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Randomized Controlled Trial
. 2024 Oct 15:387:e080122.
doi: 10.1136/bmj-2024-080122.

Intense simplified strategy for newly diagnosed type 2 diabetes in patients with severe hyperglycaemia: multicentre, open label, randomised trial

Liehua Liu  1 , Weijian Ke  1 , Hai Li  2 , Fangping Li  3 , Guanjie Fan  4 , Jian Kuang  5 , Jianhua Ma  6 , Xiuwei Zhang  7 , Bing Ji  8 , Shu Li  9 , Yinghong Du  10 , Yaoming Xue  11 , Zhaohui Lyu  12 , Leili Gao  13 , Shen Qu  14 , Yongquan Shi  15 , Li Yan  16 , Wanping Deng  1 , Chaoyan Xu  1 , Peiji Dai  1 , Lijuan Xu  1 , Juan Liu  1 , Xuesi Wan  1 , Guohong Wei  1 , Shuang Yu  1 , Shubin Hong  1 , Pengyuan Zhang  1 , Zhimin Huang  1 , Xiaopei Cao  1 , Zhihong Liao  1 , Haipeng Xiao  1 , Yiming Mu  12 , Yehuda Handelsman  17 , Yanbing Li  2
Affiliations
Randomized Controlled Trial

Intense simplified strategy for newly diagnosed type 2 diabetes in patients with severe hyperglycaemia: multicentre, open label, randomised trial

Liehua Liu et al. BMJ. .

Abstract

Objective: To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia.

Design: Multicentre, open label, randomised trial.

Setting: 15 hospitals in China between December 2017 and December 2020.

Participants: 412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA1c ≥8.5%).

Interventions: All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks.

Main outcome measures: The primary outcome was the percentage of participants achieving HbA1c <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, β cell function, and variations in insulin sensitivity.

Results: 412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA1c was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA1c <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA1c <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA1c <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and β cell function indices. All treatments were well tolerated.

Conclusions: The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and β cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus.

Trial registration: ClinicalTrials.gov NCT03194945.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Ministry of Science and Technology of China, Science and Technology Department of Guangdong Province, Guangzhou Science and Technology Bureau, and Boehringer-Ingelheim for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Trial profile
Fig 2
Fig 2
Glycated haemoglobin A1c (HbA1c) control during follow-up. Proportions of participants achieving HbA1c <7.0% or HbA1c <6.5% at week 48. LIN=linagliptin group; LIN+MET=linagliptin plus metformin group; MET=metformin group
Fig 3
Fig 3
Glycated haemoglobin A1c (HbA1c) control during follow-up. Change in HbA1c over time. LIN=linagliptin group; LIN+MET=linagliptin plus metformin group; MET=metformin group; SIIT=short term intensive insulin therapy. *P<0.0167 compared with control group in log-rank tests
Fig 4
Fig 4
Glycated haemoglobin A1c (HbA1c) control during follow-up. Change in HbA1c at week 48 from baseline. LIN=linagliptin group; LIN+MET=linagliptin plus metformin group; MET=metformin group
Fig 5
Fig 5
Glycated haemoglobin A1c (HbA1c) control during follow-up. Summarisation of participants in optimal glycaemic control using Kaplan-Meier curves. LIN=linagliptin group; LIN+MET=linagliptin plus metformin group; MET=metformin group; SIIT=short term intensive insulin therapy. *P<0.0167 compared with control group in log-rank tests
Fig 6
Fig 6
Changes of clinical parameters over time in different treatment groups. Variables are compared with generalised estimating equation models adjusted for age, gender, baseline body mass index, and baseline HbA1c. P<0.0167 compared with control group for LIN+MET in mean FPG and ISSI-2 and for all treatment groups in HOMA-β. 2HPG=two hour postprandial glucose; FPG=fasting plasma glucose; HOMA-β=homoeostasis model assessment of β cell function; HOMA-IR=homoeostasis model assessment of insulin resistance; ISSI-2=insulin secretion-sensitivity index-2; LIN=linagliptin group; MET=metformin group; LIN+MET=linagliptin plus metformin group; SIIT=short term intensive insulin therapy
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