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

For years, the standard for treating type 2 diabetes mellitus (T2DM) has been step therapy. Patients are told to make changes 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 march of deteriorating beta cell function and, possibly complications such as retinopathy or kidney disease.

But what if treatment for newly diagnosed diabetes 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 this intervention, was not metformin but 1 of the newer, more powerful drugs approved in recent years?

On Friday, a panel at the 74th Scientific Sessions of the American Diabetes Association (ADA) said this concept holds promise, even as they had to hold back some of the best news that will be unveiled before the meeting ends.

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, who gave an overview of the concept of glucolipotoxicity. The theory emerged in a 1985 paper by Roger H. Unger and Scott Grundy,¹ who wrote that severe hyperglycemia can irreversibly damage beta cells, but halting it could in turn, stop the progression and perhaps restore function. More recently, Dr Mudaliar said, Vincent Poitout’s work on glucolipotoxicity examined the relationship between glucose and fatty acids. Dr Poitout states that when levels are chronically elevated, they harm beta-cell function in the pancreas; over time, this leads to reduced insulin secretion.²

Glucose and fatty acids, “are bad actors when they act together,” Dr 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 4-8 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, Dr 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.”

Dr Retnakaran’s work has compared insulin delivery through a pump and through injections.³ In 2013, he co-authored a metanalysis 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.⁴ The quest now is to find a maintenance therapy that can help the patient retain this improvement. Dr Retnakaran’s 2010 pilot study with the dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin showed that therapy did not achieve the desired effect. He said results from the LIBRA trial, involving early insulin followed liraglutide, a glucagon-like peptide-1 receptor agonist, (GLP-1) will be presented Monday.

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,^5,6 which Richard E. Pratley, MD, said makes them particularly attractive to patients.

Dr 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 the insulin is not 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 Dr 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 glycated hemoglobin (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, Dr 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.”

References

1. Unger RH, Grundy S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function. Diabetolgoia. 1985;28(3):119-121.
2. Poitout V. Glucoliptoxicity of the pancreatic beta-cell: myth or reality? Biochem Soc Trans. 2008;36(5):901-904.
3. 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.
4. Kramer CK, Zinman B. Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1(1):28-34.

1. Incretin mimetics. www.diabetes.co.uk. Accessed June 11, 2014.
2. Terrell JM, Jacobs TF. Incretin mimetics: pros and cons, and emerging agents in diabetes treatment. Am J Manag Care. 2013;19(SP11):SP408-SP410.