Author + information
- Simon B. Dimmitt, MBBS, BMedSc(Hons)∗ (, )
- John B. Warren, MD,
- Jennifer H. Martin, MA MBChB, PhD and
- Hans G. Stampfer, MBBS
- ↵∗School of Medicine and Pharmacology, University of Western Australia, Suite 3, 10 McCourt Street, Subiaco, Western Australia 6008, Australia
The review by Waldrop et al. (1) may not have addressed all of the evidence summarized in a systematic review of 43 clinical trials and 12 observational studies (2) for increased cardiac failure with dipeptidyl peptidase-4 inhibitors (DPP-4Is). Glitazones also increase cardiac failure (3). Practitioners may be unaware that DPP-4I trials have failed to show improvements in any clinical outcomes. Side effects increase linearly with increasing dose, but with inhibitors, efficacy plateaus above the medium effective dose (ED50; the mean dose in the population that causes half maximal lowering of blood glucose concentration). Sitagliptin is prescribed at 50 to 100 mg (ED50: approximately 15 mg). Similarly, gliclazide is prescribed at 30 to 160 mg daily (ED50: approximately 20 mg) and pioglitazone at 15 to 45 mg (ED50: approximately 15 mg). Metformin, the only oral hypoglycemic which improves outcomes, is used below its ED50, approximately 2 g daily.
More intensive blood glucose lowering can increase cardiovascular events and total mortality (4). The lower glucoses may impair myocardial function or lower plasma oncotic pressure and contribute to pulmonary edema. Increased insulin can cause renal sodium retention (5).
Sulfonylureas, glitazones, and insulin have failed to reduce cardiovascular events, possibly partly because they cause weight gain, which, long-term, increases blood glucose, lipids, and blood pressure. The sodium-glucose–linked transporter 2 inhibitor (SGLT2-I) empagliflozin reduces weight (as does metformin), cardiac failure, and total mortality. Risk benefit in cardiac failure dictates that SGLT2-Is supplant gliptins. Favorable outcomes rather than glucose measurements should dictate management in type 2 diabetes mellitus.
Please note: Dr. Warren is Director of Consultancy, Medicines Assessment Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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