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What’s the Best Second-Line Drug Class for Type 2 Diabetes?

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors to treat type 2 diabetes appear to confer greater cardiovascular benefit than glucagon-like peptide-1 (GLP-1) receptor agonists among older adults with a history of cardiovascular disease (CVD), according to a new study.

But in those with no history of CVD, the two newer drug classes appear equally effective.

The findings, from an analysis of Medicare beneficiaries, were published online January 25 in Diabetes Care by Elisabetta Patorno, MD, and colleagues.

The analysis included more than 90,000 adults aged 66 years and older who started a GLP-1 agonist or SGLT2 inhibitor between April 2013 and December 2016. Use of an SGLT2 inhibitor compared with a GLP-1 agonist was associated with similar rates of major adverse cardiovascular events (MACE), fewer hospitalizations for heart failure and acute kidney injury, and greater risks for diabetic ketoacidosis (DKA), lower-limb amputations, and genital infections.

The head-to-head comparison reinforces findings from recent meta-analyses of cardiovascular outcomes trials (CVOTs) showing greater benefit for SGLT2 inhibitors than GLP-1 agonists in prevention of heart failure, while also shedding light on two type 2 diabetes populations who were not well-represented in the CVOTs, Patorno and colleagues say.

Study Fills a Knowledge Gap

“Our study focuses on routinely treated patients on average 10 years older than the patients included in these trials, providing information on a subset of the population with diabetes underrepresented in CVOTs,” say Patorno, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Harvard Medical School, Boston, Massachusetts, and colleagues.

“It includes patients across a broader spectrum of CVDs at baseline, allowing for the exploration of drug effectiveness among patients with and without established CVD,” they add.

And, they note, the database includes a far larger population than do the CVOTs, thus enabling a closer investigation of safety issues in a more vulnerable population.   

Asked to comment, Rozalina G. McCoy, MD, an endocrinologist and primary care physician at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News, “It’s really important to compare these two classes of medications to each other because over the past 5 years they have come to the forefront as the ideal medications for the management of type 2 diabetes because of these additional benefits that we see in terms of cardiovascular disease, heart failure, and kidney disease progression.”

“It’s really important to know if these medications are comparable to each other, or if one should be preferred over the other for a particular benefit, in our patients depending on what they’re at highest risk for. So, I think this fills an important knowledge gap.”

Overall, McCoy said the data suggest that older adults with baseline CVD would be the most likely to benefit from SGLT2 inhibitors or GLP-1 agonists.

Among those individuals, “If I’m trying to decide which of these two drugs to start a patient on — after confirming they can afford them — this helps us with that shared decision-making conversation. If they have heart failure, I should give them an SGLT2 inhibitor. But if they don’t have heart failure, it really doesn’t matter…between those two.”

For those individuals with baseline CVD but not heart failure, she said, the choice comes down to factors such as whether they prefer injections versus tablets, once-weekly versus daily dosing, side effect profiles, and “which one fits in their life better as opposed to these clinical factors.”

Both Classes Unaffordable for Many

However, McCoy did note several study limitations. Because it only goes through 2016, the study by Patorno and colleagues predates several of the CVOTs and mostly applies only to canagliflozin and liraglutide in terms of SGLT2 inhibitors and GLP-1 agonists.

Moreover, the high cost of both drug classes is a problem.

She pointed to a study from her group, presented at the 2020 American Diabetes Association meeting and published February 1 in JAMA Network Open, finding that the likelihood of a patient receiving a new prescription for an SGLT2 inhibitor or a GLP-1 agonist was 55%-69% lower in Medicare Advantage patients compared with those in commercial health plans.

“When we looked at early adoption of the SGLT2 inhibitors, for example, the young, healthy people who are financially well off were much more likely to start these medications,” she said.

“We see a big gap in uptake, even to this day, a dramatic difference even among those with comorbidities that call for their use…Even on formulary they’re unaffordable for most patients. Most people need to use company savings cards to decrease their cost-share, and patients with Medicare or Medicare Advantage plans aren’t eligible for those.”

