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阿卡波糖的研究

Articles Acarbose compared with metformin as initial therapy in

patients with newly diagnosed type 2 diabetes:

an open-label, non-inferiority randomised trial

Wenying Yang, Jie Liu, Zhongyan Shan, Haoming Tian, Zhiguang Zhou, Qiuhe Ji, Jianping Weng, Weiping Jia, Juming Lu, Jing Liu, Yuan Xu,

Zhaojun Yang, Wei Chen

Summary

Background Metformin is the only ?rst-line oral hypoglycaemic drug for type 2 diabetes recommended by

international guidelines with proven e?cacy, safety, and cost-e?ectiveness. However, little information exists

about its use in Asian populations. We aimed to ascertain the e? ectiveness of the α-glucosidase inhibitor acarbose,

extensively adopted in China, compared with metformin as the alternative initial therapy for newly diagnosed

type 2 diabetes.

Methods In this 48-week, randomised, open-label, non-inferiority trial, patients who were newly diagnosed with

type 2 diabetes, with a mean HbA

of 7·5%, were enrolled from 11 sites in China. After a 4-week lifestyle modi? cation

run-in, patients were assigned to 24 weeks of monotherapy with metformin or acarbose as the initial treatment,

followed by a 24-week therapy phase during which add-on therapy was used if prespeci? ed glucose targets were not

achieved. Primary endpoints were to establish whether acarbose was non-inferior to metformin in HbA

reduction at

week 24 and week 48 timepoints.The non-inferiority margin was 0·3%, with an expected null di? erence in the

change from baseline to week 48 in HbA

. Analysis was done on a modi? ed intention-to-treat population. This study

was registered with Chinese Clinical Trial Registry, number ChiCTR-TRC-08000231.

Findings Of the 788 patients randomly assigned to treatment groups, 784 patients started the intended study drug.

HbA

reduction at week 24 was –1·17% in the acarbose group and –1·19% in the metformin group. At week 48, the

HbA

reduction was ?1·11% (acarbose) and ?1·12% (metformin) with di? erence 0·01% (95% CI ?0·12 to 0·14,

p=0·8999). Six (2%) patients in the acarbose group and seven (2%) patients in the metformin group had serious

adverse events, and two (1%) and four (1%) had hypoglycaemic episodes.

Interpretation This study provides evidence that acarbose is similar to metformin in e? cacy, and is therefore a viable

choice for initial therapy in Chinese patients newly diagnosed with type 2 diabetes.

Funding Bayer Healthcare (China) and Double Crane Phama.

Introduction

Despite advances in treatment for type 2 diabetes, an optimum strategy for glycaemic control remains elusive. Metformin is the only ? rst-line oral hypoglycaemic drug for type 2 diabetes with proven e? cacy, safety, and cost-e?ectiveness that is recommended by international guidelines.1 Robust evidence for metformin has been generated mostly from white populations2,3 with extrapolations for other populations;4 few studies have assessed metformin in other populations, especially in eastern Asian patients with lower BMI5 and exaggerated postprandial glucose excursion.6,7

The α-glucosidase inhibitors acarbose and voglibose are commonly used as monotherapy for mild diabetes, and in combination with other oral drugs or insulin for more advanced diabetes, in China and other eastern Asian countries. The reason for di?erences in use of α-glucosidase inhibitors between white and Asian population remains ill de? ned.

A previous head-to-head study to compare α-glucosidase inhibitors with metformin as the initial therapy for type 2 diabetes has not been reported. One previous study in

patients with impaired glucose tolerance8s howed similar

e?cacy of metformin and acarbose in reducing the

incidence of new-onset diabetes after 3 years of follow-

up. Another study9 showed that the two drugs led to a

similar reduction in HbA

in more advanced diabetes.

The mechanisms of action for both metformin and

α-glucosidase inhibitors are related to the gastrointestinal

tract. However, information about Chinese dietary

patterns and the e?cacy of acarbose is lacking. In

addition, the relationship between glucose, insulin,

glucagon, and glucagon-like peptide-1 (GLP-1), needs to

be clari? ed especially for intervention with acarbose and

metformin. 10–18

We therefore did a non-inferiority trial to compare

acarbose with metformin as the initial therapy in

Chinese patients newly diagnosed with type 2 diabetes.

