VARIATION: Combination Therapy Beneficial in Well-Controlled Type 2 Diabetes

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A combination of basal insulin plus a GLP-1 receptor agonist was associated with the lowest glucose variability.
A combination of basal insulin plus a GLP-1 receptor agonist was associated with the lowest glucose variability.

Read more about the VARIATION study findings, as discussed by researcher Hapreet Bajaj, MD, MPH, ECNU, FACE.

Compared with 3 other treatment regimens, combination therapy with basal insulin and a glucagon-like peptide 1 (GLP-1) receptor agonist was associated with the lowest glucose variability and incidence of hypoglycemia in patients with well-controlled type 2 diabetes, according to study results published in Diabetes Care.

As part of the VARIATION (Variability of Glucose in Patients with Type 2 Diabetes Treated with 4 Different Insulin Combination Regimens) study, Harpreet S. Bajaj, MD, MPH, from LMC Diabetes & Endocrinology in Ontario, Canada, and colleagues analyzed the glucose variability in 160 patients with type 2 diabetes from 3 different endocrinology centers over a 6-day masked period using continuous glucose monitoring (CGM). Patients were on 4 common insulin regimens:  basal insulin and oral antidiabetes medications, basal insulin and a GLP- receptor agonist, premixed insulin, and basal-bolus insulin.

Patients were aged 18 to 80 years with a body mass index (BMI) of 45 kg/m2 or lower. To qualify for study inclusion, patients had to be on a stable insulin regimen for at least 6 months and have a stable HbA1c value of 7.5% or lower (58 mmol/mol).

The researchers found that daily glucose standard deviation (SD) was significantly lower in the basal insulin plusGLP-1 receptor agonist treatment group compared with the basal insulin/oral medication group (P =.03), premixed insulin group (P = 0.01), and basal-bolus insulin group (P <.01), according to the study results. Daily glucose SD remained significantly low after adjusting for duration of type 2 diabetes, age, BMI, and HbA1c.

“A second important finding from our study is that for hypoglycemia, whether measured by frequency, duration, or daily percentage of time, the most favorable results were also consistently observed among the [basal insulin plus GLP-1 receptor agonist] cohort compared with the [premixed insulin] and [basal-bolus insulin] cohorts,” Dr Bajaj and colleagues wrote. “The [basal insulin plus oral medication] cohort also had numerically higher hypoglycemia parameters on CGM and [self-monitored blood glucose] compared with the [basal insulin plus GLP-1 receptor agonist] cohort, though these did not reach statistical significance.”

Despite the findings, Dr Bajaj and colleagues noted that the study results may not be applicable in a more generalized setting where patients with diabetes have suboptimal glycemic control, since the patients chosen in VARIATION were well-controlled and were managed in a public health care setting by well-resourced endocrinologists.

“However, the VARIATION study criteria were specifically chosen to minimize the impact of mean glucose control (and HbA1c) on [glucose variability] parameters among the 4cohorts,” Dr Bajaj and colleagues wrote. “It should be emphasized that despite the low SD values observed, our study found a significant difference among cohorts in all 3 measures of SD as well as in hypoglycemia outcomes.”

Disclosures: Dr Bajaj has received fees or grants from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen Pharmaceutical, Merck & Co, Novo Nordisk, Sanofi, Pfizer, Takeda Pharmaceuticals, Valeant Pharmaceuticals, and Medtronic Inc. Dr Aslam received fees or grants from Abbott, Eli Lilly and Company, Ionis Pharmaceuticals, Takeda Pharmaceuticals, Boehringer Ingelheim, and Sanofi.


  1. 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 December 2, 2016]. Diabetes Care. doi:10.2337/dc16-1582.
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