Over the past three decades, we have seen a marked increase in prevalence of type 2 diabetes. What are the potential etiologies of this increase? Are they dietary or food density changes, changes in exercise, increased obesity, microbiome changes, or epigenetic changes 12? It is apparent that the vascular bed is clearly centered in the insulin-resistant complex. Unfortunately, cardiovascular disease continues to cause death in over 50% of type 2 diabetes patients. In addition, heart failure syndrome with preserved left ventricular function accounts for almost 50% of diabetes patient developing heart failure 13. At a more basic level, translational information in diabetes finds microRNAs as important regulators of hypoxia and growth factor pathways 14. Abnormalities of increased oxidative stress in diabetes, advanced glycosylation end products, reduced stem cells, vascular endothelial growth factor, and metabolic inflexibility at a cardiomyocyte level are among the targets for future research 15.
In summary, both trials of the new DPP-4 inhibitors have failed to show a reduction in cardiovascular events in type 2 diabetes patients. There was a significant increase in hospitalization for heart failure with saxagliptin but not alogliptin, a paradigm previously observed with the thiazolidinedione class of drugs. The reasons for increased heart failure admissions with DPP-4 inhibitors remain unclear. Could this be a play of chance or actually be an increase in heart failure due to DPP-4 inhibitor? Consideration of translational findings in animals have ranged from improvement in cardiac function 17 to a possible increased circulating blood volume from increased neuropeptide Y due to vasoconstriction of microcirculation 18. Further studies are needed to determine whether this is a problem with the drug characteristics or the drug class. Various studies on oral diabetes agents have similarly failed to consistently show a decrease in macrovascular outcomes. Current research studies in animals have not demonstrated structural cardiovascular harm, and neither the SAVOR nor EXAMINE trials showed an increase in cardiac mortality. Early diagnosis and initiation of treatment for type 2 diabetes patients may be a better strategy for reducing cardiovascular outcomes.
There are no conflicts of interest.
1. Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703–713[Erratum in BMJ
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonyl ureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837–853.
3. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003; 348:383–393.
4. Patil H, Al Badarin F, Al Shami H, Bhatti H, Lavie CJ, Bell DS, O’Keefe JH. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol. 2012; 110:826–833.
5. Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013; 11:CD008143.
6. Scirica B, Bhatt D, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al.. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes
in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369:1317–1326.
7. White W, Cannon C, Heller S, Nissen SE, Bergenstal RM, Bakris GL, et al.. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013; 369:1327–1335.
8. Gregg E, Li Y, Wang J, Burrows N, Ali M, Rolka, et al.. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014; 370:1514–1523.
9. White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Fleck P, et al.. EXamination of cArdiovascular outcoMes
with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011; 162:620–626.
10. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al.. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J. 2011; 162:818–825.e6.
11. White WB, Kupher K, Nissen S, Cushman W, Bakris G, Heller S, et al.. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. J Am Coll Cardiol. 2014; 6312_Sdoi: 10.1016/S0735-1097(14)60116-9.
12. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care. 2010; 33:2277–2284.
13. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002; 287:2570–2581.
14. Wang XH, Qian RZ, Zhang W, Chen SF, Jin HM, Hu RM. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin Exp Pharmacol Physiol. 2009; 36:181–188.
15. Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol. 2014; 34:1126–1135.
16. Aurigemma GP, Gaasch WH. Diastolic heart failure
. N Engl J Med. 2004; 351:1097–1105.
17. Aroor AR, Sowers JR, Bender SB, Nistala R, Garro M, Mugerfeld I, et al.. Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin resistant male zucker obese rats. Endocrinology. 2013; 154:2501–2513.
18. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010; 56:728–733.