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The Effects of Glucose-Lowering Agents on Mortality Rate

Metformin, sulfonylureas, and insulin studied in type 2 patients.

Glucose-lowering agents have a difficult prediction on the mortality of diabetic patients due to the characteristics of the disease state. There is limited data about the impact on survival these agents have. Sulfonylureas and insulin have been associated with increased risk of mortality in diabetic patients. Metformin has a lower mortality risk in patients with type 2 diabetes. In addition, the usefulness of statins for cardiovascular diseases that arise from type 2 diabetes has been highly debated. This study evaluated the mortality risk of glucose-lowering agents on patients with type 2 diabetes compared to control subjects. The study focused primarily on age of the patients and the concomitant use of statins.

This was a retrospective controlled cohort study. There were 115,896 patients who were selected for the study from the National Alliance of Christian Mutualities (NACM) in Belgium. The inclusion criteria for the study were that the patients needed be above the age of 18 and prescribed glucose lowering agents between the 1st of January 2003 to the 31st of December 2007. Eligible patients were assigned to cohorts depending on their glucose-lowering medications therapies. The three glucose-lowering agents taken into account for this study were metformin, sulfonylureas, and insulin. Every possible combination of the three drugs was defined as a study cohort.

Patients in the study and control groups were followed until death or a maximum of 5 years after inclusion. Patients who were treated with additional glucose-lowering agents after inclusion were additionally assigned to other combination cohorts. Control groups had similar observable characteristics as the study groups. They were sampled from the NACM who did not have any records of using any glucose lowering agents. For every patient in the study groups, five patients were assigned in the control group. They were matched exactly on age, gender, cardiovascular history, and year of they were enrolled in the study.

The study group with the youngest patients was the group with insulin monotherapy without cardiovascular risks (P < 0.001), followed by the group with metformin monotherapy without cardiovascular risks (P < 0.001). The oldest patients were in the group with sulfonylurea regardless of cardiovascular risks (P < 0.001). Patients with cardiovascular risks were generally older patients. Over the five-year follow-up, patients treated with metformin monotherapy showed no significant excess mortality when compared to the control group. In contrast, patients treated with sulfonylureas and insulin had a higher mortality rate when compared to their counter control groups. Mortality was highest in patients started on insulin (23.8%), followed by sulfonylureas (4.1%), and finally metformin (0.3%, although not significantly different). Patients who were in a combination of glucose-lowering agents also showed a higher excess mortality, when compared to the control groups. Among the combination groups, patients who had insulin in their regimen exhibited the highest increase in mortality rate. Age did not play much into the results. The age of the patients did not determine or change the mortality rates already determined by the glucose-lowering agents. However, statins played a significant role in determining the survival rates.

 

Patients on glucose lowering agents who received statin therapy had higher survival rates when compared to patients on glucose-lowering agents without statin therapy, irrespective of the cardiovascular risks. Patients on glucose-lowering agents and statin therapy with cardiovascular risks were observed to have a 57-64% lower mortality rate when compared to patients without statin therapy. Patients on glucose-lowering agents and statin therapy without cardiovascular risks were observed to have a 50-68% decrease in mortality rates when compared to patients without statin therapy.

This study determined that 5-year survival rates between glucose-lowering agents vary between the kinds of agents used. Age and statin therapy play a substantial role in determining the survival rate of individuals. Metformin was associated with the lowest mortality rate, followed by sulfonylureas, and then insulin.

Practice Pearls:

  • Quantification of survival rate on glucose-lowering agents is difficult due to the nature of type 2 diabetes.
  • Patients treated with metformin, sulfonylureas, and insulin were compared to determine the mortality rates caused by each agent.
  • Metformin had the lowest mortality rate. Sulfonylureas and insulin had increased mortality rates.

Claesen M, Gillard P, De smet F, Callens M, De moor B, Mathieu C. Mortality in Individuals Treated with Glucose Lowering Agents: a Large, Controlled Cohort Study. J Clin Endocrinol Metab. 2015; jc20153184.

Researched and prepared by Jennifer Zahn, Doctor of Pharmacy Candidate University Of South Florida College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE