Background  
The long-acting basal insulin analogue insulin glargine is used to improve glycaemic control in people with type 2 diabetes (PWD2). Insulin glargine 100 U/mL (Gla-100) was shown to improve glycaemic control for PWD2 compared with standard-of-care in the 7-year follow-up from the ORIGIN trial (NCT00069784). More recently, a longer-acting insulin glargine 300 units/mL (Gla-300) was compared with Gla-100 in PWD2 in the non-inferiority EDITION-3 trial (NCT01676220); after 12 months, Gla-300 demonstrated similar glycaemic control compared with Gla-100.

Aim  
This study aimed to simulate the 7-year macrovascular and microvascular outcomes observed for Gla-100 in the ORIGIN trial, and to predict these outcomes for Gla-300 in adults with type 2 diabetes using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model.

Method  
The BRAVO diabetes model, a discrete-time, patient-level microsimulation model, was used to predict macrovascular and microvascular outcomes. Data for key modifiable risk factors (HbA1c, SBP, LDL, BMI and severe hypoglycemia) were used to model outcomes for Gla-100, based on the 7-year follow-up from the ORIGIN study. Relative treatment effects of Gla-300 on these risk factors, based on EDITION-3 data, were applied to the Gla-100 arm to estimate outcomes for Gla-300. Both arms were simulated using the BRAVO model to predict the occurrence of events, progression of risk factors, and mortality over a 7-year time horizon. Study outcomes of interest were all-cause mortality, cardiovascular disease (CVD) death, nonfatal myocardial infarction (MI), nonfatal or fatal MI, nonfatal stroke, nonfatal or fatal stroke, hospitalization for congestive heart failure (CHF), hospitalization, angina, end-stage renal disease (ESRD), major cardiovascular adverse events (MACE: includes nonfatal MI, nonfatal stroke, and CVD death), revascularization procedure, blindness, and nephropathy.

Results  
No meaningful differences were observed between the Gla-300 and Gla-100 arms in all-cause mortality, CVD death, nonfatal MI, nonfatal or fatal MI, nonfatal stroke, nonfatal or fatal stroke, hospitalization angina, ESRD, MACE, revascularization, blindness, and nephropathy ( Table ). However, based on the upper bound of the relative risk confidence interval, Gla-300 was predicted to be associated with marginally fewer hospitalizations for CHF than Gla-100.  
  
  


Table. 7-year incidence of microvascular and macrovascular outcomes.

[ Table Removed ]

  


Discussion  
Although there was no requirement to perform a cardiovascular outcome trial for the registration of Gla-300, results from this predictive 7-year model indicate that Gla-300 and Gla-100 are likely be associated with broadly equivalent cardiovascular outcomes in PWD2. A marginally lower risk of hospitalization for CHF, combined with a trend for lower point estimates of relative risk with Gla-300, may warrant further investigation.

This study was funded by Sanofi.



**Background**  
The long-acting basal insulin analogue insulin glargine is used to improve glycaemic control in people with type 2 diabetes (PWD2). Insulin glargine 100 U/mL (Gla-100) was shown to improve glycaemic control for PWD2 compared with standard-of-care in the 7-year follow-up from the ORIGIN trial (NCT00069784). More recently, a longer-acting insulin glargine 300 units/mL (Gla-300) was compared with Gla-100 in PWD2 in the non-inferiority EDITION-3 trial (NCT01676220); after 12 months, Gla-300 demonstrated similar glycaemic control compared with Gla-100.

**Aim**  
This study aimed to simulate the 7-year macrovascular and microvascular outcomes observed for Gla-100 in the ORIGIN trial, and to predict these outcomes for Gla-300 in adults with type 2 diabetes using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model.

**Method**  
The BRAVO diabetes model, a discrete-time, patient-level microsimulation model, was used to predict macrovascular and microvascular outcomes. Data for key modifiable risk factors (HbA1c, SBP, LDL, BMI and severe hypoglycemia) were used to model outcomes for Gla-100, based on the 7-year follow-up from the ORIGIN study. Relative treatment effects of Gla-300 on these risk factors, based on EDITION-3 data, were applied to the Gla-100 arm to estimate outcomes for Gla-300. Both arms were simulated using the BRAVO model to predict the occurrence of events, progression of risk factors, and mortality over a 7-year time horizon. Study outcomes of interest were all-cause mortality, cardiovascular disease (CVD) death, nonfatal myocardial infarction (MI), nonfatal or fatal MI, nonfatal stroke, nonfatal or fatal stroke, hospitalization for congestive heart failure (CHF), hospitalization, angina, end-stage renal disease (ESRD), major cardiovascular adverse events (MACE: includes nonfatal MI, nonfatal stroke, and CVD death), revascularization procedure, blindness, and nephropathy.

**Results**  
No meaningful differences were observed between the Gla-300 and Gla-100 arms in all-cause mortality, CVD death, nonfatal MI, nonfatal or fatal MI, nonfatal stroke, nonfatal or fatal stroke, hospitalization angina, ESRD, MACE, revascularization, blindness, and nephropathy ( Table ). However, based on the upper bound of the relative risk confidence interval, Gla-300 was predicted to be associated with marginally fewer hospitalizations for CHF than Gla-100.




Table. 7-year incidence of microvascular and macrovascular outcomes.

[ Table Removed ]

**Discussion**  
Although there was no requirement to perform a cardiovascular outcome trial for the registration of Gla-300, results from this predictive 7-year model indicate that Gla-300 and Gla-100 are likely be associated with broadly equivalent cardiovascular outcomes in PWD2. A marginally lower risk of hospitalization for CHF, combined with a trend for lower point estimates of relative risk with Gla-300, may warrant further investigation.

This study was funded by Sanofi.

7-year Simulation of Clinical Outcomes In People With Type 2 Diabetes Treated With Insulin Glargine 300 U/mL vs 100 U/mL