Tips on prescribing incretin therapies for cardio-renal protection

The past year has seen major trials report the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) dual receptor agonists in people with chronic kidney disease and/or heart failure. There’s now good evidence to add these treatments to protect the heart and kidneys, but existing guidelines have yet to catch up to the findings. Experts gathered at the Canadian Cardiovascular Congress in October to discuss these therapies.The evidenceResults from the SELECT trial showed that people with diabetes and obesity had fewer cardiovascular events when randomized to receive semaglutide over placebo. Yet it was the results from STEP-HFpEF (heart failure with preserved ejection fraction) and STEP-HFpEF-DM trials, published in the New England Journal of Medicine (NEJM) in August 2023 and April 2024 that firmly established semaglutide as a cardiologist’s drug, said Dr. Shelley Zieroth, a cardiologist and director of the heart failure and transplant clinics at St. Boniface Hospital in Winnipeg and professor of internal medicine at the University of Manitoba. The trials included patients with obesity and symptomatic heart failure, with or without diabetes. Those on 2.4 mg semaglutide a week had fewer symptoms and better physical function than those on placebo. The trial results provide evidence for, “another layer of treatment for patients with HFpEF and an obesity profile who often have limited treatment options available,” noted Dr. Abhinav Sharma, a cardiologist and assistant professor at McGill University and the research institute of the McGill University Health Centre in Montreal.The SELECT-HFpEF trials showed that the effects on cardiovascular outcomes are beyond weight loss and blood sugar control, with reductions in C-reactive protein (CRP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels. “It’s not just weight loss but other physiologic changes as well that drive these outcomes,” Dr. Sharma said.Data are now available from the SUMMIT trial, published in the NEJM in December 2024, showing patients with HFpEF and obesity significantly benefited from the GLP-1/GIP dual agonist tirzepatide over placebo. More data are coming, including the results of the SURPASS CVOT trial, a comparison of tirzepatide and dulaglutide in patients with type 2 diabetes.In May 2024, NEJM published the results of the FLOW trial, involving patients with chronic kidney disease and type 2 diabetes randomized to 1 mg semaglutide (the more common dose at the time of trial initiation) or placebo. The findings add to evidence from other trials (e.g., LEADER, REWIND, SUSTAIN-6) showing GLP-1 inhibitors are renal protective. These studies are in patients with diabetes and kidney disease, but smaller randomized control trials are showing benefits of incretin therapies in people with chronic kidney disease (CKD) with or without diabetes, noted Dr. Navdeep Tangri, nephrologist and professor of medicine at the Max Rady College of Medicine at the University of Manitoba in a conversation with the Medical Post.“As an endocrinologist, I absolutely love using GLP-1s in the setting of CKD,” said Dr. Julie Lovshin, a clinician-scientist at Sunnybrook Health Sciences Centre and assistant professor at Temerty faculty of medicine at the University of Toronto. “Why? Because their A1C and their body weight loss effects have nothing to do with their glomerular filtration rate (GFR) and that’s very different from SGL2 inhibitors. They’re also safe in the setting of CKD and can be used at any GFR and any dialysis.”Discussion adviceWhen introducing these drugs, frame your discussion around organ protection instead of blood sugars, suggested Dr. Alice Cheng, an endocrinologist with Unity Health at St. Michael’s Hospital, and Trillium Health Partners in Toronto and associate professor at the University of Toronto. This way, patients won’t want to stop the medications once their blood sugars are at the target level. Dr. Cheng starts with: “I’d like to offer you medication to protect your brain, your heart and your kidneys.”GLP-1 receptor agonists and GLP-1/GIP dual receptor agonists need to be titrated. When it comes to introducing the medications, “Start slow and stay in it for the long-term,” Dr. Tangri said. Focus on the end-organ benefit, even if it takes six months to get the right dose.Dr. Sharma said he usually lets the patients auto-titrate, making them aware of the desired regimen and the baseline dose, but allowing them to escalate only when side-effects are under control.“The key thing is, as you escalate the dose, if people develop side-effects, you can always go back to the previous dose they were tolerating, stay there for a little longer, and then go back up,” Dr. Sharma said.The important thing is to maintain a baseline dose. “I always say to them, ‘Don’t quit it without calling,’” Dr. Cheng said.Physicians should counsel patients to exercise to counteract muscle loss.Whether or not patients choose to take these medications depends on cost, Dr. Tangri said. Publicly funded coverage for these medications in Canada is currently limited to people with diabetes or obesity, Dr. Cheng said.Adverse eventsThe most common adverse events, seen in about 10% to 20% of patients, are “that lovely trio of nausea, vomiting or diarrhea,” Dr. Lovshin said. Constipation is another adverse event. She warns patients that they might not feel well.“It is basically a transient effect, and it goes away,” Dr. Lovshin said. Advise patients to stop eating when no longer hungry, to eat smaller meals, avoid spicy food and stay hydrated.Dr. Lovshin warned physicians to expect patients to have an elevated heart rate thanks to a GLP-1 receptor in the sinoatrial node in the heart. This could be difficult for patients with atrial fibrillation.Some patients should not take GLP-1 receptor inhibitors, including those who are pregnant or breastfeeding. Physicians should also not offer them to people with chronic pancreatitis or a family history of medullary thyroid cancer.Whether or not to hold GLP-1 receptor agonists prior to surgery is a hot topic. They cause delayed gastric emptying and retain gastric contents, leaving a potential risk of pulmonary aspiration. Dr. Cheng noted that the decision is best left to the anesthesiologist.Patients with peripheral retinopathy should get the retinopathy treated by an ophthalmologist prior to starting GLP-1 receptor agonist treatment, Dr. Lovshin said.Other medicationsThe benefits of incretin therapies are additive. Current evidence (e.g., from STEP-HFpEF) suggests there are no or few negative interactions with other medications, including SGL2i (sodium glucose co-transport inhibitors), Dr. Zieroth said.However, be sure to stop DPP-4 inhibitors (“gliptins”) before adding a GLP-1 receptor agonist or a GLP-1/GIP dual agonist. Note that while oral semaglutide has the same safety profile as injected semaglutide, it may affect absorption of other drugs.While Diabetes Canada guidelines recommend starting on metformin first for patients with diabetes, cardiovascular risk factors and uncontrolled A1C, European and American guidelines differ, explained Dr. Akshay Jain, endocrinologist at TLC Diabetes and Endocrinology in Surrey, B.C., and clinical instructor at the University of British Columbia. He said he’d start on a GLP-1 receptor agonist first because he’d, “want to use a medication that not only works on blood sugars but other organ systems as well.”These therapies don’t cause hypoglycemia, but if a patient is on insulin or insulin secretagogues and their A1C is 8% or lower, consider lowering the dose of insulin or insulin secretagogues, Dr. Cheng said. This should be in consultation with the patient and the physician responsible for managing diabetes treatment.If weight loss is too muchFor some patients, the weight loss associated with incretin therapies isn’t needed and, “If the patient says that they’ve lost too much weight and aren’t feeling well, then that’s when you take action,” Dr. Cheng said. Consider switching the patient to a lower dose, which is still cardioprotective, or a GLP-1 receptor agonist with lower weight-loss effects.Life-long treatmentTo get organ protection, patients should remain on the treatment, Dr. Jain said. For those who need it for weight loss, it may be another conversation, Dr. Cheng noted. Patients should recognize that, “If you stop a GLP-1, people will regain the weight,” Dr. Lovshin said.There will be more data on these therapies available in the coming months that will further influence practice. “It’s a pretty exciting time,” Dr. Zieroth said.

Tips on prescribing incretin therapies for cardio-renal protection

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