In addition to glycaemic control, we investigated e? ects

on levels of insulin, glucagon, and GLP-1; β-cell insulin-

secretory capacity and insulin sensitivity; and the

in? uence of dietary carbohydrate on glycaemic control.

Published Online

October 18, 2013

https://www.wendangku.net/doc/ba7893841.html,/10.1016/

S2213-8587(13)70021-4

See Online/Comment

https://www.wendangku.net/doc/ba7893841.html,/10.1016/

S2213-8587(13)70107-4

China–Japan Friendship

Hospital, Beijing, China

(Prof W Yang MD,

Prof Z Yang MD); Shanxi Province

People’s Hospital, Taiyuan,

China (Prof J Liu PhD); The First

Hospital of China Medical

University, Shenyang, China

(Prof Z Shan PhD); West China

Hospital, Sichuan University,

Chengdu, China

(Prof H Tian MD); Xiangya

Second Hospital of Central

South University, Changsha,

China (Prof Z Zhou PhD); Xijing

Hospital, Fourth Military

Medical University, Xi’an, China

(Prof Q Ji PhD); The Third

A? liated Hospital of Sun Yat-

sen University, Guangzhou,

China (Prof J Weng PhD);

Shanghai Jiaotong University

A? liated Sixth People’s

Hospital, Shanghai, China

(Prof W Jia PhD); Chinese People’s

Liberation Army General

Hospital, Beijing, China

(Prof J Lu MD); Gansu Provincial

Hospital, Lanzhou, China

(Prof J Liu PhD); Beijing Chao

Yang Hospital, Beijing, China

(Y Xu MD); and Peking Union

Medical College Hospital,

Beijing, China (Prof W Chen PhD)

Correspondence to:

Prof Wenying Yang, Department

of Endocrinology, China–Japan

Friendship Hospital, Beijing

100029, China

ywying_1010@https://www.wendangku.net/doc/ba7893841.html,

Articles

Methods

Participants

For this non-inferiority, multicentre, randomised controlled trial we recruited 788 patients newly diagnosed with type 2 diabetes, aged between 30 and 70 years, from 11 clinical sites in China, after completion of the Chinese national diabetes and metabolic disorders study.6 All patients were diagnosed within the past 12 months with type 2 diabetes according to 1999 WHO criteria, had either not received oral anti-diabetic drugs or had been on short-term (1 month) treatment that had been discontinued 3 months before enrolment, had suboptimum glucose control (HbA

1c between 7% and 10% and fasting plasma glucose [F PG]

≤11·1 mmol/L), and had a BMI of 19–30 kg/m2.

Exclusion criteria were a history of renal disease with a

plasma creatinine concentration of 133 μmol/L (1·5 mg/dL)

or more; severe gastrointestinal diseases; cardiac diseases

(a history of unstable angina or myocardial infarction

within the previous 6 months or New York Heart

Association class III or IV congestive heart failure); hepatic

diseases, or an aspartate amino t ransferase or alanine

aminotransferase concentration at least twice as high as the

upper limit of the normal range; chronic hypoxic diseases

(emphysema or cor pulmonale); haematological diseases;

endocrine diseases (hypo t hyroidism, hyperthyroidism,

Cushing’s syndrome); uncontrolled hypertension (systolic

pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg);

acute illness; a history of intestinal surgery; women with

the potential to become pregnant, who were preparing for

conception, or who were pregnant or breastfeeding;

participation in any drug clinical trials during the past

3 months before enrolment; mental disorders; drug or

other substance misuse; requirement for insulin therapy;

diabetic ketoacidosis; or hyperosmolar non-ketotic coma.

Key withdrawal criteria included an allergic reaction or

intolerance to study drugs; inability to continue according

to protocol requirements; unwillingness to follow the

study; or FPG greater than 11·1 mmol/L with hypoglycaemic

drugs titrated to the maximum dose. All patients provided

written informed consent and con? rmed their willingness

to participate. The protocol was approved by an ethics

committee from each clinical site and was implemented in

accordance with provisions of the Declaration of Helsinki

and Good Clinical Practice guidelines.

