In December 2019, the American Diabetes Association (ADA) released updated 2020 Standards of Medical Care in Diabetes.¹ The recently updated pharmacologic treatment algorithm for people with type 2 diabetes supports the early use of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or a sodium-glucose cotransporter-2 (SGLT-2) inhibitor after metformin. The ADA recommends considering important comorbidities such as atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure when selecting a second pharmacological agent, and in certain high-risk persons with diabetes the decision to use a GLP-1 RA or SGLT-2 inhibitor to reduce cardiovascular risk or slow renal disease progression should be made without regard to baseline hemoglobin A1c (HbA1c) or HbA1c target.  This recommendation is based on recent findings from cardiovascular outcomes trials with these therapies.  Understanding and applying the updated recommendations provides opportunities to improve patient care and the potential to educate patients and other healthcare practitioners about how to improve diabetes-related outcomes beyond HbA1c-lowering.  This article includes clinical pearls to help guide decision-making with regard to GLP-1 RAs and SGLT-2 inhibitors and how to communicate these recommendations to other members of the healthcare team. 

First, understanding the mechanism of action of these agents will be extremely helpful when communicating both the benefits and risks of therapy to patients and providers.  The GLP-1 RAs (Table 1) are synthetic analogs of human GLP-1, an incretin hormone, that bind to GLP-1 receptors.  These analogs work by enhancing glucose-dependent insulin secretion, decreasing glucagon secretion - and therefore hepatic glucose production - and slowing gastric emptying to increase satiety and promote weight loss.  The main adverse effects associated with GLP-1 RAs are gastrointestinal, with nausea being the most common.  This effect is a natural byproduct of their ability to slow gastric emptying, which typically results in patients feeling fuller for longer periods of time.  However, this may predispose patients who are accustomed to eating larger meals very quickly to an increased risk of overeating, which can precipitate nausea and even vomiting in severe cases.  To mitigate the risk of gastrointestinal effects, these agents are typically titrated slowly (e.g., after 1-2 weeks for shorter-acting agents, and after 1 month for once-weekly agents) up to their maximum tolerated doses.  Tolerability will also improve if patients are counseled to initially consume their meals very slowly to avoid overeating, or to consider smaller, more frequent meals as opposed to larger meals as the body adjusts to the delayed gastric emptying.  While initially bothersome to some patients, this adverse effect is also the mechanism behind the associated weight loss seen with GLP-1 RAs, as it curbs patients’ appetites and promotes decreased caloric consumption. 

The SGLT-2 inhibitors (Table 2) block glucose reabsorption in the proximal renal tubule to increase urinary glucose excretion.  As 90% of all glucose is reabsorbed via SGLT-2 receptors, blocking this cotransporter provides a novel way to eliminate glucose from the body.² Insulin-treated patients initiated on SGLT-2 inhibitors typically have lower insulin requirements since there is physically less glucose in the body.  As a result, patients experience weight loss due to the elimination of approximately 50-100 g of urinary glucose (approximately 200-400 kcal) per day.³ The  adverse effect most commonly associated with SGLT-2 inhibitors are genitourinary complications, with greater risk demonstrated in patients with a history of frequent genitourinary infections.⁴ Selecting the appropriate patients and highlighting the importance of proper personal hygiene and overall cleanliness to patients initiated on these medications may help mitigate the risk of infections and improve the likelihood that patients are maintained on these agents.

Assuming patients’ insurance plans cover these agents and patients are able to afford the copayments, there are a variety of patient factors to consider when choosing between these two drug classes.  These include, but are not limited to, desired HbA1c-lowering to achieve patient-specific goals, comorbid chronic conditions, and desire for weight loss.  A major consideration to keep in mind is the patients’ amenability to injections.  Most GLP-1 RAs are administered subcutaneously, while SGLT-2 inhibitors are oral tablets. Thus, determining if a patient is willing to perform injections is the first step when selecting an agent. Of note, an oral formulation of semaglutide has recently received FDA approval and provides an option to patients who may benefit from a GLP-1 RA, but are not willing to perform injections.⁵