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Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

ABSTRACT: To evaluate the efficacy and safety of adding insulin degludec (IDeg) to treatment in patients with type 2 diabetes receiving liraglutide and metformin and qualifying for treatment intensification because of inadequate glycaemic control.In this 26-week, double-blind trial, patients who still had inadequate glycaemic control after a 15-week run-in period with initiation and dose escalation of liraglutide to 1.8?mg in combination with metformin (?1500?mg) were randomized to addition of once-daily IDeg ('IDeg add-on to liraglutide' arm; n?=?174) or placebo ('placebo add-on to liraglutide' arm; n?=?172), with dosing of both IDeg and placebo based on titration guidelines.At 26?weeks, the mean change in glycated haemoglobin level was greater in the IDeg add-on to liraglutide arm (-1.04%) than in the placebo add-on to liraglutide arm (-0.16%; p?

SUBMITTER: Aroda VR

PROVIDER: S-EPMC5074260 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

Aroda V R VR Bailey T S TS Cariou B B Kumar S S Leiter L A LA Raskin P P Zacho J J Andersen T H TH Philis-Tsimikas A A

Diabetes, obesity & metabolism 20160502 7

<h4>Aim</h4>To evaluate the efficacy and safety of adding insulin degludec (IDeg) to treatment in patients with type 2 diabetes receiving liraglutide and metformin and qualifying for treatment intensification because of inadequate glycaemic control.<h4>Methods</h4>In this 26-week, double-blind trial, patients who still had inadequate glycaemic control after a 15-week run-in period with initiation and dose escalation of liraglutide to 1.8 mg in combination with metformin (≥1500 mg) were randomize ...[more]

PMID: 26990378

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Project description:BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879.

Project description:Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce glycated hemoglobin (HbA1c), but randomized controlled trial data on their combined use are limited. The LIRA-ADD2SGLT2i trial compared the effect on glycemic control of liraglutide 1.8 mg/day (a GLP-1 analog) vs placebo as add-on to SGLT2i ± metformin in patients with type 2 diabetes (T2D). In this phase 3b trial, patients with T2D on a stable dose of SGLT2i ± metformin and with HbA1c 7.0-9.5% were randomized 2:1 to add either liraglutide 1.8 mg/day or placebo. Exclusion criteria included a history of diabetic ketoacidosis (DKA) while being treated with SGLT2i and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. The primary endpoint was change in HbA1c from baseline at 26 weeks; also assessed after 26 weeks were change in body weight, the proportion of patients achieving HbA1c <7%, and safety. All were analyzed regardless of premature trial product discontinuation or initiation of glucoselowering rescue medication. Overall, 412 patients were screened, 303 were randomized and 280 (92.4%) completed treatment (92.1% with liraglutide, 93.0% with placebo). Baseline characteristics were balanced between treatment groups: mean HbA1c 8.0%, mean body weight 91.1 kg, mean duration of diabetes 9.9 years. At week 26, the mean change in HbA1c from baseline with liraglutide was 0.98% (n=203) vs 0.30% with placebo (n=100) (estimated treatment difference [ETD]: 0.68%, 95% confidence interval [CI]: 0.89, 0.48; p<0.001). The mean change in body weight from baseline with liraglutide was -2.81 kg vs 1.99 kg with placebo (ETD: 0.82 kg; 95% CI: -1.73, 0.09, p=0.077). In the liraglutide group, 51.8% of patients achieved HbA1c <7.0% vs 23.2% in the placebo group (odds ratio: 5.1, 95% CI: 2.67, 9.87; p<0.001). A higher proportion of patients in the liraglutide group reported ≥1 treatment-emergent adverse event (AE) than in the placebo group (66.3% vs 47.0%). Nausea was the most frequent AE, occurring in 26.2% of the liraglutide group and 6.0% of the placebo group, and it generally had early onset in the initial 4 weeks and was transient. Similar incidences of hypoglycemic episodes were reported in both groups (8.9% with liraglutide vs 8.0% with placebo); none were severe. The proportion of patients reporting serious AEs was low in both groups (liraglutide 2.5% vs placebo 1.0%). No fatalities occurred in either group and there were no reports of acute renal failure, DKA, diabetic foot ulcers or amputations with liraglutide in combination with SGLT-2i. In patients with T2D, the addition of liraglutide to SGLT2i therapy (± metformin) provided superior glycemic control vs placebo, and had a safety profile consistent with the known safety profile of both drug classes. The LIRA-ADD2SGLT2i is registered with ClinicalTrials.gov NCT02964247.

Project description:IntroductionThe progressive nature of type 2 diabetes necessitates treatment intensification. This often involves intensification with oral antidiabetic drugs (OADs) initially, followed by other agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), with the majority of patients eventually requiring insulin therapy. Therefore, this trial aimed to investigate the efficacy of IDegLira (combination of insulin degludec and liraglutide) in controlling glycemia in adults with type 2 diabetes who were inadequately controlled on a GLP-1RA and OADs.MethodsIn this 26-week open-label phase 3b trial, patients on maximum-dose GLP-1RA therapy (liraglutide once daily or exenatide twice daily) with metformin alone or with pioglitazone and/or sulfonylurea were randomized 2:1 to IDegLira once daily (n = 292) or to unchanged GLP-1RA therapy (n = 146), continuing OADs at the pre-trial dose.ResultsAfter 26 weeks, HbA1c reductions were superior with IDegLira versus unchanged GLP-1RA; estimated treatment difference -0.94% (-10.3 mmol/mol), p < 0.001. Mean HbA1c reduced from 7.8% to 6.4% (61.5 to 46.9 mmol/mol) with IDegLira and from 7.7 to 7.4% (60.8 to 57.1 mmol/mol) with unchanged GLP-1RA. With IDegLira, 75% and 63% of patients achieved HbA1c <7% and ≤6.5%, compared with 36% and 23% on unchanged GLP-1RA, respectively. Fasting plasma glucose and 9-point self-monitored blood glucose profiles improved significantly more with IDegLira versus unchanged GLP-1RA. The mean change in weight was +2.0 kg with IDegLira, versus -0.8 kg with unchanged GLP-1RA. Rates of confirmed hypoglycemia were low, but higher with IDegLira versus unchanged GLP-1RA. The safety profile of IDegLira was consistent with previous findings; both treatments were well tolerated and the rate of nausea was low in both groups. IDegLira improved patient-reported outcomes versus unchanged GLP-1RA.ConclusionsIDegLira provided superior glycemic control versus unchanged GLP-1RA and represents an efficacious intensification approach in patients inadequately controlled on GLP-1RAs.Trial registrationClinicalTrials.gov #NCT01676116.FundingNovo Nordisk.

Dataset Information

Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

Publications

Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

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