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Controversy Between SGLT-2 Inhibitors and GLP-1 Agonists as Preferred Second-Line Therapy

Jan 20, 2018

Patient specific considerations have to be taken into account prior to choosing GLP-1 agonist or SGLT-2 inhibitor as second-line anti-hyperglycemic agent.

Adults with type 2 diabetes who are not achieving their glycemic control solely with metformin are in need of a second-line agent to optimize their HbA1c ranges.  Recurrently, choosing a second-line therapy has been demanding. American Diabetes Association guidelines outline all the possible agents that can be used in the second-line setting, however, they do not advocate for a specific class of medication to be used over another. On the other hand, American Association of Clinical Endocrinologists proposes GLP-1 agonists and SGLT2 inhibitors as the most promising agents for second-line therapy. Both the GLP-1 agonists and the SGLT2 inhibitors lead to a valuable HbA1c  decrease and weight loss while having minimal effect on hypoglycemia. Since there are no head-to-head trials to date to compare between these two medication classes, the review of available literature has been completed and its results are discussed here to help clinicians deliberate the most suitable second-line therapy for their patients.


Observational studies and clinical trials involving SGLT2 inhibitors and GLP-1 agonists from the past 10 years were identified utilizing Medscape. Articles covered in this review included the effects of these medication classes on HbA1c weight, cardiovascular influence, and adverse events that have been reported. Excluded from the review are the articles assessing Saxenda, due to its approval for weight loss, and articles that evaluated the combination therapy with SGLT2 inhibitors or GLP-1 agonists with medications other than metformin.

GLP-1 receptor agonists are subcutaneous injections given typically twice daily, daily, or weekly varying with each specific agent in question. Available medications in this class include: exenatide (Byetta), liraglutide (Victoza), exenatide ER (Bydureon), albiglutide (Tanzeum), and dulaglutide (Trulicity). To address the glycemic control, GLP-1 agonists can lead to 0.7-1.7% decrease in HbA1c levels. Studies comparing liraglutide to other medications in its class demonstrated liraglutide’s superiority in decreasing the A1c levels. When compared to placebo, GLP-1 agonists were not found to increase the probability of hypoglycemia. By delaying gastric emptying and increasing the feeling of early satiety in an individual, GLP-1 agonists lead to dose-dependent weight reduction. On average, individuals may experience a drop in 2 to 5 kg.

However, the results have not been replicated throughout the class; clinical trials did not show the benefit of albiglutide in reducing weight. Cardiovascular benefits with GLP-1 agonists are not clear. ELIXA trial offers limited insight in CV outcomes with these agents – rates of CV death, myocardial infarction, stroke, or hospitalization occurred in 13.4% of patients who were receiving lixisenatide compared to 13.2% of those who were receiving placebo (HR 1.02). Gastrointestinal side effects are dose dependent and are seen in 35 to 44% of individuals treated with GLP-1 agonists. Thyroid malignancies or neoplasms and pancreatic malignancies or pancreatitis are not associated with use of these medications.

The three available SGLT2 inhibitors on market include the canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). Reductions of 0.32 to 1.17% in HbA1c were seen with these agents. Greater reductions are seen with higher doses and in those patients with a higher baseline HbA1c level. Choosing a specific agent within this class is proven to be problematic, as there are no trials that compare the efficacy between canagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors are glucose dependent agents, and therefore, are not correlated to hypoglycemia. In contrast to GLP-1 agonists, SGLT2 inhibitors cause less weight loss. On average, individuals can experience a loss of anywhere between 1.5 to 3 kg.  However, cardiovascular benefits are seen with this medication class. Clinically significant reductions in non-fatal MI, non-fatal stroke, or CV death were seen with empagliflozin compared to placebo in patients with established ASCVD as shown with the hazard ratio of 0.86 favoring the empagliflozin group; 10.5% versus 12.1% of patients experienced one of the mentioned events in the empagliflozin and placebo treatment arms, respectively. Owing to its mechanism of action, SGLT2 inhibitors have a potential to cause genitourinary infections, more specifically vulvovaginal candidiasis. Canagliflozin, exclusively, has shown to increase the risk of bone fractions while decreasing the bone mineral density; this has not been seen with the other two drugs in the class.

Patient-specific characteristics have to be taken into account in order to select the most suitable second-line agent for treatment of type 2 diabetes mellitus. Considering the comparable effects SGLT2 inhibitors and GLP-1 agonists have on the HbA1c reduction, and the minimal risk of hypoglycemia, clinicians should weigh the potential benefits and adverse events of each agent before choosing a specific one. Patient preferences as well as comorbid conditions may help with the ultimate decision.

Regarding the controversy of whether GLP-1–based therapy can increase the risk for specific malignant disease like pancreatic carcinoma and thyroid cancer, our conclusion is that apparently there is neither firm evidence in favor of this hypothesis nor evidence strong enough to rule out any such increased risk based on results available at present.

Practice Pearls:

  • GLP-1 agonists and SGLT2 inhibitors cause comparable reduction in HbA1c levels and are associated with low risk of hypoglycemia.
  • GLP-1 agonists lead to a weight loss of 2 to 5 kilograms compared to 1.5 to 3 kilograms of weight loss seen with SGLT2 inhibitors.
  • Patient specific characteristics have to be taken into account when deciding on the optimal second-line agent.


Holy E Gurgle, Karen White. “SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives.” June 2016.  Dove Press, Vascular Health and Risk Management. June 2016. www.dovepress.com/sglt2-inhibitors-or-glp-1-receptor-agonists-as-second-line-therapy-in–peer-reviewed-article-VHRM. Accessed Jan 2018.

Pfeffer MA, Claggett B, Diaz R, et al. “Lixisenatide in patients with Type 2 Diabetes and Acute Coronary Syndrome.” New England Journal of Medicine. 2015. www.nejm.org/doi/full/10.1056/NEJMoa1509225# t=article. Accessed Jan 2018.

Zinman B, Wanner C, Lachin JM, et al. “Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes” New England Journal of Medicine. 2015. nejm.org/doi/full/10.1056/NEJMoa1504720. Accessed Jan 2018.

John Buse, Micheal Nauck, Thomas Forst, et al.”Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study”. Lancet. November 2012. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61267-7/fulltext. Accessed on Jan. 2018.

Melanie Davies, Richard Bergenstal, Bruce Bode, et al. “Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes Randomized Clinical Trial.” JAMA. Aug. 2015. https://jamanetwork.com/journals/jama/fullarticle/2428956. Accessed Jan. 2018.

Lamija Zimic, PharmD(c), University of South Florida, College of Pharmacy