The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. OBJECTIVE To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.DESIGN, SETTING, AND PARTICIPANTS Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020 follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.INTERVENTIONS Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. MAIN OUTCOMES AND MEASURESThe primary end point was mean change from baseline in glycated hemoglobin A 1c (HbA 1c ) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA 1c levels. RESULTS Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA 1c , 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA 1c change from baseline was −2.40% with 10-mg tirzepatide and −2.34% with 15-mg tirzepatide vs −0.86% with placebo (10 mg: difference vs placebo, −1.53% [97.5% CI, −1.80% to −1.27%]; 15 mg: difference vs placebo, −1.47% [97.5% CI, −1.75% to −1.20%]; P < .001 for both). Mean HbA 1c change from baseline was −2.11% with 5-mg tirzepatide (difference vs placebo, −1.24% [95% CI, −1.48% to −1.01%]; P < .001]). Mean body weight change from baseline was −5.4 kg with 5-mg tirzepatide, −7.5 kg with 10-mg tirzepatide, −8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, −7.1 kg [95% CI, −8.7 to −5.4]; 10 mg: difference, −9.1 kg [95% CI, −10.7 to −7.5]; 15 mg: difference, −10.5 kg [95% CI, −12.1 to −8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA 1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.

Background & AimsNon‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH.Methods & ResultsHepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA‐mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2‐LX2 Coculture studies. In mice with choline‐deficient high‐fat diet‐induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride‐induced fibrosis model.ConclusionsSaroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.

Aims To evaluate adherence, persistence, glycaemic control and costs at 12‐month follow‐up for patients initiating dulaglutide versus liraglutide or exenatide once weekly. Materials and methods The present retrospective observational claims study included patients with type 2 diabetes (T2D) and ≥ 1 pharmacy claim for dulaglutide, liraglutide or exenatide once weekly from the HealthCore Integrated Research Database. Adherence was defined as proportion of days covered ≥80%, and persistence was measured by time to discontinuation of index therapy. Change from baseline in glycated haemoglobin (HbA1c) concentration was assessed in a subset with pre‐ and post‐index HbA1c results. Propensity scores were used to match the cohorts. Results The baseline characteristics were balanced for the matched cohorts, dulaglutide versus liraglutide (n = 2471) and dulaglutide versus exenatide once weekly (n = 1891). Among those initiating dulaglutide there was a significantly higher proportion of adherent patients compared with the groups initiating liraglutide (51.2% vs. 38.2%; P < 0.001) and exenatide once weekly (50.7% vs. 31.9%; P < 0.001). At 12 months, 55% of patients in the dulaglutide group versus 43.8% in the liraglutide group (P < 0.001), and 54.9% in the dulaglutide versus 34.4% in the exenatide once‐weekly group (P < 0.001) were persistent. The dulaglutide group had a significantly greater reduction in HbA1c than the liraglutide group (−34.24 vs. −31.94 mmol/mol; P = 0.032), and a greater, but nonsignificant, reduction in HbA1c than the exenatide once‐weekly group (−34.46 vs. −31.94 mmol/mol; P = 0.056). The diabetes‐related total costs were not significantly different between the dulaglutide and the liraglutide group ($16,174 vs. $16,694; P = 0.184), and were significantly higher for dulaglutide than for exenatide once weekly ($15,768 vs. $14,615; P = 0.005). Conclusions Adherence and persistence are important considerations in patient‐centric treatment selection for patients with T2D. Higher adherence and persistence for dulaglutide compared with liraglutide or exenatide once weekly are relevant criteria when choosing glucagon‐like peptide‐1 receptor agonist treatment for patients with T2D.

AimsTo report 1-year clinical and economic outcomes from the retrospective DISPEL (Dulaglutide vs Basal InSulin in Injection Naïve Patients with Type 2 Diabetes: Effectiveness in ReaL World) Study.Materials and methodsThis observational claims study included patients with type 2 diabetes (T2D) and ≥1 claim for dulaglutide or basal insulin between November 2014 and April 2017 (index date=earliest fill date). Propensity score matching was used to address treatment selection bias. Change from baseline in hemoglobin A1c (HbA1c) was compared between the matched cohorts using analysis of covariance; diabetes-related costs were analyzed using generalized linear models.ResultsMatched cohorts (903 pairs total; 523 pairs with complete cost data) were balanced in baseline characteristics with mean HbA1c 8.6%, mean age 54 years. At 1 year postindex, dulaglutide patients had significantly greater reduction in HbA1c than basal insulin (−1.12% vs −0.51%, p<0.01), lower medical costs ($3753 vs $7604, p<0.01), higher pharmacy costs ($9809 vs $6175, p<0.01), and similar total costs ($13 562 vs $13 779, p=0.76). Medical and total costs per 1% HbA1c reduction were lower for dulaglutide than basal insulin (medical: $3128 vs $12 673, p<0.01; total: $11 302 vs $22 965, p<0.01), while pharmacy costs per 1% HbA1c reduction were lower without reaching statistical significance ($8174 vs $10 292, p=0.15).ConclusionsIn this real-world study, patients with T2D initiating dulaglutide demonstrated greater HbA1c reduction compared with those initiating basal insulin. Although total diabetes-related costs were similar, the total diabetes-related costs per HbA1c reduction were lower for dulaglutide, highlighting the importance of evaluating effectiveness along with the economic impact of medications.

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AimsTo assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorized by subgroups of baseline glycated haemoglobin (HbA1c; ≤9% and >9% [≤74.9 and >74.9 mmol/mol]), age (<65 and ≥65 years), and duration of diabetes (<10 and ≥10 years) at 6 months in patients with type 2 diabetes (T2D).Materials and methodsThis pooled analysis was conducted in a population of patients with T2D with similar baseline characteristics who were included in the AWARD‐4 and AWARD‐9 clinical trials and randomized to dulaglutide 1.5 mg (pooled mean baseline age 59 years, duration of diabetes 13 years, HbA1c 8.4% [68.3 mmol/mol]). Weight and hypoglycaemia were analysed by individual trial. In AWARD‐4, dulaglutide plus lispro three times daily was assessed against glargine plus lispro three times daily. In AWARD‐9, dulaglutide added to glargine was assessed against placebo added to glargine. Insulins were titrated to target in both trials.ResultsA total of 445 patients were included in this analysis (73% with HbA1c ≤9%, 27% [≤74.9 mmol/mol] with HbA1c >9% [>74.9 mmol/mol]; 70% aged <65 years, 30% aged ≥65 years; 36% with duration of diabetes <10 years, 64% with duration of diabetes ≥10 years). At 6 months, dulaglutide 1.5 mg significantly reduced HbA1c in all subgroups (P < .001), with the highest reduction observed in patients with baseline HbA1c >9% (>74.9 mmol/mol) (range − 1.3% to −2.5% [−14.2 to −27.3 mmol/mol]). The incidence rates of documented symptomatic and severe hypoglycaemia were similar in all subgroups in both trials. The most common adverse events observed in each trial were gastrointestinal in nature.ConclusionDulaglutide 1.5 mg combined with basal or prandial insulin is efficacious for patients with T2D irrespective of age, duration of diabetes or baseline HbA1c.

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Aim To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. Materials and Methods The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS‐2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin‐only treated patients were used for primary analysis. Results The SURPASS‐2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin‐only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of −0.36% (95% confidence interval [CI] −0.63, −0.09) and −0.4% (95% CI −0.67, −0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of −3.15 kg (95% CI −4.84, −1.46) and −5.15 kg (95% CI −6.85, −3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. Conclusions In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head‐to‐head clinical trial.