DPP-4 inhibitors show benefits over sulfonylureas as add-on diabetes therapy

Patients with diabetes who add dipeptidyl peptidase-4 inhibitors to their metformin therapy have a lower risk of stroke and hypoglycaemia, study shows.

Diabetes patients who add dipeptidyl peptidase-4 (DPP-4) inhibitors to their metformin therapy have a lower risk of stroke and hypoglycaemia, researchers find. In the image, a woman with diabetes takes a sugar level blood test

Diabetes patients who add dipeptidyl peptidase-4 (DPP-4) inhibitors to their metformin therapy have a lower risk of stroke and hypoglycaemia than patients who take add-on sulfonylureas, according to a study carried out by Taiwan-based researchers.

The research, published in Annals of Internal Medicine
, shows that, compared with add-on sulfonylureas, DPP-4 inhibitors also confer lower risks for all-cause death and major adverse cardiovascular events (MACE) when used with metformin therapy in patients with type 2 diabetes mellitus.

“This large, retrospective, nationwide database study gives further insight into the studied combination of oral hypoglycaemics in type 2 diabetes, however, longer-duration studies are still warranted,” says Mujahid Saeed, consultant in diabetes at Queen Elizabeth Hospital, Birmingham, who was not involved in the study. “The burden of diabetes on cardiovascular disease is huge. We need a strong evidence-base that newer therapies do not increase this burden.”

The American Diabetes Association and the European Association for the Study of Diabetes recommend metformin as the best glucose-lowering first-line drug. But many patients on metformin therapy alone fail to achieve optimal glycaemic control, and the relative merits of second-line drugs sulfonylureas and DPP-4 inhibitors have been debated. Previous studies have suggested that sulfonylureas used as add-ons to metformin therapy may increase cardiovascular risks[2],[3],[4]
, and a recent study raised concerns about an increased risk of heart failure in patients with type 2 diabetes treated with DPP-4 inhibitors[5]
. But there is a paucity of comparative data on these second-line drugs.

The Taiwanese study investigated the relative risk among patients with type 2 diabetes for all-cause death, MACEs, hospitalisation for heart failure and hypoglycaemia among 10,089 matched pairs of DPP-4 inhibitor users and sulfonylurea users. Participants were aged 20 years or older with a diagnosis of type 2 diabetes between March 2009 and June 2012, and follow-up continued until death or until the end of 2013.

DPP-4 inhibitors were associated with lower risks for all-cause death, stroke and hypoglycaemia compared with sulfonylureas, but had no effect on heart attack risk and hospitalisation for heart failure.

DPP-4 inhibitors improve glycaemic control by increasing the concentration of incretins — gut-derived peptides — which stimulate insulin secretion in a glucose-dependent manner. Although the precise mechanism behind the neuroprotective effects conferred by DPP-4 inhibitors in relation to stroke is unknown, the researchers suggest that increased expression of glucagon-like peptide-1 receptors on neurons, plus reduced microglial cell activation after a stroke, “might protect neurons against metabolic and oxidative stress and further limit infarction size”.

“Activation of the incretin pathway in neurons by DPP-4 inhibitors may also promote proliferation and neuronal differentiation of neural precursor cells into neurons and provide cellular protection,” the researchers add.

According to Diabetes UK, there are around 3.9 million people with diabetes in the UK — a figure expected to reach 5 million by 2025. This includes around 590,000 people with type 2 diabetes who do not realise they have it; 11.5 million people in the UK are at increased risk of getting type 2 diabetes; and about 90% of those diagnosed with diabetes in the UK have type 2 diabetes.


[1] Ou S-M, Shih C-J, Chao P-W et al. Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Annals of Internal Medicine 2015. doi:10.7326/M15-0308

[2] Roumie CL, Greevy RA, Grijalva CG et al. Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA 2014;311:2288-2296. doi:10.1001/jama.2014.4312

[3] Roumie CL, Hung AM, Greevy RA et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Annals of Internal Medicine 2012;157:601–610. doi:10.7326/0003-4819-157-9-201211060-00003

[4] Li Y, Hu Y, Ley SH et al. Sulfonylurea use and incident cardiovascular disease among patients with type 2 diabetes: prospective cohort study among women. Diabetes Care 2014;37:3106–3113. doi:10.2337/dc14-1306

[5] Scirica BM, Bhatt DL, Braunwald E et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New England Journal of Medicine 2013;369:1317–1326. doi:10.1056/NEJMoa1307684 

Last updated
The Pharmaceutical Journal, PJ, October 2015, Vol 295, No 7882;295(7882):DOI:10.1211/PJ.2015.20069558

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