In 2018, a joint consensus statement by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) advised that glucagon-like peptide (GLP)-1 receptor agonists are preferred over insulin as the first injectable for managing type 2 diabetes.
But that apparently didn’t settle the matter.
On December 5, during a debate here at the International Diabetes Federation (IDF) Congress 2019, Daisuke Yabe, MD, PhD, of the department of diabetes and endocrinology at Gifu University, Japan, defended the ADA/EASD recommendation to use GLP-1 receptor agonists as a first-line injectable in patients who don’t achieve A1c targets with one or more oral glucose-lowering agents.
But Guillermo Umpierrez, MD, director of clinical research at the Diabetes & Metabolism Center of Emory University School of Medicine, Atlanta, Georgia, argued for turning to insulin first.
GLP-1 Agonists Should Be Started Early to Maximize A1c Lowering
Yabe began by pointing out that GLP-1 agonists ameliorate the two early primary defects of type 2 diabetes: impaired secretion of insulin and glucagon. Work from his group with the GLP-1 agonist liraglutide (Victoza, Novo Nordisk) illustrates that the drug enhances insulin secretion and suppresses glucagon secretion, thereby reducing post-prandial glucose excursions.
But both of those properties disappeared during induced hypoglycemia, indicating that liraglutide carries little risk for hypoglycemia, said Yabe, who is a speaker for and/or has received research grants from Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Ono, Taisho, Takeda, Kowa, MSD, Terumo, and Arklay.
And a study using functional MRI imaging demonstrated that liraglutide suppresses appetite by reducing central nervous system activation in response to visual food cues, leading to reduced food consumption and subsequent body weight reduction, Yabe added.
Although GLP-1 agonists reduce A1c in the short-term, Yabe and colleagues found that in some patients GLP-1 agonists failed to sustain the initial A1c-lowering effect by 1 year and that C-peptide was a major predictor of sustained response.
In other words, the A1c-lowering effect of liraglutide was maintained at 1 year only in patients with sufficient beta-cell function, arguing for its use earlier in the natural history of type 2 diabetes.
“The earlier the initiation of GLP-1 agonists, the better A1c-lowering effects can be achieved,” Yabe emphasized.
GLP-1 Agonists Reduce Cardiovascular Disease Risk
Yabe continued by noting that the ADA/EASD guidance to use GLP-1 agonists before insulin was made on the basis of their low hypoglycemia risk, their propensity for body weight reduction, and their demonstrated cardiovascular and renal benefits.
And a recent systematic review of cardiovascular outcomes trials (CVOTs) of GLP-1 agonists documented the drug class’ benefits in preventing major adverse cardiac outcomes (MACE), including cardiovascular death, myocardial infarction, stroke, all-cause mortality, and heart failure hospitalization.
Another analysis of the CVOTs showed that GLP-1 agonists, together with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin and the thiazolidinedione pioglitazone, exert greater effects to prevent MACE compared with pre-existing diabetes drugs, including insulin, he stressed.
For GLP-1 agonists, their mechanism of action results in suppression of systemic inflammation, improved endothelial function and lipid metabolism, and reduced blood pressure, he noted.
And in terms of safety, recent evidence has failed to demonstrate an association of GLP-1 agonists with pancreatic diseases, despite initial concerns.
“Of course these studies are of short duration so long-term careful evaluations are still needed. But, clearly, at this point in time there is no sign of pancreatic diseases with GLP-1 agonists,” Yabe commented.
And, despite, their high cost, one analysis showed that when prevention of complications was taken into account, the once-weekly GLP-1 agonist dulaglutide (Trulicity, Lilly) was associated with higher quality-adjusted life-years (QALYs), life-years, and total costs compared with insulin glargine.
Yabe concluded, “Earlier initiation of GLP-1 agonists, including once-weekly agents, exerts greater benefits to people with type 2 diabetes.”
Gastrointestinal Side Effects of GLP-1 Agonists Affect Adherence
Umpierrez began by listing the “absolute indications to use insulin over GLP-1 agonists” including type 1 diabetes, pediatric patients, pregnancy, severe hyperglycemia, symptomatic hyperglycemia with A1c > 10%, cirrhosis, dialysis, post-transplant diabetes, cystic fibrosis-associated diabetes, and medullary cancer.
“These are real contraindications that we see every day in the clinic,” he commented.
Insulin is more effective than GLP-1 agonists in lowering A1c, by about 1.8% compared with 1.2% in one study examining insulin glargine versus liraglutide added to oral agents in patients with baseline A1c 7.5%-12.0%, he noted.
In fact, most studies of patients with elevated A1c levels report higher efficacy of insulin over GLP-1 agonists, said Umpierrez, who reported that his institution receives grants for investigator-initiated research from Sanofi, Novo Nordisk, AstraZeneca, and Dexcom.
Regarding safety, of course insulin is associated with a greater risk for hypoglycemia (41.3% vs 13.7%; P < .001) for glargine versus liraglutide in the aforementioned study, but rates of nausea (30.4% vs 2.7%) and vomiting (9.6% vs 1.7%) were much higher with the GLP-1 agonist, he pointed out.
And those gastrointestinal side effects result in low adherence, with discontinuation rates of 20%-53% at 180 days, according to one analysis from six European countries.
In surveys, top reasons given by patients for discontinuing GLP-1 agonists in the past 6 months included “made me feel sick” (64.4%) and “made me throw up” (45.4%).
Among physicians, reasons given for their patients discontinuing them included lack of blood glucose control (45.6%) and nausea/vomiting (43.8%).
Umpierrez: GLP-1 Agonists Superior to Insulin if Patient Has CVD
Umpierrez did acknowledge that for patients with established cardiovascular disease or risk factors, evidence from CVOTs including LEADER and SUSTAIN-6 do demonstrate benefits for GLP-1 agonists above those derived from glucose-lowering, suggesting that “in patients with cardiovascular disease or at high risk, GLP-1 agonists are superior to insulin.”
But, he noted, in patients without cardiovascular disease or who are at high risk “there is limited evidence.”
And then of course, there is the cost. In the United States, a 30-day supply of GLP-1 agonists can run between $600 and $968, roughly 10-40 times more costly than human insulin, and even two to three times more expensive than insulin analogs, he noted.
Cost and access are likely reasons why GLP-1 agonists aren’t widely used worldwide, he added.
In a 2017 study, GLP-1 agonists made up only 7% of the second-line drugs prescribed in the United States for type 2 diabetes, and 2019 market data show that they still account for less than 12%.
Similarly low usage has been seen in the United Kingdom.
Moreover, Umpierrez pointed out, now that an oral GLP-1 agonist is available, it “will likely replace injectable GLP-1 agonists…if the cost is right.”
He concluded: “Insulin is and will continue to be the preferred injectable after oral agents.”
International Diabetes Federation (IDF) Congress 2019. Debate presented December 5, 2019.