Randomisation and masking

Randomisation codes were generated with a computer

programme (SAS version 9.10) for eligible patients with

PG between 7·0 and 11·1 mmol/L. Patients were

randomly assigned (1:1) to each of the two treatment groups

(block size 8) at 11 centres. Neither patients nor investigators

involved in the study were masked to treatment allocation. Procedures

A 4-week screening and run-in phase was used for

therapeutic lifestyle modi?cation with group patient

education, according to Chinese diabetes management

guidelines. The rule of “start low, go slow” was followed for

the drug intervention to avoid and attenuate possible

gastrointestinal e?ects. After the 4-week run-in phase,

patients were assigned to receive sustained-released

metformin hydrochloride up to 1500 mg, once daily

(500 mg per tablet, Beijing Double Crane Pharma, Beijing,

China), or up to 100 mg of acarbose, three times daily

(50 mg per tablet, Bayer Healthcare, Beijing, China),with

24-week monotherapy and 24-week add-on therapy with

insulin secretagogues if needed Acarbose was started from

50 mg once a day at dinner during the ?rst week and

Figure 1: Trial pro? le

Total dropout rate was 18·8%. ITT=intention to treat.

Articles titrated up to 50 mg twice a day at lunch and dinner in the

second week, 50 mg three times a day at three meals in the

third week, and 100 mg three times a day from the fourth

week onwards. Metformin was started at 500 mg once a day

after dinner for the ? rst 2 weeks and titrated up to 1000 mg

once a day after dinner in the third week and to 1500 mg

once a day after dinner from the fourth week onwards.

According to 2007 Chinese management guidelines for

type 2 diabetes, add-on therapy with insulin secretagogues

was started at week 24 in patients whose HbA

was higher

than 7%, or in those who had FPG higher than 7 mmol/L

or postprandial glucose of more than 10 mmol/L for

3 consecutive days by self-monitored blood glucose.

The primary endpoints were reduction in HbA

24 weeks and 48 weeks. Key secondary endpoints included

the proportion of patients with HbA

of 6·5% or less;

change in F PG, postprandial 2-h glycaemic pro? le,

bodyweight, insulin, glucagon, GLP-1, and insulin

sensitivity or β-cell function by HOMA index, all measured

at baseline, 24 weeks, and 48 weeks. We measured plasma

glucose, insulin, glucagon, and GLP-1 before and after a

standardised breakfast (70 g instant noodle equivalent to

an energy intake of 500 kilocalories) at baseline, 24 weeks,

and 48 weeks. W e also investigated the relation between

glucose pro? le and dietary pattern at baseline, 24 weeks,

and 48 weeks. Safety endpoints included hypoglycaemic

episodes, adverse events, vital signs, 12-lead electro-

cardiogram, biochemistry, lipid pro? le, haematology

measures, and routine urine tests.

BMI was calculated at baseline. Visits with patients were

scheduled every 2 weeks, or every 4 weeks after week 4.

Blood pressure, waist circumference, and bodyweight were

measured at all visits. HbA

levels were measured and

seven-point glucose pro?les were requested (on the day

before each visit for investigators’ clinical appraisal for

safety and e? cacy; data not reported since not a primary

nor secondary outcome; OneTouch Ultra glucose meter,

Johnson & Johnson, Shenzen, China). Plasma creatinine

con c en t rations were measured at baseline and at 4, 12, 24,

and 48 weeks. Plasma creatinine, lipids (including HDL

cholesterol, LDL cholesterol, triglycerides), and alanine

aminotransferase were measured at local sites’ laboratories

at baseline, 24 weeks, and 48 weeks. Plasma samples were shipped in dry ice to a central laboratory at the China–Japan Friendship Hospital (Beijing, China). HbA

was measured by high-performance liquid chromatography at the China–Japan Friendship Hospital (Biorad Variant-II, Biorad, CA, USA)(normal range, 4·5–6·2%). Serum insulin (Beckman insulin kit, Prague, Czech Republic), plasma glucagon (Linco GL-32K kit, CA, USA), and active GLP-1 (Linco GLP1A-35HK kit, CA, USA) were measured by radioactive immunoassay in an authorised laboratory by certi? ed technicians from China National Nuclear Corporation (with XH6020 4-detector RIA automatic gamma counter, Xi’An nuclear instrument factory/China state-owned 262 factory). All values had to meet quality-control standards, including a coe? cient of variation of 25% or less.

