Linagliptin and Glimepiride

According to current research, linagliptin had a significantly lower risk of hypoglycemia and adverse events in geriatric patients with type 2 diabetes. 

Diabetes prevalence increases with age. Approximately 27% of those above 65 in the United States have diabetes, specifically type 2 diabetes. However, clinical trials of glucose-lowering drugs have been inadequately examined in the older population, particularly those over 75. The problem arises when those older patients need treatment, and we know older patients tend to have a high prevalence of other comorbidities. In addition, safety is a significant concern within this population due to the risk of hypoglycemia which could have severe consequences such as cognitive impairment, falls, and traffic accidents. Linagliptin is a dipeptidyl peptidase-4 inhibitor, and glimepiride is a widely used second-generation sulfonylurea. These medications are often used as second-line for glucose-lowering regimens. Sulfonylureas are used primarily due to low cost; however, they are associated with increased hypoglycemia and weight gain. 

This trial, named the CAROLINA cardiovascular outcomes trial, sought to compare linagliptin with glimepiride concerning cardiovascular safety in geriatric patients with type 2 diabetes. Dr. Espeland and his colleagues submitted this research to the Journal of Diabetes, Obesity, and Metabolism to examine and summarize the benefits of using these drugs in this patient population. The name CAROLINA comes from the title Cardiovascular Outcome Study of Linagliptin verse Glimepiride in Type 2 Diabetes. They used a randomized, double-blind, active-controlled, noninferiority approach. Screening for this study lasted from November 2010 to December 2012 and was conducted at 607 hospitals in 43 countries. A total of 6033 participants were involved in this study. They ranged from 40 to 85 years of age, had type 2 diabetes and uncontrolled glycemia. Patients were randomly assigned to receive 5 mg of linagliptin or 1 to 4 mg of glimepiride. Elevated cardiovascular risk was defined by the following criteria: previous vascular disease, systolic blood pressure higher than 140, current smoker, more than one antihypertensive medication, and microvascular complications. The primary outcome was time to the occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The secondary outcomes were time to any confirmed cardiovascular events, fatal stroke, and fatal myocardial infarction. 

This study showed that, generally, the incidence of all cardiovascular and mortality outcomes was more significant among older patients in both treatment groups. About the primary outcome of time to the first occurrence, the hazard ratio for linagliptin compared to glimepiride was 0.98 (95.47% CI 0.84, 1.14), with no significant difference among the age groups. Similarly, linagliptin was comparable to glimepiride in regard to secondary outcomes. Mean HbA1c initially decreased more in the glimepiride group, but there were no significant differences over the whole trial among the groups. Fewer patients in the linagliptin group experienced hypoglycemia-related events than the glimepiride group. During the final assessment of the participants, 16.0% of the linagliptin group and 10.2% of the glimepiride group had an HbA1c of less than or equal to 7%. These results were also consistent throughout all age groups.  

In conclusion, the role of linagliptin and glimepiride in geriatric populations has not been thoroughly examined. This trial did show more effectiveness with linagliptin, with fewer adverse events such as hypoglycemia reported than glimepiride. Guidelines for older patients and glycemic control are typically less aggressive to avoid hypoglycemia, but more stringent targets may be more appropriate, specifically in non-frail elderly. The strengths of this study include the large number of participants, as well as the length of time the patients were observed and treated, with a mean period of six years. Also, this trial focused on elderly patients that were not extensively studied in the past. Limitations of this study include the researchers not assessing functional status and frailty before starting the research. Participants may have been healthier than typical patients seen in everyday practice. This may limit the generalizability of these findings.  

Practice Pearls: 

• Clinical trials of glucose-lowering drugs have been inadequately examined in the underrepresented older population, particularly those over 75 years of age. 
• This trial compared linagliptin with glimepiride concerning cardiovascular safety in geriatric patients with type 2 diabetes. 
• 16.0% of the linagliptin group and 10.2% of the glimepiride group had an HbA1c of less than or equal to 7% by the final assessment in the study.

“National Diabetes Statistics Report, 2020.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 11 Feb. 2020, link 

 Espeland, Mark A., et al. “Cardiovascular Outcomes and Safety with Linagliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Compared with the Sulphonylurea Glimepiride in Older People with Type 2 Diabetes: A Subgroup Analysis of the Randomized Carolina Trial.” Diabetes, Obesity and Metabolism, vol. 23, no. 2, 2020, pp. 569–580., link  

Kmeone Kingdom, MPH, PharmD Candidate, South College School of Pharmacy