The study doesn’t look at other commonly used second-line type 2 diabetes medications, the dipeptidyl peptidase 4 (DPP-4) inhibitors or sulfonylureas.

“So the question still remains: How much better are either of these [SGLT2 inhibitors and GLP-1 agonists] compared with the other drugs that are much less expensive than these two classes, and that more patients can afford, and that more patients use?”

Adverse Event Reports Limited by Claims Data

Regarding safety, McCoy noted that while the investigators of this new study included side effects commonly seen with SGLT2 inhibitors, such as genital infections, they were limited to claims data which often don’t include GLP-1 agonist-related adverse events like nausea and vomiting.

“Especially in this older frail population, I would have wanted to see things like malnutrition or failure to thrive, because if older people, who are already at risk for not eating well, are [then] given a GLP-1 agonist and they become more frail because they’re not able to eat and maintain nutrition, that’s really bad. I know it’s hard or almost impossible to look at some of those outcomes in claims, but they definitely should have acknowledged it.”

These Are Not New Drugs Any More: Expand Access  

The study population involved a total of 90,094 Medicare beneficiaries initiating an SGLT2 inhibitor or GLP-1 agonist. With propensity matching for factors including age, gender, comorbidities, frailty, and use of other glucose-lowering medications, there were 45,047 in each treatment group.

Around 67% of the patients were taking metformin, 37% were on sulfonylureas, 24% were taking DPP-4 inhibitors, and 24% were on insulin.  

Canagliflozin and liraglutide comprised 77% and 59% of the respective SGLT2 inhibitors and GLP-1 agonists used. Mean follow-up was 8.5 months, but more than 5000 patients were followed for more than 2 years.

For MACE, the incidence per 1000 person-years for SGLT2 inhibitors vs GLP-1 agonists was 18.0 vs 18.4, an insignificant difference with a hazard ratio (HR) of 0.98.

For heart failure hospitalization, however, the incidences were 7.0 vs 10.3, which was significant (HR, 0.68) in favor of SGLT2 inhibitors.

There were no differences in individual MACE components of myocardial infarction, stroke, cardiovascular mortality, all-cause mortality, or composites (hazard ratios ranging from 0.83 to 1.04) between the two drug classes.   

Adverse events seen significantly more often with SGLT2 inhibitors than GLP-1 agonists were DKA (2.4 vs 1.7 per 1000; HR, 1.46), lower-limb amputations (3.1 vs 2.2; HR, 1.44), and genital infections (82.3 vs 25.2; HR, 3.34). The risk for acute kidney injury was lower with SGLT2 inhibitors than GLP-1 agonists (38.5 vs 45.5; HR, 0.85).

Among the subgroup of patients with a history of CVD, the initiation of SGLT2 inhibitors was associated with reductions in the risk of heart failure hospitalization (5.9 fewer events per 1000 person-years), cardiovascular death (2.6 fewer events per 1000 person-years), and all-cause mortality (2.8 fewer events per 1000 person-years) compared with GLP-1 agonists.

Among those without a history of CVD, SGLT2 inhibitors versus GLP-1 agonist initiation produced reductions in heart failure hospitalization, though with a benefit of substantially lower magnitude (1.1 fewer events per 1000 person-years) and no benefit in the risk of the other efficacy outcomes.

McCoy said the data suggest that SGLT2 inhibitors and GLP-1 receptor agonists should be used more often in older adults who could benefit from them.

“Clinicians tend to be very cautious in older people, and sometimes too much so, to the point of depriving them of good evidence-based treatments. These aren’t new drugs anymore. I think we should be using them a lot more, including in our older adults.”

And when they finally go off-patent and become more affordable, she said, “that will be a great day.”

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. Patorno was supported by a career development grant from the National Institute on Aging and is co-investigator of an investigator-initiated grant to the Brigham and Womens Hospital from Boehringer Ingelheim, not directly related to the topic of the submitted work. McCoy receives funding from the National Institute of Diabetes, Digestive, and Kidney Diseases.

Diabetes Care. Published online January 25, 2021. Abstract

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