F or analysis of dietary macronutrients, patients com-pleted a questionnaire about dietary information the day before visits. Energy intake from carbohydrates, proteins, and fats was calculated by independent and dedicated clinical nutrition experts at baseline, 24 weeks, and 48 weeks. For calculation of HOMA index, we used the following formulae (INS=fasting insulin): HOMA-IR=INS × FPG/22·5; HOMA-B=20 ×FINS/(FPG–3·5); early insu l in secretion index=ΔI30/ΔG30; whole body insulin sensitivity index=10 000/(F P

G [mg/dL] × F INS) × (mean glucose [mg/dL] × mean insulin).1/2

Statistical analysis

We concluded non-inferiority if the upper limit of the 95% CI for the treatment di? erence was less than 0·3%

Articles

in change in HbA

from baseline to week 48. With the assumption of a SD of 1·3%, 295 patients per treatment group (a total of 590 patients) were required to achieve 80% power for the per protocol analysis. To allow for a 20% dropout rate, we aimed to randomise a total of 738 patients (369 patients per treatment group).

We did e? cacy analyses using prespeci? ed modi? ed intention-to-treat and per-protocol populations. Patients included in the modi? ed intention-to-treat analysis had received at least one dose of study drug, had e? cacy data at baseline, and had at least one post-baseline measurement of the respective variable. We included all patients randomly assigned to treatment groups with documented safety data in the safety analysis. We used SAS (version 9.1.0) for data analysis, and used the

last observation carried forward (LOCF) approach for

missing data for the primary endpoints only. For HbA

1c data, we used ANCOVA with treatment and centre as

factors, and baseline as a covariate, and included

treatment by centre interaction. We calculated least-

squares means and 95% CIs for mean di? erences

between the two treatment groups. We used repeated

measures ANCOVA to assess e? cacy parameters over

the course of the study. Category variables were

analysed with χ2 tests, CMH-χ2 tests, or Fisher’s exact

test where appropriate. These tests were also used to

assess di? erences in the incidence of adverse events

between treatments.

45Articles

Role of the funding source

The Chinese Diabetes Society was involved in study design and implementation, appointment of contract research organisations, data analysis and interpretation, and medical writing. Independent sta? masked to randomisation analysed data and evaluated safety. Bayer Healthcare (China) provided ? nancial support and acarbose, and Beijing Double Crane Pharma provided metformin. Neither Bayer nor Double Crane had a role in study design, implementation, data analysis, interpretation, or writing of the report. All the authors had full access to all the data in

the study and the corresponding author had ?

nal responsibility for the decision to submit for publication.Results

F igure 1 shows the study pro? le. F rom Nov 8, 2008, to June 27, 2011, we screened 1099 patients and randomly allocated 788 to the two treatments. Four withdrew consent before drug intervention. 784 patients commenced study drug (393 metformin and 391 acarbose). 16% of patients in

Figure 2: Primary outcome according to treatment group

Δ acarbose–Δ metformin represents the di? erence in the primary outcome of HbA 1c reduction between acarbose group and metformin group at 24 weeks and 48 weeks.

Articles

the acarbose group (40 at the ? rst 24-week monotherapy phase and 25 at the add-on therapy phase) and 20% of patients in the metformin group (46 at the ? rst 24-week monotherapy phase and 33 at the add-on therapy phase) discontinued study drugs before the end of follow-up. Only ? ve patients in the acarbose group and three patients in the metformin group received insulin secretagogues as add-on therapy after 24-week monotherapy and until study completion. No patients stopped the study on the basis of our withdrawal criteria (F PG of more than 11·1 mmol/L with maximum dose of hypoglycaemic drugs based on clinical decisions). The two treatment groups were balanced with respect to baseline characteristics (table 1).

