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Study Shows Advantage of SGLT2’s Over DPP-4’s

Jan 27, 2018

Systematic review and meta-analysis show lead in HbA1c reduction, weight loss, and favorable fasting blood glucose levels.

In today’s era, there are numerous medication classes on the market to choose from to  treat type 2 diabetes. Selecting the ideal medication class for consumers has been a demanding challenge. One of the latest medication classes on market — the SGLT2 inhibitors — has shown a substantial reduction in hemoglobin A1c levels; in addition, they have shown a significant impact on weight loss. DPP-4 inhibitors have a low side-effect profile when compared to other antihyperglycemic agents such as sulfonylureas, though they deliver a modest reduction of A1c ranges. Thus far, there have not been any randomized control trials comparing safety and efficacy of SGLT2 inhibitors and DPP-4 blockers. A systematic review and meta-analysis have been completed to weigh in on the decision between choosing one drug class over the other as a monotherapy or an add-on to metformin in the treatment of type 2 diabetes.


Zhiying Wang and colleagues performed a literature search utilizing PubMed, Embase, and ClinicalTrials.gov websites to find relevant randomized controlled trials pertaining to SGLT2 inhibitors or DPP-4 blockers. Included in the meta-analysis were those studies that enrolled subjects over 18 years of age, studies that assessed the levels of HbA1c and FPG, and studies that looked at weight reduction, adverse events, or incidence of hypoglycemia with SGLT2i‘s or DPP-4i’s.  Non-randomized controlled trials, letters, care reports, or RCT’s lasting less than 12 weeks were excluded from the review. Primary outcomes were as follows: hemoglobin A1c levels, fasting plasma glucose, and rates of hypoglycemia. Secondary efficacy outcome observed subjects who achieved the A1c level of less than 7% per the ADA criteria.

Researchers employed the use of the Jadad score scale to independently gauge the quality of included studies. As a result, 24 randomized controlled trials concerning the use of SGLT2 inhibitors and DPP-4 inhibitors as either monotherapy, or an add-on to metformin were eligible to be included in the meta-analysis.

Compilation of data across the RCT’s demonstrated SGLT2 inhibitors’ victory over DPP-4 inhibitors in achieving desirable primary outcomes when used as single agents for treatment of type 2 diabetes. Hemoglobin A1c levels, fasting plasma glucose ranges, and weight were lowered further with the use of SGLT2 inhibitors by 0.13% with p<0.05, 0.80 mmol/L with p<0.00001, and 2.35kg with p<0.00001, respectively.  However, the number of patients who received a reduction of A1c  below 7% was equal between the study arms, with a relative risk of 0.91.

Combination therapy with metformin and DPP-4i agents led to a statistically significant improvement in the reduction of HbA1c ranges by -0.55%, and FBG by -0.72 mmol/L when compared to metformin monotherapy. Furthermore, a higher number of patients achieved the ADA goal of <7% A1c with combination therapy, with relative risk of 1.78.   Similar results were seen with the SGLT2i combination with metformin; combination therapy reduced A1c levels by -0.55%, FBG levels by -1.25 mmol/L, and increased the number of patients who achieved <7% A1c with RR of 1.39. Dual therapy with metformin and SGLT2i also offered increased body weight loss by 1.82 kg with p<0.00001 compared to single agent metformin. Safety outcome rates were equal with SGLT inhibitor or DPP-4 blocker monotherapy. Metformin combination with DPP-4 inhibitors put patients at a risk of hypoglycemia, which was not seen with metformin plus SGLT2i therapy.

AACE guidelines give the same level of recommendation to SGLT2i and DPP-4i for monotherapy of diabetes, while in dual therapy recommendations they give a slightly better preference to SGLT2i’s when combined with metformin over the combination with DPP-4i’s. On the other hand, ADA guidelines do not recommend a specific drug class as the add-on therapy to metformin.

Therefore, results presented here offer clinicians insight of benefits seen with the use of SGL2 inhibitors over DPP-4 blockers, primarily in better reduction of FPG levels and decreased rates of hypoglycemic events. Randomized controlled trials are needed before implementing the results seen in this meta-analysis on a greater scale in order to determine the long-term efficacy, safety, and diabetic complications outcomes seen with SGLT2’s and DPP-4’s.

Practice Pearls:

  • SGLT2i monotherapy offers a higher reduction in HbA1c levels, FBG, and body weight.
  • Comparable reduction in HbA1c levels is seen with metformin plus SGLT2i and metformin plus DPP-4i.
  • Dual therapy with SGLT2i and metformin leads to better fasting plasma glucose lowering and weight loss.
  • Metformin combination with a DPP-4 inhibitor puts patients at an increased risk of hypoglycemic events.


Zhiying Wang, Jiahui Sun, Ruobing Han, et al. “Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis” Diabetes Obes Metab. 2018. http://onlinelibrary.wiley.com/doi/10.1111/dom.13047. Accessed on Jan 2018.

AACE/ACE Comprehensive Diabetes Management Algorithm, Endocrine Practice. 2015. www.aace.com/sites/all/files/diabetes-algorithm-executive-summary.pdf. Accessed Jan 2018.

Bakris G, Blonde L, Boulton AJ, et al. “The Journal of Clinical Diabetes Care and Applied Research and Education.”  American Diabetes Association. 2017. care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf. Accessed Jan 2018.

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