell: myth or reality? Biochem Soc Trans. 2008;36(5):901-904.

4. Retnakaran R, Zinman B. Short-term intensified insulin treatment in type 2 diabetes: long-term effects on beta cell function. Diabetes Obes Metab. 2012;14(suppl 3):161-166.

5. Kramer CK, Zinman B. Retnakaran R. Shortterm intensive insulin therapy in type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1(1):28-34.

6. Incretin mimetics. Accessed June 11, 2014.

7. Terrell JM, Jacobs TF. Incretin mimetics: pros and cons, and emerging agents in diabetes treatment. Am J Manag Care. 2013;19(SP11):SP408-SP410.
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