VARIATION Study: Investigator Insights
In the VARIATION study, basal insulin combined with a GLP-1 agonist compared favorably with other insulin regimens.
Quality of glucose, as measured by glucose variability and hypoglycemia, is one of the emerging hot topics in diabetes research as well as clinical management nowadays, especially after the surprising negative results of the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes; ClinicalTrials.gov identifier: NCT00000620) in 2008,1 in which more than three-quarters of the participants in the intensive glucose-lowering arm were on insulin treatment. We believe that the question of hypoglycemia and glucose variability, as it relates to the overall increased mortality in ACCORD, has not been adequately answered.
There is an emerging need to devise strategies to minimize hypoglycemia and glucose variability in people using insulin for management of their type 2 diabetes. The VARIATION study2 idea arose from a clinical observation that patients using the combination of basal insulin and glucagon-like peptide-1 (GLP-1) receptor agonists had minimal fluctuations in their glucometer recordings on their logbook compared with those on the “gold standard” regimen of basal-bolus insulin injections taken 4 times a day. Hence, we set out to investigate this clinical question of whether there is in fact a difference in glucose variability on continuous glucose monitoring between 4 commonly used injectable insulin regimens. We enrolled 160 “super-star” patients from 3 specialist clinics in Toronto, Canada, with average HbA1c values close to 7% so as to minimize confounding from hyperglycemia.
To provide perspective on the results of VARIATION, the lowest daily standard deviation of glucose for the combination GLP-1 receptor agonist and basal insulin among the 4 insulin regimens was expected; however, the lowest hypoglycemia end points (frequency, duration, or daily percentage of time) observed in this cohort were surprising. Whether GLP-1 receptor agonism plays a protective role in insulin-induced hypoglycemia needs to be investigated further in research studies. If time in range between 3.9 to 10 mmol/L (70 to 180 mg/dL) is chosen as the parameter to define good quality of glucose control, we found a spectrum of results in our study, ranging from 84% time in range for the basal plus GLP-1 receptor agonist cohort to 75% in the basal-bolus regimen cohort.2
In conclusion, we believe that the emerging preclinical and clinical data surrounding glucose variability and hypoglycemia calls for earnest scientific efforts to design a large, randomized outcomes trial to test the hypothesis that reduced glucose variability may have long-term cardiovascular benefit.
Harpreet Bajaj, MD, MPH, ECNU, FACE, is a clinical endocrinologist and epidemiologist at LMC Diabetes & Endocrinology in Brampton, Ontario, Canada. He is also a research associate at Leadership Sinai Centre for Diabetes at Mount Sinai Hospital in Toronto, Canada.
Disclosures: Dr Bajaj has received grants or personalfees,outside the submitted work, from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen Pharmaceutical, Merck & Co., Novo Nordisk, Sanofi, Pfizer, Takeda Pharmaceuticals, Valeant Pharmaceuticals, and Medtronic Inc.
- The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559. doi:10.1056/NEJMoa0802743.
- Bajaj HS, Venn K, Ye, C, et al. Lowest glucose variability and hypoglycemia are observed with the combination of a GLP-1 receptor agonist and basal insulin (VARIATION study) [published online December2, 2016]. Diabetes Care. doi:10.2337/dc16-1582.