ORLANDO, Fla. — Using fixed-ratio insulin combinations (FRC) can reduce side effects such as nausea in treating diabetes, an advantage that should persuade clinicians to consider these drugs more often, according to a presentation at the American Diabetes Association (ADA) 84th Scientific Sessions.
"People treating diabetes tend to kind of grimace at fixed ratio combinations," Liana K. Billings, MD, MMSc, of NorthShore University Health System, Skokie, Illinois, during the presentation. "They tend to shy away. They want to be tinkering and micromanaging, up and down, here and there. And maybe it's improving outcomes, but maybe it's not."
The ADA session on "off-target" effects of diabetes medications featured Billings' arguments, based on previously published data, about the potential advantages for patients from fixed-ratio insulin combinations such as insulin degludec/liraglutide (IDegLira). In her presentation, Billings emphasized both reduced side effects and increased convenience for patients with FRC.
A 2016 paper in the journal Diabetes Care reported there were lower rates of nausea (9.6%) and vomiting (3.2%) events for patients on iGlarLixi, a fixed-ratio combination of insulin glargine (iGlar) and lixisenatide than for lixisenatide alone (24% and 6.4%, respectively) in a study.
Physicians need to keep in mind how patients react to nausea and vomiting, as these can lead people to abandon therapies. It's essential to build trust with patients in new therapies, especially in the first 12 weeks of use, she said.
"If you give them a therapy and they feel really sick on it, they may not continue it," she said.
Other research indicates FRCs lower hypoglycemia risk compared to basal bolus or basal insulin alone, while also minimizing other side effects such as weight gain, Billings said. In addition, the FRCs are more convenient for patients and their clinicians, with a potential to get the same kind of A1c control with 365 injections a year as opposed to about 1460, she said.
"You can kill two birds with one stone, or whatever idiom you want to use, with fixed-ratio combinations," Billings said. "They're simple. They relieve treatment burden by reducing fingersticks and injections. They allow for safe patient managed titration. They reduce burden on diabetes clinicians."
"I challenge you to change your paradigm and don't shy away from fixed-ratio combinations," she concluded. "Use it as a key piece in your toolbox in treating type 2 diabetes."
In her presentation, Billings also emphasized that the FRC approach may be a cost-effective option. According to Billings, for every $1 spent on insulin degludec/liraglutide (IDegLira) to achieve an A1c target of less than 7.5% without hypoglycemia or weight gain, it costs:
- $2.43 for IGlar up-titration
- $6.33 for basal bolus therapy
Examining SGLT2 Inhibitors Side Effects
At the session, Ronald M. Goldenberg, MD, of Toronto-based LMC Diabetes and Endocrinology addressed concerns about sodium-glucose cotransporter-2 (SGLT2) inhibitors, including ones raised in recent years in safety warnings issued by the US Food and Drug Administration (FDA).
In general, the benefits of SGLT2 inhibition, when indicated, outweigh the low risk of off-target adverse effects, he said. And risk mitigation strategies can help in managing these effects. Accepted as rare potential side effects are diabetic ketoacidosis and lower limb amputation.
Among his key conclusions were:
Acute kidney injury. In 2016, the FDA strengthened its warnings about the risk for acute kidney injury for canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR).
But the view on this risk appears to be changing, with some research suggesting this class of drugs may actually offer protection against acute kidney injury, Goldenberg said. He added that there ongoing studies looking at prescribing an SGLT2 inhibitor vs a placebo in cardiac surgery patients, a high-risk group for acute kidney injury
- Fournier's gangrene. In 2018, the FDA warned about reported cases of a serious rare infection, called necrotizing fasciitis of the perineum, also referred to as Fournier's gangrene, in people who had used these drugs.
"It’s extremely nasty, and if you look at pictures of this, you will have nightmares for weeks to come," he said.
The FDA found 12 cases from 2013 to 2018, seven in men and five in women. A theoretical connection between SGLT2 inhibitors could be as a follow-on effect of genital and urinary tract infections, leading to a cascade of events including endothelial damage and microthrombosis and then gangrene, Goldenberg said.
Goldenberg said he did a meta-analysis of 15 published large outcome trials of SGLT2 inhibitors, finding a total of 17 events, seven from SGLT2 arms and 10 in placebo. This analysis was inconclusive due to the limited number of events, he said. In looking at reviews of case reports, Goldenberg concluded that "diabetes is a risk factor for Fournier's [gangrene] but causality to SGLT2 inhibitors has not been proven."
GLP-1s and Surgery
At the end of the session, panelists fielded a question about a 2023 recommendation from the American Society of Anesthesiologists (ASA). That group last year suggested withholding GLP-1 receptor agonists for patients ahead of elective procedures, given the concerns about potential for delayed gastric emptying and an associated high risk for regurgitation and aspiration of gastric contents.
The ADA panelists were united in disagreeing with a blanket recommendation about pausing these drugs ahead of anesthesia. Tina Vilsbøll, MD, of the Steno Diabetes Center in Copenhagen, Denmark, said she wouldn’t initiate a GLP-1 right before a procedure but also would not have strong concerns for a patient well established on one of these drugs.
"I'm not too worried about it actually," she said.
John Buse, MD, PhD, the panel moderator and a professor at the University of North Carolina School of Medicine, Chapel Hill, said there's been "a lot of chaos and mayhem" resulting from this ASA recommendation. Buse said some clinicians have done preoperative ultrasound and examined the stomach contents or asked patients to refrain from eating.
Goldenberg said there's a need for a risk-stratification protocol to identify people more likely to have complications under anesthesia. Such screening might look for people who have symptoms of gastroparesis or who have been on a GLP-1 for a relatively short time and thus may be more likely to have an issue with gastric emptying.
But it would be "blatantly wrong" to employ a "blanket recommendation to stop GLP-1s in asymptomatic people who have been on them for ages," he said.
Billings reported honoraria or having served as a principal investigator for Bayer, Dexcom, Eli Lilly, Endogenex, Iventiva, Medtronic, Novo Nordisk, Pfizer, Sanofi, and Xeris.
Buse has reported relationships in connection with other ADA presentations as follows: Novo Nordisk. Consultant: Corcept Therapeutics, Alkahest, Anji Pharmaceuticals, Aqua Medical, Altimmune Inc., AstraZeneca, Boehringer Ingelheim, CeQur, Eli Lilly, Embecta, GentiBio, Glyscend Inc., Mellitus Health, Metsera, Pendulum Therapeutics, Praetego LLC, Stability Health, Terns Pharmaceuticals, Insulet Corporation, Vertex Pharmaceuticals, vTv Therapeutics. Research Support: Corcept Therapeutics, Dexcom, Inc., Insulet. Other Relationship: Medtronic. Stock/Shareholder: Glyscend Inc., Mellitus Health, Pendulum Therapeutics, Praetego LLC, Stability Health.
Goldenberg reported having received honoraria or research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS, Janssen, Novo Nordisk, Sanofi.
Vilsbøll has reported having the following relationships: Consultant: AstraZeneca. Advisory Panel: Boehringer Ingelheim. Speaker's Bureau: Mundipharma, Bayer Inc., Gilead Sciences, Inc. Advisory Panel: Novo Nordisk, Lilly Diabetes, Sanofi, Sun Pharmaceutical Industries Ltd. Research Support: Lilly Diabetes.
Kerry Dooley Young is a freelance journalist based in Washington, DC.