At week 24 and at week 48, HbA 1c was reduced compared with baseline in both acarbose and metformin groups (table 2, ? gure 2). At week 48, the least-squares mean treatment di? erence between acarbose and metformin for reduction of HbA 1c was 0·01% (two-sided 95% CI –0·12 to 0·14; p=0·8999), demonstrating non-inferiority (? gure 2).The reduction in FPG at week 48 was greater in patients taking metformin than in those taking acarbose, whereas reduction in 2-h postprandial glucose was greater in patients taking acarbose than those taking metformin (table 2). We observed a progressive decrease in bodyweight in both treatment groups, although patients taking acarbose had lost more weight than had those taking metformin at week 24 (?0·67 kg, 95% CI –1·14 to –0·20; p=0·0054) and at week 48 (–0·63 kg, –1·15 to –0·10; p=0·0194; table 2). Results from the modi? ed intention-to-treat analysis were in agreement with ? ndings from the per-protocol analysis (appendix).HbA 1c reduction di? ered signi? cantly within the acarbose group as well as the metformin group when patients were strati? ed by baseline HbA 1c (ie, <7%, 7–8%, >8%) by Nemenyi test (all p<0·0001 within subgroups; ? gure 3). There was no signi? cant di? erence in change from baseline HbA 1c between acarbose and metformin when strati? ed by baseline HbA 1c . There was no di? erence in the proportion of patients with HbA 1c of 6·5% or less between metformin (67%) and acarbose (69%) at 24 weeks (p=0·6231) and between metformin (62%) and acarbose (64%) at 48 weeks (p=0·5422; table 2).The contribution of carbohydrates for energy intake in the study overall was higher than the China dietary

Figure 3: Least-squares mean change in glycated haemoglobin from baseline strati? ed by (A) baseline glycated haemoglobin and (B) baseline percentage of energy intake from carbohydrate

The results by carbohydrate intake from the intention-to-treat and per-protocol populations were consistent.

See Online for appendix

Articles

recommendations (up to 65%) and international guidelines (45–65%), with mean 67% (SD 9) at baseline, 66% (SD 11) at 24 weeks, and 68% (SD 9) at 48 weeks. There was no signi? cant association between reduction in HbA

and proportion of dietary carbohydrate intake from baseline to week 24 or week 48 for either metformin or acarbose (? gure 3). Neither was there an association between baseline BMI and HbA

reduction (appendix). On the whole, no di?erence in indices for insulin sensitivity and β-cell function were found between acarbose and metformin groups at week 24 or 48 (table 2); however, there was a signi? cant di? erence between groups in whole body insulin sensitivity index at 48 weeks (p=0·0424). We consider this a chance ? nding. After 24-week and 48-week treatment, there was no di? erence between the metformin and acarbose group in the fasting state for serum insulin, glucagon, and GLP-1 concentration. With the standard meal test after 24-week intervention, (?gure 4) acarbose monotherapy was associated with a signi? cantly greater insulin-sparing e? ect compared with metformin (change in serum insulin concentration at 30 min, p=0·0022; at 120 min, p<0·0001; at 180 min, p=0·0657). Similar results were shown after 48-week treatment, although di? erences were not signi?cant at all timepoints (change in serum insulin concentration at 30 min, p=0·2661; at 120 min, p=0·0002; at 180 min, p=0·0521; ? gure 4B). A signi? cant di?erence between metformin and acarbose groups was shown for change in area under the curve for serum insulin after the 180 min standard meal test (at 24 weeks, p=0·0001, and at 48 weeks, p=0·0047; table 2).

