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GLP-1 Receptor Agonist vs Insulin: Mortality Rate and Cardiovascular Risk

Does insulin cause more deaths and cardiovascular outcomes than GLP-1 agonist receptors?

Patients with type 2 diabetes mellitus experience increased risk of cardiovascular morbidity and mortality over time; treatment therefore needs to be addressed as disease progresses. Cardiovascular risks including body weight, blood pressure and lipids are some of the elements that need to be looked at. Normally patients start with oral antidiabetics drugs to help regulate hyperglycemia, followed by long acting insulin which causes hypoglycemia and weight gain. GLP-1 receptor agonist is believed to have cardio-protective effects through various mechanisms such as reduced body weight, adiposity, decreased blood pressure, improved endothelial and myocardial function, and improved functional recovery of failing and ischemic hearts. Others include increased diuresis, natriuresis, and reduced circulating lipids. Previous studies done reported drastic decreases in rates of heart failure, myocardial infarction and stroke in patients treated with exenatide for 31 days as compared to those treated with insulin.

The purpose of this study is to evaluate rates of HF, MI, stroke in patients managed on exenatide twice daily (EBID) and conventional oral anti- diabetic drugs (OADs) (EBID group), insulin plus OADs (insulin group), and those who changed medications between EBID and insulin or had combination of EBID and insulin. A retrospective longitudinal pharmaco-epidemiological study is done. Data was obtained from a large ambulatory care to evaluate the risks of HF, myocardial infarction and stroke established in type 2 diabetes patients. Inclusion criteria included; ≥18years of age, no missing data on age sex, ethnicity, smoking status, HbA1c and at least two consecutive prescriptions of EBID. Other criteria included complete information on even dates for HF, MI and stroke. Patients who received their first prescription of exenatide twice daily (EBID) or insulin between June 2005 and May 2009 with follow up data available until December 2012. The three treatment groups were a) insulin group, n = 28,551, b) EBID group, n = 2,804 and c) EBID +insulin group, n = 7,870. Laboratory measurements included measures of HbA1c within 3-month window prior to the index date. Information on OADs, anti-hypertensive and cardio-protective medications (CPMs) were obtained with dates of prescriptions. Multivariate Cox- regression models were used to evaluate the association of treatment groups with the risks of macrovascular events.

HF, MI and stroke were higher among patients in insulin group compared to those in the EBID or EBID + insulin groups. Proportion of patients with history of HF was higher in the insulin group (3.2%) than in the EBID group (1.7%) and EBID + insulin group (2.4%). Compared to insulin, patients in EBID and EBID+ insulin groups were 17.1, 4.1 and 5.7 respectively. Only 1% (n=381) of patients had a history of MI, most in the insulin group. Among those without MI history the rates of MI in the insulin, EBID and EBID+ insulin groups were 2.4, 0.95 and 0.99 respectively. For patients without history of cardiovascular and renal disease, compared to insulin group, patients in the EBID and EBID + insulin group had a 77% (HR CI: 0.06, 0.95) and 55% (HR CI: 0.28, 0.85) reduced risk of MI respectively. The rate of stroke was nearly threefold higher in the insulin compared to the other treatment groups.

GLP-1 agonist receptor EBID treatment with or without insulin was linked to reduced rates and risks of major macrovascular events. The comparative longitudinal study showed that patients with type 2 diabetes treated with EBID in addition to OADs have a lower rate and comparative risks of HF, MI and stroke than those treated with conventional combination treatment of insulin with OADs. 49 % and 36% of patients had HbA1c above 1053mg/L and 1150.2mg/L.  All these have set the background for inflammatory state, cardiac function impacting both diastolic and systolic heart failure, peripheral vascular function and blood pressure control and acute states of myocardial ischemia. Some of the weaknesses of this study include patients with incomplete information and a thorough matching process resulting in selection of optimally treated patients. Also patient’s information on socio-economic status was relevant in this study since EBID is expensive and most likely only individuals with good insurance could afford it.

Practice Pearls:     

  • Chronic hyperglycemic state is normally connected by dyslipidemia, hypertension, low grade systemic inflammation and oxidative stress which collectively result in high risk micro and macrovascular complication.
  • There is a CV potential benefit in treatment with GLP-1 agonist receptor agonist exenatide in type 2 diabetes
  • Since GLP-1 agonist receptor is a new drug its long term CV outcomes have not yet been established


Davies, M J et al. “Exenatide Compared with Long-Acting Insulin to Achieve Glycaemic Control with Minimal Weight Gain in Patients with Type 2 Diabetes: Results of the Helping Evaluate Exenatide in Patients with Diabetes Compared with Long-Acting Insulin (HEELA) Study.” Diabetes, Obesity & Metabolism 11.12 (2009): 1153–1162. PMC. Web. June 30 2016.

Nathan, David M. et al. “Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes.” Diabetes Care 32.1 (2009): 193–203. PMC. Web. June 30 2016.

Paul, Sanjoy K et al. “The Association of the Treatment with Glucagon-like Peptide-1 Receptor Agonist Exenatide or Insulin with Cardiovascular Outcomes in Patients with Type 2 Diabetes: A Retrospective Observational Study.” Cardiovascular Diabetology 14 (2015): 10. PMC. Web. June 30 2016.

American Diabetes Association. “Standards of Medical Care in Diabetes—2009.” Diabetes Care 32.Suppl 1 (2009): S13–S61. PMC. Web. June 30 2016.