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10-23-2017 | Insulin | Review | Article

Insulin and Its Cardiovascular Effects: What Is the Current Evidence?

Journal: Current Diabetes Reports

Authors: Sahana Pai Dongerkery, Pamela R. Schroeder, Mansur E. Shomali

Publisher: Springer US



Purpose of Review

In this article, we examine the nature of the complex relationship between insulin and cardiovascular disease. With metabolic abnormalities comes increased risk for cardiovascular complications. We discuss the key factors implicated in development and progression of cardiovascular disease, its relationship to insulin therapy, and what can be learned from large, recent cardiovascular outcome studies.

Recent Findings

Preclinical studies suggest that insulin has positive effects of facilitating glucose entry into cells and maintaining euglycemia and negative effects of favoring obesity and atherogenesis under certain conditions. Confounding this relationship is that cardiovascular morbidity is linked closely to duration and control of diabetes, and insulin is often used in patients with diabetes of longer duration. However, more recent clinical studies examining the cardiovascular safety of insulin therapy have been reassuring.


Diabetes and cardiovascular outcomes are closely linked. Many studies have implicated insulin resistance and hyperinsulinemia as a major factor for poor cardiovascular outcomes. Additional studies link the anabolic effects of therapeutic insulin to weight gain, along with hypoglycemia, which may further aggravate cardiovascular risk in this population. Though good glycemic control has been shown to improve microvascular risks in type 1 and type 2 diabetes, what are the known cardiovascular effects of insulin therapy? The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes. Recent studies have demonstrated that ultra-long-acting insulin analogs like insulin degludec are non-inferior to insulin glargine with regard to cardiovascular outcomes.
van Dieren S, Beulens JW, van der Schouw YT, Grobbee DE, Neal B. The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil. 2010;17(Suppl 1):S3–8. https://​doi.​org/​10.​1097/​01.​hjr.​0000368191.​86614.​5a. PubMed
Dailey G. Overall mortality in diabetes mellitus: where do we stand today? Diabetes Technol Ther. 2011;13(Suppl 1):S65–74. https://​doi.​org/​10.​1089/​dia.​2011.​0019. PubMed
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39. https://​doi.​org/​10.​1056/​NEJMoa0808431. CrossRefPubMed
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72. https://​doi.​org/​10.​1056/​NEJMoa0802987. CrossRefPubMed
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59. https://​doi.​org/​10.​1056/​NEJMoa0802743. CrossRefPubMed
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.
Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC study 30-year follow-up. Diabetes Care 2016;39:686–93. doi: https://​doi.​org/​10.​2337/​dc15-1990
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89. https://​doi.​org/​10.​1016/​S0140-6736(05)67528-9. CrossRefPubMed
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22. https://​doi.​org/​10.​1056/​NEJMoa1603827. CrossRefPubMedPubMedCentral
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. https://​doi.​org/​10.​1056/​NEJMoa1504720. CrossRefPubMed
Neal B, Perkovic V, Mahaffey KW, de ZD, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; https://​doi.​org/​10.​1056/​NEJMoa1611925.
•• Lane W, Bailey TS, Gerety G, Gumprecht J, Philis-Tsimikas A, Hansen CT, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA. 2017;318:33–44. https://​doi.​org/​10.​1001/​jama.​2017.​7115. Treatment with insulin degludec was associated with a reduced rate of hypoglycemic episodes in people with type 1 diabetes CrossRefPubMed
•• Wysham C, Bhargava A, Chaykin L, de la Rosa R, Handelsman Y, Troelsen LN, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA. 2017;318:45–56. https://​doi.​org/​10.​1001/​jama.​2017.​7117. Treatment with insulin degludec was associated with a reduced rate of hypoglycemic episodes in people with type 2 diabetes CrossRefPubMed
•• Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017; https://​doi.​org/​10.​1056/​NEJMoa1615692. Treatment with insulin degludec was noninferior to insulin glargine with respect to the incidence of cardiovascular events
Luan FL, Nguyen K. Intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1519–20. CrossRefPubMed
Riddle MC, Ambrosius WT, Brillon DJ, Buse JB, Byington RP, Cohen RM, et al. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care. 2010;33:983–90. https://​doi.​org/​10.​2337/​dc09-1278. CrossRefPubMedPubMedCentral
Muniyappa R, Yavuz S. Metabolic actions of angiotensin II and insulin: a microvascular endothelial balancing act. Mol Cell Endocrinol. 2013;378:59–69. https://​doi.​org/​10.​1016/​j.​mce.​2012.​05.​017. CrossRefPubMed
Manrique C, Lastra G, Sowers JR. New insights into insulin action and resistance in the vasculature. Ann N Y Acad Sci. 2014;1311:138–50. https://​doi.​org/​10.​1111/​nyas.​12395. CrossRefPubMedPubMedCentral
Potenza MA, Addabbo F, Montagnani M. Vascular actions of insulin with implications for endothelial dysfunction. Am J Physiol Endocrinol Metab. 2009;297:E568–77. https://​doi.​org/​10.​1152/​ajpendo.​00297.​2009. CrossRefPubMed
Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev. 2006;22:423–36. https://​doi.​org/​10.​1002/​dmrr.​634. CrossRefPubMed
Ziegler D. Type 2 diabetes as an inflammatory cardiovascular disorder. Curr Mol Med. 2005;5:309–22. CrossRefPubMed
Cleland SJ, Petrie JR, Ueda S, Elliott HL, Connell JM. Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. Clin Exp Pharmacol Physiol. 1998;25:175–84. CrossRefPubMed
Schnell O, Cappuccio F, Genovese S, Standl E, Valensi P, Ceriello A. Type 1 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2013;12:156. https://​doi.​org/​10.​1186/​1475-2840-12-156. CrossRefPubMedPubMedCentral
Amour J, Brzezinska AK, Jager Z, Sullivan C, Weihrauch D, Du J, et al. Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms. Anesthesiology. 2010;112:576–85. https://​doi.​org/​10.​1097/​ALN.​0b013e3181cded1f​. CrossRefPubMedPubMedCentral
Reichard P, Britz A, Cars I, Nilsson BY, Sobocinsky-Olsson B, Rosenqvist U. The Stockholm Diabetes Intervention Study (SDIS): 18 months’ results. Acta Med Scand. 1988;224:115–22. CrossRefPubMed
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–8. https://​doi.​org/​10.​1056/​NEJMoa1003795. CrossRefPubMed
Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes. 2014;63:1738–47. https://​doi.​org/​10.​2337/​db13-0468. CrossRefPubMed
•• Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28. https://​doi.​org/​10.​1056/​NEJMoa1203858. In this study, individuals with prediabetes or early diabetes were treated with insulin glargine U100 or standard of care. No significant differences in cardiovascular outcomes were found in the two groups CrossRefPubMed
Hanefeld M, Monnier L, Schnell O, Owens D. Early treatment with basal insulin glargine in people with type 2 diabetes: lessons from ORIGIN and other cardiovascular trials. Diabetes Ther. 2016;7:187–201. https://​doi.​org/​10.​1007/​s13300-016-0153-3. CrossRefPubMedPubMedCentral
Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10:711–22. https://​doi.​org/​10.​1038/​nrendo.​2014.​170. CrossRefPubMed