Figure 4: Mean glucose (A), insulin (B), glucagon (C), and GLP-1 (active; D) concentrations during standard meal test, by intention to treat

Values show means with SE (at week 0) and least-squares means with SE (at week 24 and 48). The values at weeks 24 and 48 are adjusted for baseline values and centre where appropriate. Note that y axes in C and D do not start at 0. GLP-1=plasma glucagon-like peptide-1 (active). *p<0·05, ?p<0·01, for comparisons between acarbose and metformin groups at week 24 or 48. p values for treatment di? erence (acarbose–metformin) were: (A) week 24: p<0·0001 (0 min), p=0·0892 (30 min), p=0·0421 (120 min), p=0·5149 (180 min); week 48: p=0·0385 (0 min), p=0·0050 (30 min), p=0·0003 (120 min), p=0·0604 (180 min); (B) week 24: p=0·9829 (0 min), p=0·0022 (30 min),

p<0·0001 (120 min), p=0·0657 (180 min); week 48: p=0·1857 (0 min), p=0·2661 (30 min), p=0·0002 (120 min), p=0·0521 (180 min); (C) week 24: p=0·0490 (0 min),

p=0·1707 (30 min), p=0·0176 (120 min), p=0·4075 (180 min); week 48: p=0·8073 (0 min), p=0·3556 (30 min), p=0·9147 (120 min), p=0·2912 (180 min); (D) week 24:

p=0·7073 (0 min), p=0·2652 (30 min), p=0·5722 (120 min), p=0·1467 (180 min); week 48: p=0·3280 (0 min), p=0·5956 (30 min), p=0·0826 (120 min), p=0·3183 (180 min).

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In the metformin group, there was no di? erence between baseline and week 24 in glucagon concentrations during the standard meal test, but there was a signi? cant reduction at week 48 compared with baseline (p<0·0001 at all time points; ? gure 4C). However, in the acarbose group, there was a signi? cant decrease compared with baseline at week 24 at all but the 180 min timepoint (p=0·0009 for fasting, p=0·0476 for 30 min and p=0·0190 for 120 min) and further reduction in concentrations at week 48 (p<0·0001 at all timepoints). The dynamics in the change di? ered in each group: glucagon concentrations remained level after 120 min in the acarbose group, but decreased further from 120 min to 180 min in the metformin group at both week 24 and week 48 (? gure 4C). Overall, however, the two drugs did not di? er signi? cantly from each other in their e? ects on glucagon during the standard meal test. Both acarbose and metformin treatment were associated with a similar increase in GLP-1 concentrations from baseline during a standard meal test at 24 weeks and 48 weeks (p<0·0001 compared with baseline at all timepoints, except p=0·0003 for acarbose at 30 min at week 24, and p=0·0002 for metformin at 30 min, week 48; ? gure 3D). However, the two drugs showed di? erences in the time of peak GLP-1 concentrations: the peak occurred at 120 min in the metformin group and was delayed until after 120 min in the acarbose group (? gure 4D).

Table 3 shows serious adverse events and adverse events

that occurred in more than 5% of patients in either group.

Six serious adverse events in the acarbose group and seven

in the metformin group were reported. Consistent with

the known safety pro? le of both drugs, the most common

adverse events were mild to moderate gastrointestinal

symptoms (100 [27%] patients in the acarbose group vs 107

[29%] in the metformin group). There were no deaths or

severe hypoglycaemic events in either group. Two patients

in the acarbose group and four in the metformin group

reported hypoglycaemic episodes.

Discussion

In this study we have shown that acarbose treatment was

non-inferior to metformin treatment in view of HbA

1c reduction after 48 weeks of treatment. Metformin’s

e?cacy in reducing HbA

is independent of baseline

BMI (panel).19 We also show that 100 mg acarbose three

times a day decreases HbA

to a greater extent in Chinese

patients (1%) than previously reported in white

populations (0·5–1%).20 Higher baseline HbA

(8%) was

associated with greater treatment-emergent glycaemic

reductions (2%). These ? ndings are in agreement with

results from the China vildagliptin phase 3 study,21,22 in

which this drug was compared head-to-head with

acarbose in drug-naive Chinese patients newly diagnosed

with diabetes. That study used the same acarbose dose

(up to 300 mg daily), and reported a greater reduction in

HbA

(1·36%), higher baseline HbA

(8·6%), and a

longer duration of diabetes (1·3 years), but without using

an initial washout phase and lifestyle advice. The changes

in fasting and postprandial glucose with metformin and

acarbose treatment are also in agreement with previous

studies.8,18 However, concomitant with glucose-lowering

e? ect, we did not observe changes in β-cell function or

insulin resistance indices between the two groups.

