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Amazing Outcomes with Combination Therapy of GLP-1 Receptor Agonist and SGLT2 Inhibitors

Jun 23, 2018

Combination therapy of GLP-1 RAs and SGLT2is: different MOAs of these drugs make them an excellent combination in treating patients with type 2 diabetes mellitus (T2DM).

The Ominous Octet is the combination of at least eight pathophysiologic abnormalities that contribute to glucose intolerance in T2DM. Decreased incretin effect, increased lipolysis, enhanced renal glucose reabsorption, decreased glucose uptake in the muscles, neurotransmitter dysfunctions, increased hepatic glucose production, excess glucagon secretion by α-cells, and decreased insulin secretion. Moreover, clinical studies have been shown that GLP-1 receptor agonist (GLP-1 RAs) can correct six out of eight pathogenic abnormalities that comprise the ominous octet and SGLT2 inhibitors can correct another one. Therefore, we can say that when used as a dual therapy, both drugs can almost cover in full the pathophysiologic abnormalities contributing to glucose intolerance in T2DM.


Dr. Ralph A. DeFronzo, author of Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor, has reviewed the articles EMPA-REG OUTCOME, LEADER and SUSTAIN among many others to compile the evidence about the benefits of these two drug classes. A total of 16 parameters were analyzed to determine the effect of the combination therapy in the metabolic, cardiovascular, and renal functions.  The most relevant are listed below.

  1.    Glycemic Control

In patients with  type 2 who have a baseline HbA1c between 8.0% and 8.2%, it has been observed that the GLP-1 RAs and SGLT2i can reach an average reduction in HbA1c between 1.2% to 1.4% and 0.8% to 1.0% respectively. Those reductions in HbA1c are observed when both drug classes are used as monotherapy. On the other hand, another study conducted in 695 patients with type 2 who have consistently high blood glucose, baseline HbA1c of 9.3%, and using maximum doses of metformin, were randomly assigned in three groups; first two groups in monotherapy with GLP-1RAs or SGLT2i and the third group in dual therapy. The results have shown an HbA1c reduction of 1.4%, 1.6%, and 2.0% respectively. Although it would be expected that the sum of both monotherapies equals the combination, the reduction of HbA1c in the third group was considerable.

  1.    Insulin secretion and insulin sensitivity

Since both classes increase the beta cell function and enhance insulin sensitivity, a synergistic effect would be expected when both drugs are used together. Therefore, more studies should be conducted.

  1.    Body Weight

By two different mechanisms, both agents are capable of reducing body weight. GLP-1 RAs reduce the appetite while SGLT2i increase the excretion of calories in the urine.  Likewise, with the combination therapy, we would expect a significant reduction in weight loss.

  1.    Blood Pressure

An increase in renal sodium excretion is a common characteristic of GLP-1 RAs and SGLT2i. By different mechanisms, both drugs have demonstrated a reduction in blood pressure. An additive effect with a combination therapy could be expected.

  1.    Inflammation

Multiple studies have been demonstrated that GLP-1 RAs and SGLT2i carry a cardio protection effect. DeFronzo et al. in SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME Study have suggested that since the cardiovascular benefit observed in SGLT2i is most likely related to the drug’s hemodynamic benefit, whereas the GLP-1 RAs are related to their anti-atherogenic/anti-inflammatory actions, both drugs may produce an additive cardiovascular benefit.

  1.    Protection from diabetic neuropathy

The author concludes that since the mechanisms responsible for the renal protective effects of GLP-1 RAs and SGLT2i are not similar, this dual therapy may cause an additive effect to prevent diabetic neuropathy.

  1.    Hypoglycemia

In both drug classes, hypoglycemia is uncommon when used as monotherapy. This is also true when used as a combination therapy unless there is an addition of a third drug class such as insulin or an insulin secretagogue.

The adverse event profile is unlikely to have an additive or synergistic effect since the two drug classes differ from their side effects. With this review article, Dr. DeFronzo has concluded that these new antidiabetic agents are capable of helping to maintain glycemic control and additionally prevent micro and macrovascular complications, and  should be considered as first-line therapy for the treatment of T2DM in patients at high cardiovascular risk as well in those patients with a lesser risk.

Practice Pearls:

  • When combined, SGLT2i and GLP-1 RAs agents may correct 7 of the 8 components of the Ominous Octet with a reduction in HbA1c and a possible synergistic effect that can help to reduce macro and microvascular complications and prevent diabetic nephropathy.
  • Because of their different mechanisms of action, we would expect a reduction in HbA1c when using the SGLT2i and GLP-1 RAs as dual-therapy.
  • More studies should be done to determine the real world benefits of the combination therapy of GLP-1 RAs and SGLT2i in the prevention of micro and macrovascular complications


DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017; 19:1353–1362. https://doi.org/10.1111/ dom.12982

Kennen Munoz Munoz, Pharm. D. Candidate 2019, LECOM School of Pharmacy