2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin

Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012;380(9840):475-483.  

A recent position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) cites metformin as the optimal first-line drug for diabetes treatment. However, the statement acknowledges that limited data exist regarding treatments to be used beyond metformin.1   In this analysis, Gallwitz and colleagues compared two agents cited by ADA/EASD as treatment options for glucose lowering, a DPP-4 inhibitor, linagliptin, and a sulfonylurea, glimepiride, in a randomized, double-blind, active-controlled, non-inferiority trial.  

Subject profile:  

  • Aged 18-80 years  
  • Type 2 diabetes not at goal on metformin monotherapy: A1C 6.5%-10.0% (metformin alone) or 6.0%-9.0%  (on metformin + one other OAD)  
  • Receiving stable metformin dose 1,500 mg/day (or maximum tolerated dose <1,500 mg/day) alone or with another oral antidiabetic drug (OAD)  
  • BMI 40 kg/m2  

Subjects receiving metformin monotherapy at study outset were included in a 2-week open-label placebo-run-in; those receiving metformin + one other OAD participated in a 6-week washout period followed by the 2-week placebo run-in. Eligible subjects received linagliptin (5 mg once daily; n=777) or glimepiride (starting dose: 1 mg once daily; uptitrated in 1-mg increments to maximum dose of 4 mg once daily over 12 weeks; n=775) in a double-blind, double-dummy fashion over 2 years. Subjects were assigned to treatment via a random computer-generated sequence stratified by A1C (<8.5% vs 8.5%) and previous OAD use (metformin monotherapy vs metformin + another agent). If a subject had confirmed FPG >13.3 mmol/L at any visit or A1C >8.5% from Week 28 to Year 2, rescue treatment with pioglitazone could be initiated.  

Change in A1C from baseline to Year 2 was the study’s primary efficacy endpoint. Two key secondary endpoints were also examined: occurrence of hypoglycemic episodes up to 2 years and change in body weight from baseline to Year 2. Cardiovascular safety was assessed prospectively. Clinical characteristics, demographics, and cardiovascular risk factors were similar between groups.  

Results at Year 2 for the full analysis set (n=776 in the linagliptin group; n=775 in the glimepiride group):  

Primary endpoint  

Change in A1C from baseline to Year 2  

  • Linagliptin was noninferior to glimepiride in reducing A1C  
  • Adjusted mean changes from baseline in A1C were -0.16% for linagliptin and -0.36% for glimepiride; between-group difference was 0.20% (97.5% CI, 0.09-0.30; P=0.0004), which met non-inferiority criteria of 0.35%  

Secondary endpoints  

Occurrence of hypoglycemic episodes up to Year 2  

  • 7% of those in the linagliptin group vs 36%, in the glimepiride group; P<0.0001  
  • Severe hypoglycemia occurred among 1 subject in the linagliptin group vs 12 subjects in the glimepiride group  

Change in body weight from baseline to Year 2 (at baseline: 86.0 kg linagliptin; 87.0 kg glimepiride)*  

  • Decreased with linagliptin but increased with glimepiride: -1.4 kg vs +1.3 kg, respectively; treatment difference: -2.7 kg (97.5% CI, -3.2 to -2.2; P<0.0001)  

Cardiovascular safety  

Major CV events occurred among 2% of linagliptin-treated patients vs 3% of glimepiride-treated patients (RR, 0.46 [95% CI, 0.23-0.91; P=0.0213]); this finding was mainly due to significantly lower number of nonfatal strokes in the linagliptin group.  

Additional parameters at Year 2  

  • A1C <7%: 30% linagliptin vs 35% glimepiride  
  • A1C <6.5%: 12% linagliptin vs 16% glimepiride  
  • Decreases in FPG: -0.13 mmol/L (-2.34 mg/dL) linagliptin vs -0.48 mmol/L (-8.65 mg/dL) glimepiride; between-group difference 0.35 mmol/L (6.31 mg/dL; 95% CI, 0.14-0.57; P=0.0012)  
  • No substantial changes in lipid values  
  • Overall incidence of adverse events lower with linagliptin than glimepiride  

 *Linagliptin and glimepiride are not FDA-approved for weight loss  

1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.  

 

September 2012  

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

Related content: 

Read more about this study and additional cutting-edge diabetes data in the September 2012 issue of Clinical Insights® in Diabetes. Click here. 

Linagliptin vs Glimepiride for Type 2 Diabetes Not at Goal on Metformin Monotherapy: Design 

Linagliptin vs Glimepiride for Type 2 Diabetes Not at Goal on Metformin Monotherapy: Change in A1C from Baseline 

Linagliptin vs Glimepiride for Type 2 Diabetes Not at Goal on Metformin Monotherapy: Secondary Endpoints 

Linagliptin vs Glimepiride for Type 2 Diabetes Not at Goal on Metformin Monotherapy: CV Safety, Glucose, Adverse Events 

 

Last Modified: 3/23/2015