Gliptins, Glitazones Tied to Lower Cardiac Risk in UK Type 2 Diabetes Cohort

Marlene Busko

August 16, 2016

NOTTINGHAM, UK — In a population-based cohort of patients with type 2 diabetes who were seen in the past decade in clinical practices in the UK, those who received thiazolidinediones (TZDs or glitazones) or dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) alone or in combination therapy had a lower risk of heart failure, cardiovascular disease, and all-cause mortality compared with those who did not receive these drugs[1]. However, two experts caution that these results need to be taken in context with other studies.

The observational study reports that compared with patients who did not received gliptins, those who did had a significant 14% lower risk of HF and a significant 18% lower risk of all-cause mortality, but a similar risk of CVD.

Compared with patients who did not receive glitazones, those who did had a significant 23% to 26% lower risk of each of these three outcomes.

Thus, "these results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, may have implications for prescribing of diabetes drugs," Drs Julia Hippisley-Cox and Carol Coupland (University of Nottingham, UK) conclude, in their article published online July 13, 2016 in the BMJ.

However, Dr Shari D Bolen (MetroHealth System/Case Western Reserve University, Cleveland, OH), who recently coauthored an editorial about risks with gliptins[2], told heartwire from Medscape: "I am not convinced by this study that glitazones or gliptins do not cause heart failure. There are several randomized trials with better evidence indicating otherwise." This study may have been affected by drug misclassification bias. "Given this limitation, I do not think we can conclude anything on any of the clinical outcomes . . . in the study," she said.

Similarly, Dr Anne Peters (Keck School of Medicine, University of Southern California, Los Angeles) told heartwire , "I am surprised that TZDs didn't increase the risk for CHF, as they have in other trials. This should still be a concern."

"But I can tell you that for me, my practice of medicine has changed since we have data suggesting cardiovascular benefit of metformin, pioglitazone, empagliflozin, and liraglutide," she added.

32,000 Gliptin Users and 21,000 Glitazone Users

There is still uncertainty about the long-term safety of gliptins and glitazones alone and in combination with other diabetes drugs, Drs Hippisley-Cox and Coupland note.

For example, in SAVOR-TIMI, saxagliptin (Onglyza, AstraZeneca/Bristol-Myers Squibb) was associated with an increased risk of HF, but this was not seen with alogliptin (Nesina, Takeda Pharmaceuticals) in the EXAMINE trial or with sitagliptin (Januvia , Merck) in the TECOS trial. Pioglitazone was associated with an increase in risk of HF in some studies and with a lower risk of HF compared with rosiglitazone in other studies.

Thus, they carried out a cohort study to investigate the associations between new use of gliptins or glitazones and risks of HF, CVD, and all-cause mortality for patients with type 2 diabetes.

They identified 469,688 adult patients (aged 25 to 84) with type 2 diabetes who were seen in 1243 general practices in England between April 1, 2007 and January 31, 2015 and were part of the QResearch database.

A total of 58% of the patients received a prescription for one or more of the following diabetes drugs: metformin (55%), a sulfonylurea (29%), a glitazone (5%), a gliptin (7%), another oral diabetes drug (3%), or insulin (4%)—where prescriptions for glitazone, gliptin, and insulin were for new prescriptions.

Compared with a study by Eurich et al[3], this study had four times more gliptin users (32,500 patients), who were a decade older (mean age 63 vs 52), and it looked at a longer median exposure (5.7 years vs 2.5 years). "Our findings of a reduction in risk of all-cause mortality are relatively novel and deserve further investigation, especially as there was no overall reduction in cardiovascular events," Drs Hippisley-Cox and Coupland write.

This study also included 21,308 patients who received glitazones, primarily pioglitazone (in 90% of cases) with a mean exposure of 4.5 years. The decrease in HF among these glitazone users contrasts with the increase in HF in other studies, such as the PROactive study, possibly due to differences in the patient populations, the researchers suggest.

Since in clinical practice, gliptins or glitazones are included in guidelines as second-line treatments added to metformin or third-line treatments added to metformin and a sulfonylurea, it is important to know whether combination uses is associated with net harm or benefit, they add.

They found that compared with metformin monotherapy, dual therapy with metformin and a gliptin was associated with a 13% decreased risk of CVD and 20% decreased risk of all-cause mortality; and triple therapy with metformin, a sulfonylurea, and a gliptin was associated with a 24% decreased risk of all-cause mortality.

Similarly, compared with metformin monotherapy, dual therapy with metformin and a glitazone was associated with a 26% lower risk of HF and 40% lower risk of CVD and a borderline 14% lower risk of all-cause mortality. Triple treatment with metformin, a sulfonylurea, and a glitazone was associated with a 21% to 32% reduced risk of all three outcomes, compared with metformin alone.

Although according to the researchers, these results can help inform clinical practice, Bolen cautions that "while interesting, we will need to compare this with other additional studies to determine the true effects of these drugs alone and in combination on important clinical outcomes."

Hippisley-Cox is a codirector of QResearch and a paid director of ClinRisk. Coupland is a paid consultant statistician for ClinRisk.

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