Combination Therapy with DPP-4 and SGLT2 Inhibitors Safe and Effective


It can be difficult to determine which combinations of antihyperglycemic medications might work best, and for which patients. A recent review investigates combined therapy, with a focus on the newer DPP-4 and SGLT2 inhibitors.

Various studies have investigated the safety and efficacy of combining different antihyperglycemic medications. With the wide range of choices available, though, it can be difficult to make sense of which combinations might work best, and for which patients. 

A recent review has looked at this issue, particularly regarding combined therapy with the newer DPP-4 and SGLT2 inhibitors. The review included clinical trials with at least 200 patients, and focused on change in HbA1c from baseline after 24 or more weeks of treatment with combination antihyperglycemics. Included articles were limited to those published in English, and studies looking at medications with FDA approval. 

The review included 33 articles from the DPP-4 class and 24 from the SGLT2 inhibitor class. In general,  the studies indicated that adding a DPP-4 or SGLT2 inhibitor as a second or third agent resulted in improved glycemic control, reductions in weight (or at least a neutral weight effect), and low rates of hypoglycemia, especially when combined with metformin.

Key results included:

• DPP-4 Inhibitors:

     * Dual and triple therapy with a DPP-4 inhibitor, metformin and/or a thiazolidinedione (TZD) improved HbA1c compared to monotherapy, without markedly increased hypoglycemia.

     * No major safety concerns were found.

     * There was a tendency for increased hypoglycemia when combined with a sulfonylurea.

     * There was a tendency for weight increases associated with TZDs.

• SGLT2 Inhibitors:

     * Dual and triple therapy with an SGLT2 inhibitor and metformin, a TZD, and/or a DPP-4 inhibitor improved HbA1c compared to monotherapy or active comparators, without markedly increased hypoglycemia.

     * There was a tendency toward hypoglycemia when combined with insulin or a sulfonylurea. 

• The overall safety and tolerability of DPP-4 or SGLT2 inhibitors were consistent with their known side effect profiles.

“These findings demonstrate the beneficial effects of a DPP-4 inhibitor and/or an SGLT2 inhibitor on glycemia when used in dual or triple combination therapy,” wrote Robert Guthrie, MD.

“For some treatment-naïve patients, monotherapy may not be sufficient to achieve glycemic goals, and initial combination therapy with metformin and a DPP-4 inhibitor or an SGLT2 inhibitor, agents with complementary mechanisms of action, may be helpful,”  he added.

In patients for whom metformin is contraindicated, Dr. Guthrie suggested initial combination therapy with a DPP-4 inhibitor and a TZD or SGLT2 inhibitor.  Recent studies have suggested an additive benefit on glycemic control when DPP-4 or SGLT2 inhibitors are added as a third drug to dual therapy regimens, he explained. 

Healthcare providers should also consider each agent’s individual adverse effect profile when choosing drug combinations, he advised.  For example, weight tends to decrease or stay neutral with DPP-4 and SGLT2 inhibitors, but increase with a sulfonylurea or TZD.  Though DPP-4 and SGLT2 inhibitors both carry low risk for hypoglycemia, the risk increases when they are added to a sulfonylurea, although not necessarily when added to insulin. 

“A novel treatment approach is the use of a DPP-4 inhibitor with an SGLT2 inhibitor in triple combination therapy,” Dr. Guthrie proposed.

Research has suggested that the antihyperglycemic actions of these two agents may be “complementary rather than additive,” Dr. Guthrie wrote. SGLT2 inhibitors have been linked to increased endogenous glucose production (EGP). DPP-4 inhibitors, however, have an inhibitory action on glucose production which may offset the increased EGP with SGLT2 inhibitors. In addition, both DPP-4 and SGLT2 inhibitors may have beneficial effects on beta cell function.  Combining type 2 diabetes mellitus (T2DM) medications with synergistic actions could potentially delay or prevent beta cell failure that occurs during the natural history of T2DM, Dr. Guthrie explained.

 “[C]linical studies in a variety of patients with T2DM support the efficacy, safety and tolerability of dual and triple combination treatment regimens, including a DPP-4 inhibitor and/or an SGLT2 inhibitor,” Dr Guthrie concluded, “Although a step-wise approach remains the standard treatment algorithm, initiating combination treatment early may help address the multiple sites of dysfunction that occur early in the disease and help prevent future complications.”


Guthrie RM. Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. Postgrad Med. 2015 May 8:1-17. [Epub ahead of print]

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