HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea.

AIMS/HYPOTHESIS: The aim of this study was to compare the efficacy and safety of once-weekly albiglutide with once-daily insulin glargine (A21Gly,B31Arg,B32Arg human insulin) in patients with type 2 diabetes inadequately controlled on metformin with or without sulfonylurea. METHODS: This was a randomised, open-label, multicentre (n = 222), parallel-group, non-inferiority out-patient clinical trial, with 779 patients enrolled in the study. The study was conducted in 222 centres located in four countries. Patients aged ≥18 years with type 2 diabetes treated with metformin (±sulfonylurea) for at least 3 months with a baseline HbA1c 7.0-10.0% (53.0-85.8 mmol/mol) were randomly assigned (2:1) via a computer-generated randomisation sequence with a voice response system to receive albiglutide (30 mg once a week, n = 504) or insulin glargine (10 U once a day, n = 241) added to current therapy. Participants and investigators were not masked to treatment assignment. Doses of each medication were adjusted on the basis of the glycaemic response. The primary endpoint was change from baseline in HbA1c at week 52. RESULTS: In the albiglutide group, HbA1c declined from 8.28 ± 0.90% (67.0 ± 9.8 mmol/mol) (mean ± SD) at baseline to 7.62 ± 1.12% (59.8 ± 12.2 mmol/mol) at week 52. A similar reduction occurred in the insulin glargine group (8.36 ± 0.95% to 7.55 ± 1.04% [67.9 ± 10.4 to 59.0 ± 11.4 mmol/mol]). The model-adjusted treatment difference of 0.11% (95% CI -0.04%, 0.27%) (1.2 mmol/mol [95% CI -0.4, 3.0 mmol/mol]) indicated non-inferiority of albiglutide to insulin glargine based on the pre-specified non-inferiority margin of 0.3% (3.3 mmol/mol, p = 0.0086). Body weight increased in the insulin glargine group and decreased in the albiglutide group, with a mean treatment difference of -2.61 kg (95% CI -3.20, -2.02; p < 0.0001). Documented symptomatic hypoglycaemia occurred in a higher proportion of patients in the insulin glargine group than in the albiglutide group (27.4% vs 17.5%, p = 0.0377). CONCLUSIONS/INTERPRETATION: Albiglutide was non-inferior to insulin glargine at reducing HbA1c at week 52, with modest weight loss and less hypoglycaemia. Both drugs were well tolerated. Albiglutide may be considered an alternative to insulin glargine in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00838916 (completed) FUNDING: This study was planned and conducted by GlaxoSmithKline.

Three-year data from 5 HARMONY phase 3 clinical trials of albiglutide in type 2 diabetes mellitus: Long-term efficacy with or without rescue therapy.

AIMS: Diabetes therapies that provide durable glycaemic control for people with type 2 diabetes mellitus (T2DM) are needed. We present efficacy results of albiglutide, a glucagon-like peptide-1 receptor agonist, in people with T2DM over a 3-year period. METHODS: Five of the 8 HARMONY phase 3 trials, comparing albiglutide with other therapies or placebo across a spectrum of clinical care, lasted for a preplanned 3years. Participants with uncontrolled hyperglycaemia who met predetermined criteria could receive rescue medication. The ability to remain on study medication without needing additional rescue was an efficacy measure. Glycaemic measures and body weight were analysed in 2 populations: those who remained rescue-free and all participants. RESULTS: Participants (n=3132) were randomised to albiglutide or comparator. A greater proportion of participants who received albiglutide remained rescue-free (55-71%) compared with placebo (35-51%; p<0.001 to p=0.002). The proportion of rescue-free participants with albiglutide did not differ from glimepiride or insulin glargine, was higher than with sitagliptin (p=0.013), and lower than with pioglitazone (p=0.045). At 3years, albiglutide was associated with clinically significant reductions in hyperglycaemia (eg, rescue-free participants: HbA1c -0.52% [SE0.11] to -0.98% [0.12]; -5.7mmol/mol [1.2] to -10.7mmol/mol [1.3] and all participants: HbA1c -0.29% [0.11] to-0.92% [0.13]; -3.2mmol/mol [1.2] to -10.1mmol/mol [1.4]). Albiglutide was also associated with modest reductions in body weight vs pioglitazone, glimepiride, and insulin glargine, which were associated with weight gain. CONCLUSION: These 3-year efficacy data support long-term use of albiglutide in the management of people with T2DM. ClinicalTrials.gov NCT00849056, NCT00849017, NCT00838903, NCT00838916, NCT00839527.

Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study.

OBJECTIVE: To compare the effects of rosiglitazone added to metformin with dose escalation of metformin on cardiovascular risk biomarkers in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Cardiovascular biomarkers were assessed in a sub-population of 122 subjects with type 2 diabetes mellitus (mean age 54.6 and 56.0 years, BMI 34.7 and 32.1 kg/m2; for the rosiglitazone plus metformin and metformin groups, respectively) from the multicenter (63 centers in the USA), double-blind, randomized parallel-group Escalation of Metformin theraPy vs. Initiation of Rosiglitazone Early (EMPIRE) study. Treatment group sizes were slightly imbalanced owing to central, rather than local, randomization. Subjects receiving metformin 1000 mg/day at baseline were randomized to rosiglitazone 4 mg/day plus metformin 1000 mg/day (RSG + MET) or metformin 1500 mg/day (up-titrated MET) for 24 weeks. At 8-weeks, rosiglitazone was increased to 8 mg/day in RSG + MET recipients and metformin to 2000 mg/day in up-titrated MET recipients. RESULTS: Reductions from baseline in HbA1c at week 24 (mean +/- SD) occurred in both groups (RSG + MET: -0.61% +/- 1.16%; up-titrated MET: -0.65% +/- 1.18%). Post-prandial glucose levels (AUC(0-3h)) decreased with RSG + MET (-3.5 mmol/L.h; 95% confidence interval [CI]: -5.2 to -1.8) and up-titrated MET (-1.3 mmol/L.h; 95% CI: -3.8 to 1.1). Homeostasis Model Assessment (HOMA)-estimated insulin sensitivity increased by 37.7% (95% CI: 22.8 to 54.5) in RSG + MET and 6.9% (95% CI: -6.2 to 21.9) in up-titrated MET recipients. RSG + MET reduced C-reactive protein (CRP; -23.9%; 95% CI: -40.4 to -2.8), plasminogen activator inhibitor-1 (PAI-1) activity (-30.1%; 95% CI: -44.5 to -11.9), PAI-1 antigen (-15.5%; 95% CI: -28.3 to -0.3) and matrix metalloproteinase-9 (MMP-9; -13.8%; 95% CI: -25.1 to -0.9), but increased tumor necrosis factor-alpha (TNF-alpha; 27.0%; 95% CI: 6.8 to 50.9). Corresponding values for up-titrated MET were CRP -9.3% (95% CI: -36.9 to 30.2), PAI-1 activity -7.2% (95% CI: -28.2 to 20.0), PAI-1 antigen -1.5% (95% CI: -17.4 to 17.5), MMP-9 29.0% (95% CI: -1.3 to 68.6) and TNF-alpha -6.0% (95% CI: -22.0 to 13.2). CONCLUSIONS: These results suggest that rosiglitazone plus metformin has positive cardiovascular effects against a background of similar glycemic improvements.