COMMENTARY

GLP-1 Receptor Agonists at EASD 2020: Poster Pearls

Akshay B. Jain, MD

Disclosures

December 11, 2020

The European Association for the Study of Diabetes annual meeting is known for presenting the newest, cutting-edge research, and this year's virtual edition was no different. One of the highlights of attending any conference is browsing through the poster halls. For those who couldn't attend this year's virtual meeting, here are my top poster picks on GLP-1 receptor agonist (RA) therapies, curated for you.

Side Effects and A1c Reduction, Weight Loss

GLP-1 RAs have fast become one of the main classes of medications used for the management of type 2 diabetes (T2D). They are commonly associated with gastrointestinal (GI) side effects, including nausea and vomiting. The authors of this post hoc analysis took a closer look at 9680 patients in the SUSTAIN studies, representing a broad spectrum of patients with T2D. The absolute reductions in mean A1c were very similar between the group experiencing GI side effects and those that did not. Similarly, weight loss was similar between the group experiencing GI side effects and those that did not.

The occurrence of GI side effects was greater in females, older patients, those with renal impairment, and current or former smokers. However, these factors contributed in both the semaglutide and non-GLP-1 comparator arms; no risk factor was specific to semaglutide alone.

My take: Many clinicians feel that these side effects are what contribute to decreased appetite, thereby leading to decreases in weight and A1c levels. This study helps to show that the glycemic and weight loss efficacy of semaglutide is independent of the occurrence of GI side effects.

Treatment Intensification With GLP-1 RAs vs Others

The retrospective PATHWAY study was designed to provide guidance at different treatment intensification stages by comparing therapeutic options for glycemic control using linked US electronic health records and administrative claims data. The aim of this analysis was to compare intensification with oral antidiabetic drugs (OADs), GLP-1 RAs, or insulin in patients with T2D who are already taking two OADs.

Using propensity score matching, the researchers identified 530 matched patients for comparing A1c in those taking a GLP-1 vs OAD, and 398 patients for GLP-1 vs insulin. The most common GLP-1s received at intensification were liraglutide, exenatide extended-release, and dulaglutide, whereas the most common OADs were DPP-4 inhibitors, sulfonylureas, and SGLT-2 inhibitors. Most of the patients in the insulin group were intensified with long-acting insulin.

Patients intensifying with GLP-1 RAs were statistically significantly more likely to achieve A1c < 7% than those who intensified with OADs or insulin. Similarly, weight loss targets were statistically significantly more likely to be reached with GLP-1 intensification than with OAD and insulin. Absolute A1c and weight reductions were greater in the GLP-1 group vs in the OAD and insulin groups.

My take: This real-world study helps to illustrate that when treatment with two OADs is failing, choosing a GLP-1 RA over a third OAD or insulin therapy will lead to greater likelihood of achieving glycemic goal, weight loss, and potentially even reduction of other antihyperglycemic therapies

Racial Differences in Cardiovascular Benefits With GLP-1 RAs

The researchers added three recent cardiovascular outcomes trials (HARMONY, REWIND, and PIONEER 6) to a previously presented meta-analysis of the LEADER, SUSTAIN-6, and EXSCEL trials. The focus was to compare the cardiovascular benefits in Asian vs non-Asian persons. On subgroup analysis of 3-point major adverse cardiovascular event (MACE) based on race, the researchers found much greater reduction of relative risk in Asian patients compared with White, Black, and other patients.

My take: This meta-analysis raises the interesting question of whether the cardioprotective effects of GLP-1 RAs are dependent on the ethnicity of the patient. It is important to note that in this meta-analysis, I-squared values for the comparison of White, Black, Asian, and other races among the six studies indicated substantial heterogeneity in the Asian subgroup analysis. Dedicated randomized controlled trials are needed to answer this question more conclusively.

Cardiovascular Outcomes in Patients With Kidney Disease

The purpose of this post hoc analysis of REWIND was to compare the occurrence of cardiovascular events with dulaglutide in patients with renal impairment or micro/macroalbuminuria vs those without renal impairment or with normoalbuminuria. The hazard ratio (95% CI) in the overall study group was 0.88 (0.79-0.99). It was similar in those with eGFR < 60 mL/min/1.73 m2 vs those with eGFR ≥ 60 mL/min/1.73 m2. Likewise, it was similar in those with micro/macroalbuminuria vs those with normoalbuminuria.

The authors thus concluded that regardless of baseline eGFR or albuminuria status, dulaglutide reduces 3-point MACE outcomes in patients with T2D and cardiovascular disease or multiple risk factors.

My take: Patients with renal disease have a higher likelihood of CV morbidity and mortality. This post hoc analysis suggests that renal patients might derive a similar degree of CV protection with dulaglutide as those with normal renal function.

 GLP-1 RAs in Hospitalized Patients

This study in perioperative patients compared 48 patients on basal-bolus insulin therapy with 30 patients on a combination of basal insulin and liraglutide. Primary endpoints were differences in blood glucose readings (fasting and postprandial), as well as other endpoints such as blood pressure, laboratory testing results, and glycemic and blood pressure variability.

The investigators found a statistically significant higher occurrence of hypoglycemia events in the multiple daily injection group compared with none in the insulin plus GLP-1 RA group (P = .05). There were no significant differences in the occurrence of nausea/vomiting, percentage of readings in target range, glucose variability, blood pressure variability, or duration of hospitalization.

My take: Basal-bolus insulin therapy is the mainstay of glycemic control in hospitalized patients. This small study showed reduced hypoglycemia in the basal insulin + GLP-1 RA group, but larger studies may be required to evaluate the risk for GI side effects and the logistics of titrating GLP-1 RAs in hospitalized patients.

Akshay B. Jain, MD, is a clinical endocrinologist who has practiced in three countries, focusing on mitigating the complications of diabetes and obesity. He is fluent in six languages and has spoken at more than 500 programs internationally.

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