Fewer MACE in Diabetic Patients Taking SGLT2 Inhibitors vs DPP-4 Inhibitors

Lower cardiovascular event rates were seen in patients both with and without a history of CVD. A new AHA statement weighs in.

Fewer MACE in Diabetic Patients Taking SGLT2 Inhibitors vs DPP-4 Inhibitors

Across a broad swath of patients, short-term use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor appears to reduce the risk of major adverse cardiovascular events, most notably cardiovascular death and heart failure, as compared to the other established class of second-line antidiabetic drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors. Those are the findings from a nonrandomized, “multidatabase” retrospective analysis combining patient data from Canada and the United Kingdom published last week in the BMJ.

Speaking with TCTMD, lead researcher Kristian B. Filion, PhD (McGill University, Montreal, Canada), pointed out that the major trials supporting the cardiovascular benefits of SGLT2 inhibitors (“gliflozins”) have used a placebo comparator and were in patients with established risk factors for cardiovascular disease.

“Our study confirmed that the cardiovascular benefits reported in clinical trials compared with placebo are present in a real-world setting when comparing SGLT2 inhibitors to DPP-4 inhibitors among patients with type 2 diabetes,” he said. While the current analysis was focused on reduction in MACE, Filion said “it's likely that the cardiovascular and renal benefits outweigh the potential adverse events that have been reported” in earlier series, including analyses by this same group at Canadian Network for Observational Drug Effect Studies (CNODES).

For their latest analysis, Filion and colleagues matched 209,867 patients taking a DPP-4 inhibitor (“gliptin”) with the same number of new SGLT2 inhibitor users using healthcare databases from seven Canadian provinces and the United Kingdom. Matching took into account exposure time to the comparator agent and whether patients were starting on an SGLT2 inhibitor or switching from a DPP-4 inhibitor. Included in the analysis for the former class were canagliflozin (Invokana; Janssen), dapagliflozin (Farxiga; AstraZeneca), and empagliflozin (Jardiance; Boehringer Ingelheim), while the DPP-4 inhibitors were alogliptin (Nesina; Perrigo), linagliptin (Tradjenta; Boehringer Ingelheim), saxagliptin (Onglyza; AstraZeneca), sitagliptin (Januvia; Merck), and vildagliptin (Galvus; Novartis); this last was only available in the United Kingdom.

Patients were followed for a mean of just under 1 year, at which time MACE rates per 1,000 person years were significantly higher for patients taking gliptins than for those on a gliflozin. For a range of secondary endpoints, event rates all favored SGLT2 inhibitors, with the exception of ischemic stroke. Here the numbers were lower with SGLT2 inhibitors but did not reach statistical significance.

Incidence Rates per 1000 Person-Years


SGLT2 Inhibitors

DPP-4 Inhibitors

Adjusted HR (95% CI)




0.76 (0.69-0.84)




0.82 (0.70-0.96)

CV Death



0.60 (0.54-0.67)

Heart Failure



0.43 (0.37-0.51)

All-Cause Mortality



0.60 (0.54-0.67)

Ischemic Stroke



0.85 (0.72-1.01)

Similar benefits in terms of MACE reduction (hazard ratio; 95% CI) were seen for the three SGLT2 inhibitors included in the analysis—canagliflozin (0.79; 0.66-0.94), dapagliflozin (0.73; 0.63-0.85), and empagliflozin (0.77; 0.68-0.87).

“It does illustrate that compared with an active comparator—and both of these are used as second-line therapy—the SGLT2 inhibitors are associated with reduced cardiovascular risks relative to the DPP-4 inhibitors. That's something that guideline writers and provincial and territorial drug plan managers may want to consider when making policy,” Filion said.

Importantly, he noted, the analysis showed that while the reduction in all-cause mortality appeared greater among patients with a history of CVD, a reduction in MACE was seen in patients both with and without a history of CVD.

AHA Statement Urges Uptake

A few days after the BMJ paper came out, the American Heart Association (AHA) released a scientific statement summarizing the evidence supporting the cardiovascular and renal benefits of SLGT2 inhibitors, as well as the glucagon-like peptide-1 (GLP-1) receptor agonists, which have also demonstrated cardiovascular benefits in clinical trials. The data support the “prompt and appropriate integration of these therapeutic classes in the management of patients with [type 2 diabetes] and [chronic kidney disease],” the statement reads.

In the same vein, the American College of Cardiology put out a “decision pathway” last month to guide physicians in the use of both agents.

“A collaborative treatment approach among primary care doctors and specialists in diabetes, cardiology, and kidney disease that, when indicated, includes treatment with these two classes of medications could add more heart- and kidney disease-free years and greatly extend survival for people with type 2 diabetes,” AHA writing committee chair Janani Rangaswami, MD (Thomas Jefferson University, Philadelphia, PA), said in a press statement. They add that in addition to patients with diabetes, in whom risks for cardiovascular and kidney disease should be monitored on an ongoing basis, two other groups with or without diabetes could also be considered for these agents: patients with heart failure and reduced ejection fraction and patients with chronic kidney disease.

“Currently in the US, primary care professionals or endocrinologists typically initiate the use of these medications in patients with type 2 diabetes, yet a more multispecialty approach that includes kidney and heart specialists could help more patients benefit from treatment,” the statement authors conclude.

Shelley Wood is Managing Editor of TCTMD and the Editorial Director at CRF. She did her undergraduate degree at McGill…

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  • Filion and Rangaswami had no conflicts of interest.