We did not ? nd a signi? cant correlation between glucose

control and weight reduction in our study.α-glucosidase

inhibitors are thought to have a neutral e? ect on

bodyweight, whereas metformin is associated with mild

weight reduction in overweight and obese patients with

type 2 diabetes.1 Acarbose’s e?ects on bodyweight

reduction in this study are in line with those of previous

studies in Chinese22 and other populations.23 The mean

BMI in the present study and in the China national cross-

sectional epidemiological study,6 under t aken during the

same period, are consistent and are characteristic of the

Chinese population with newly diagnosed diabetes. Thus,

our ?ndings are generalisable to patients with newly

diagnosed type 2 diabetes in China. However, the

underlying mechanisms of weight reduction by acarbose

and its clinical relevance need to be examined further.

China is experiencing rapid nutritional transition from

a traditional high-carbohydrate dietary pattern to a

combination of traditional and western dietary patterns.

Eastern Asian populations, especially in China, have

cultivated cereal (rice) and pulses (soy bean) as major

Articles sources of energy for thousands of years. α-glucosidase

inhibitors delay the degradation of complex carbohydrates

into glucose, so that carbohydrates remain in the

intestine. In view of the perceived di? erences in e? cacy

of acarbose in reduction in HbA

between white and

Chinese populations, one hypothesis of this study was to

test whether the e? cacy of acarbose vs metformin was

correlated with a relative proportion of dietary

carbohydrates. We show here that the relative proportion

of dietary carbohydrates consumed by most newly

diagnosed Chinese patients with type 2 diabetes is higher

than that recommended by Chinese and international

dietary guidelines for macronutrients.24–27We did not ? nd

that e? cacy was signi?cantly associated with baseline

dietary carbohydrate intake, but we detected a trend to

suggest that acarbose (but not metformin) might lower

HbA

to a greater extent in patients with dietary

carbohydrate intake greater than 65·5% than in those

with less than 65·5%. However, this needs investigation

in further studies with larger sample sizes.

Both acarbose and metformin monotherapy were

associated with signi? cant insulin-sparing e? ects in both

the fasting state and after standard meal test. We found

that metformin and acarbose attenuate glucagon response

with late and slow modes of action (no change at week 24 and signi? cant reduction at week 48 for the metformin group; stepwise reduction at 24 weeks and 48 weeks for the acarbose group); this hints at an indirect e? ect of glucagon in these treatments. Both drugs also have signi? cant e?ects on GLP-1, boosting and prolonging concentrations before and after standard meals compared with baseline, although the GLP-1 response after the standard meal test in both groups at baseline seemed blunted. These ? ndings also need to be veri? ed further. Both metformin and acarbose were associated with changes from baseline in insulin, glucagon, and GLP-1 concentrations after the standard meal test. The acarbose group showed a greater insulin-sparing e?ect than the metformin group, and a di?erent pattern of glucagon response with a peak at 120 min; GLP-1 responses also might be prolonged with acarbose compared with metformin. Thus, in addition to a? ecting HBA

, the capacity of acarbose and metformin to a? ect the concentrations of glucose, insulin, GLP-1, and glucagon—and the complex gastrointestinal, endocrine, and metabolic interplay between these molecules—should be considered. This interplay could include glucose-stimulated insulin secretion, potentiation of insulin secretion by GLP-1, and the balance between insulin and glucagon. Relationships between glucose, insulin, GLP-1, and glucagon and the short-term and long-term e? ects of glucose reduction need to be investigated. The two drugs might act via di? erent underlying mechanisms: metformin acting possibly through peroxisome proliferator-activated receptor-α, as shown in in animal studies,11,12 and inhibition of DPP-4 activity,10 as shown in patients with type 2 diabetes; and acarbose acting by increased stimulation of L-cells through delayed absorption and altered transit of dietary carbo-

