New guidance on preventing cardiovascular (CV) and renal complications in type 2 diabetes (T2D) emphasizes tailoring therapy to a patient’s individual risk profile.
The living guidelines, published as part of the BMJ’s “Rapid Recommendations” initiative, include a strong recommendation for SGLT2 inhibitors and GLP-1 receptor agonists (RAs) in patients at high risk for CV or kidney complications but recommend against their routine use in lower-risk patients with a preference for treatments based on each individual’s specific needs.
“These risk-stratified recommendations provide personalized medicine and represent the first international living guidelines on this topic, meaning they will be dynamically updated and therefore continue to be relevant for all doctors in the world,” senior author Per Olav Vandvik, MD, PhD, of the MAGIC Evidence Ecosystem Foundation and the Institute of Health and Society, University of Oslo’s Faculty of Medicine, Oslo, Norway, told Medscape Medical News.
With T2D significantly associated with multiorgan morbidity and representing the ninth leading cause of death, preventing CV and kidney complications is a high priority.
SGLT2 inhibitors and GLP-1 RAs, along with finerenone, a nonsteroidal selective mineralocorticoid RA, and tirzepatide, a dual glucose-dependent insulinotropic polypeptide/GLP-1 RA, have transformed the management of T2D in recent years.
However, with evidence rapidly advancing regarding which drugs or drug combinations are most effective for the prevention of complications in specific patient types, the need for living guidelines to continuously provide updates on emerging evidence was deemed necessary.
The guideline, created by an international panel of clinicians, methodologists, and two patient partners, is based on a systematic review and network meta-analysis of evidence from nearly half a million adults with T2D across 869 randomized controlled trials, involving 63 medications and 26 outcomes.
In assessing the data to determine the benefits of the four key medications for adults with T2D based on their risk level for CV and kidney-related complications, the panel concluded that:
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For patients at higher risk, defined as having established CV disease (CVD) and/or chronic kidney disease (CKD) with high risk for complications, or established heart failure, the use of SGLT2 inhibitors or GLP-1 RAs for treatment is strongly recommended, with a weak recommendation in favor of the use of finerenone in adults with CKD.
“The cardiovascular and kidney benefits of GLP-1s are independent of significant reductions in weight,” Vandvik noted. “These benefits are more or less equal to those of SGLT2 inhibitors, meaning that patients at moderate to highest risk should be offered one of these drugs for cardiorenal protection,” he said.
- For patients at moderate risk, defined as having more than three CV risk factors without established CVD or CKD, or established CVD and/or CKD at a lower risk for complications, the panel issued a weak recommendation in favor of treatment with SGLT2 inhibitors or GLP-1 RAs, while making a weak recommendation against the use of finerenone in adults with CKD.
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For those at lower risk, defined as having three or fewer CV risk factors without established CVD or CKD, the panel issued a weak recommendation against the use of SGLT2 inhibitors or GLP-1 RAs.
“[In low-risk patients], the benefits are not considered to outweigh the harms and burdens of the drugs,” Vandvik said. “Experts did not find drugs clinically effective [in those patients], and they will also represent a waste of precious health resources for patients and society.”
- Across all levels of risk, the panel issued a weak recommendation supporting the use of tirzepatide in adults with obesity.
‘Real World Prescribing’
With the soaring popularity of the newer drugs, particularly GLP-1s, the key issue of the level of risk for complications is often overlooked in real-world prescribing, Vandvik noted.
“To our knowledge, there is both undertreatment, ie, not ensuring all those patients at highest risk get the right drug, and overtreatment, ie, offering the drugs to those with the lowest risk, potentially [leading to] more harms and burden than benefits,” he said.
Newer drugs, meanwhile, come with the caveat of having less robust evidence on safety and efficacy.
For instance, with a lack of evidence of benefits with finerenone, as well as notable potential harms, including hyperkalemia, the drug was recommended only among the highest-risk patients with CKD.
And regarding tirzepatide, although the drug had consistently been shown to provide greater weight loss than GLP-1 RAs, the authors suggest consideration of the stronger evidence of CV and kidney benefits with GLP-1 RAs.
The guidelines feature MATCH-IT, “an interactive decision support tool that allows further visualization of the comparative benefits and harms across therapeutics to support shared decision-making,” according to the authors. Details on the guideline’s recommendations and evidence base are available for download in the MAGIC app.
The goal of the tools is to “empower patients and allow them to take an active part in shared decisions about what drug is best for them,” Vandvik said.
Managing Glycemia Along With Complications Is Key
In a related editorial, Aikaterini Theodoraki, MD, consultant/physician in endocrinology and diabetes with the Chelsea and Westminster National Health Service Foundation Trust, London, England, noted that the recommendations expand on existing guidelines with “a pragmatic approach.”
“Given the wide variation in cardiovascular and kidney outcomes among individuals with diabetes, risk stratification is essential in guiding therapy in modern diabetes care,” Theodoraki said.
However, due to ongoing uncertainty regarding the optimal glycemic targets needed to balance risks and benefits, poor glycemic control remains a key cause of complications.
“Therefore, managing glycemia in parallel with cardiovascular and renal risk factors remains essential, particularly for complications less affected by newer therapies,” he stated.
“Overall, the new recommendations may be most applicable to patients with HbA1c [glycated hemoglobin] values between 6.5% (48 mmol/mol) and 8% (64 mmol/mol), in line with the evidence base supporting these guideline interventions,” Theodoraki wrote.
Further commenting on the research, Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine in the Division of Endocrinology at the Internal Medicine Subspecialties Clinic, University of Texas Southwestern Medical Center in Dallas, underscored that the study’s risk-stratified approach “complements guidance from the American Diabetes Association, European Society of Cardiology, and KDIGO [Kidney Disease: Improving Global Outcomes] by providing clearer gradations of risk rather than broad categories.”
“Importantly, it prioritizes prevention of cardiovascular and renal complications beyond glucose control alone, reflecting the growing evidence that targeting outcomes beyond HbA1c improves survival and quality of life for people with type 2 diabetes,” he told Medscape Medical News.
“For lower-risk patients, modest benefits may not outweigh the current cost or potential adverse effects,” Almandoz said. “These guidelines highlight the need to match therapy intensity to risk so that those most likely to benefit are prioritized.”
The guideline authors underscore that considerations of cost-effectiveness are inevitable factors, with the costs of some of the drugs being prohibitive, and Almandoz agreed.
“Most importantly, cost and access remain major barriers worldwide, and the guideline appropriately acknowledges that implementation will look very different depending on the health system context,” he said.
Vandvik, the other authors of the recommendations, and Theodoraki reported having no disclosures. Almandoz reported serving on advisory boards and receiving consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly and Company, Haleon, Kailera Therapeutics, Metsera Inc., Novo Nordisk, Rhythm Pharmaceuticals, and Rivus Pharmaceuticals, Inc.
Nancy A. Melville is a Maine-based medical and science journalist with more than 25 years of writing experience in specialties including endocrinology, oncology, hematology, psychiatry, and neurology.