hydrates. The trend we observed for the delayed but

prolonged GLP-1 e? ect after the standard meal test in the

acarbose group compared with the metformin group is in

line with current evidence.13–18 The delayed but prolonged

GLP-1 response with acarbose might partly explain earlier

inconsistent ? ndings.28

We speculate that the action of α-glucosidase inhibitors

partly mimics the e? ect of gastric bypass surgery,29 with

increased and prolonged stimulation of the enteroinsulinar

axis and a decreased hyperinsulinemic response. Another

possible mechanism of the e?ect of acarbose on bodyweight

might be related to improved microbiota after delayed

carbohydrate passage into the small intestine.30–33 Unlike

the action of acarbose, sparing energy use and cellular

energy depletion with AMPK-dependent and AMPK-

independent pathway,34 metformin exerts bene? cial e? ects

on insulin sensitivity and metabolic pro? le, partly through

modulation of multiple components of the incretin axis,

including gut hormones and gastric emptying.11,12 Both

acarbose and metformin are known from use over many

years in clinical practice to cause gastrointestinal adverse

e?ects including ?atulence, diarrhoea, and abdominal

discomfort; slow titration can attenuate these symptoms.

The main limitation of our study is that there was no

placebo-controlled group, for ethical reasons, although

there was a 4-week run-in phase compared with a previous

study.22 Another limitation is that there was no hyperglycaemic clamp or duodenal nutrient perfusion to

eliminate di?erences in blood glucose and gastric

emptying. The study did not assess the role of other gut

hormones that could be a? ected by these drugs, especially

gastric inhibitory peptide.

Panel: Research in context

Systematic review

We searched PubMed up to March 22, 2013, with the search terms “α-glucosidase inhibitors”, “metformin”, and “randomised trial”. We reviewed randomised clinical trials and meta-analyses published in English and were unable to ? nd a comparative e? ectiveness trial that compared the two strategies as an initial treatment in drug-naive patients with type 2 diabetes.

Interpretation

This study was the ? rst large randomised controlled trial to assess acarbose as an initial treatment in newly diagnosed Chinese patients by comparison with metformin, the only ? rst-line therapy recommended by American Diabetes Association and European Association for the Study of Diabetes guidelines. Our ? ndings show that acarbose was

non-inferior to metformin in reduction of HbA

for these patients. The safety pro? le also showed that acarbose was well tolerated in Chinese patients with less frequent safety events than was seen in white populations. Furthermore, a trend suggested that e? cacy of

acarbose in reduction in HbA

and postprandial glucose was prospectively related to the proportion of dietary carbohydrates in Chinese patients. There was greater weight loss with acarbose than with metformin. Both metformin and acarbose diminish insulin and glucagon concentrations while increasing GLP-1 concentration. The evidence provided by this comparative e? ectiveness trial might help physicians in considering α-glucosisdase inhibitors as an alternative initial therapy for type 2 diabetes.

Articles

This study is the ?rst head-to-head comparison of metformin and acarbose as initial therapy for type 2 diabetes after failure of therapeutic lifestyle modi? cation. We report that both acarbose and metformin are well tolerated and have similar e?cacy as initial therapy for HBA

reduction in Chinese patients with type 2 diabetes. Our ? ndings are consistent with those of previous studies of acarbose with mild weight reduction, which has been neglected previously in clinical practice. Both metformin and acarbose have insulin-sparing and glucagon-sparing e?ects and increase GLP-1 concentrations. The possible interplay between e?ects on glucose, insulin, glucagon, and GLP-1 with these drugs needs to be assessed further. Metformin should remain as ?rst-line treatment for patients with newly diagnosed type 2 diabetes, while patients with exaggerated postprandial excursion can be treated with an α-glucosidase inhibitor as an alternative therapy before cardiovascular bene?ts of acarbose are validated and con? rmed in ongoing studies.35

Contributors

WY designed, submitted, and wrote the report. All authors were involved in study protocol discussion and data collection, and writing the Discussion. Con? icts of interest

We declare that we have no con? icts of interest.

Acknowledgments

We thank Wenbin Yang for his constructive discussion of the manuscript preparation.

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