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Acarbose: an alternative to metformin for first-line treatment in type 2 diabetes?
Comment
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Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 2012; 153: 3613–19. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, Flum DR, Belle SH, et al. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med 2009; 361: 445–54.
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Still CD, Wood GC, Benotti P, et al. Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study. Lancet Diabetes Endocrinol 2013; published online Sept 13. http://dx.doi.org/10.1016/S2213-8587(13)70070-6.
Acarbose: an alternative to metformin for first-line treatment in type 2 diabetes? Published Online October 18, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70107-4 See Articles page 46
6
Most guidelines currently recommend metformin as the first-line treatment for type 2 diabetes1–3 on the basis of data mostly generated in European populations. Asia represents the region with the largest number of patients with diabetes worldwide, with more than 90 million in China alone.4 Asians with type 2 diabetes can have several characteristics in terms of pathophysiology and pattern of complications that might therefore need a slightly different approach to treatment.5,6 Nevertheless, large-scale randomised controlled trials in different ethnic groups are scarce, and most current national or regional treatment guidelines are largely based on those of the USA or Europe. In The Lancet Diabetes & Endocrinology, Wenying Yang and colleagues7 report the findings of a randomised controlled trial that compared the α-glucosidase inhibitor acarbose with metformin as initial treatment for type 2 diabetes. Investigators in the MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) trial recruited 788 Chinese patients aged 30–70 years who were newly diagnosed with type 2 diabetes.7 Patients were randomly assigned to receive metformin (up to 1500 mg sustained release preparation) or acarbose (titrated gradually up to a maximum of 100 mg three times a day). At the end of the 48-week study period, acarbose was found to be non-inferior to metformin in terms of its HbA1clowering effect (least-squares mean difference 0·01% [95% CI –0·12 to 0·14; p=0·8999]), and both treatment regimens achieved weight loss, although patients in the acarbose group lost slightly more weight (–0·63 kg [–1·15 to –0·10; p=0·0194]). Patients assigned to the acarbose group also had a more favourable lipid profile, with improved HDL and lower triglycerides at 48 weeks. As expected, treatment with acarbose was associated with less postprandial hyperinsulinaemia than with metformin.
Of particular note is the detailed characterisation of changes in gastrointestional hormones during treatment. Although both treatments show similar patterns of changes in glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucagon levels, there were also important differences (figure). Both metformin and acarbose showed a significant rise in GLP-1 concentrations from 24 weeks onwards, although the decreases in glucagon seen in both groups were apparent mainly from 24 weeks onwards and occurred earlier with acarbose than with metformin. Further studies to investigate these changes would be of interest. The increase in GLP-1 concentrations after acarbose is a marker of delayed and more distal intestinal absorption of carbohydrate.8 Gastrointestinal adverse effects were reported in 27% of patients receiving acarbose and 29% of those receiving metformin. The low incidence of gastrointestinal intolerance seen in the acarbose group could be partly related to the “start low, go slow” approach adopted, with gradual weekly titration from 50 mg a day during the first week to 100 mg three times a week over a 4-week period. The authors concluded that although metformin should still be considered the first-line treatment, in patients with a marked postprandial glucose excursion or with a body-mass index similar to those recruited in the current study, acarbose would be a worthy alternative. α-glucosidase inhibitors remain most popular in countries such as China and Japan, where rice forms a major component of the diet and the dietary contribution of carbohydrate is high. In the MARCH study, the mean contribution of carbohydrates for energy intake was more than 65%, which was higher than what was recommended in international guidelines (45–65%) and guidelines in China (up to 65%). The results of this large study indicate that the efficacy of acarbose could be related to the carbohydrate content in the patients’ diet, www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
Comment
which suggests that acarbose would be more effective in populations with a high carbohydrate intake. In a recent meta-analysis of 46 studies,9 the glucose-lowering effects of acarbose did seem greater in patients with type 2 diabetes consuming an eastern Asian diet than in those on a western diet (including patients in Europe and North America). The mean HbA1c reduction in studies from eastern Asia was significantly lower at 1·54% (SD 2·0%) compared with 0·52% (1·2%) in studies of patients on a western diet.9 Whether this difference in efficacy is driven entirely by the higher carbohydrate content in eastern diets is not clear. Another study has suggested that Asian patients had greater glycaemic responses to the same foods than did white patients.10 Other potential factors that could contribute to the difference in efficacy in different populations include underlying genetic factors and the composition of the gut microbiome. With the advent of newer agents including GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, α-glucosidase inhibitors might have moved down in the list of preferred choices of glucose-lowering treatment. Nevertheless, there is also the increasing appreciation that the choice of treatment agents, as well as glycaemic targets, should be individualised on the basis of patient characteristics.1 In the recent glycaemic control algorithm developed by the American Association of Clinical Endocrinologists, newer agents including DPP4 inhibitors, GLP-1 receptor agonists, and α-glucosidase inhibitors have been proposed as alternative first-line treatments to metformin.3 Although these important results from the MARCH study provide evidence to support acarbose as a useful alternative to metformin as first-line treatment, there are currently little medium-term data for the other agents being compared with metformin as monotherapy. Additional data for the medium-term and long-term outcome of patients receiving these newer agents compared with metformin are eagerly awaited. Metformin has been linked with beneficial cardiovascular outcomes, as well as decreased risk of cancer in type 2 diabetes. The long-term cardiovascular effect of acarbose will be addressed in the Acarbose Cardiovascular Evaluation (ACE) Trial (NCT00829660, ISRCTN91899513), which is examining the cardiovascular outcome in patients with established cardiovascular disease or acute coronary syndrome who also have impaired glucose tolerance. www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
↓VLDL synthesis ↓Triglyceride
Meal ingestion
↓Hyperinsulinaemia ↓Glucagon
Reduced postprandial glucose excursion
ACARBOSE
α-glucosidase
Delayed distal intestinal absorption of carbohydrates
Altered gut microbiome
↑ GLP-1
Delayed gastric emptying
Decreased appetite Weight loss
Figure: Mechanisms of action of acarbose
The MARCH trial has provided invaluable information about the efficacy and benefits of acarbose compared with metformin. MARCH represents an applaudable contribution and important step towards the development of evidence-based and population-specific treatment guidelines for type 2 diabetes. Ronald CW Ma Department of Medicine and Therapeutics, Prince of Wales Hospital; The Li Ka Shing Institute of Health Sciences; and Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China [email protected] I have received speaker honoraria or consultancy fees from BoehringerIngelheim, Eli Lilly, Bayer, Danone, Nestle, Pfizer, and Takeda, and research support for clinical studies and trials from Astra Zeneca and Merck Sharp and Dohme. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research. 1
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Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577–96. The International Diabetes Federation. Global guidelines for type 2 diabetes. Brussels: International Diabetes Federation, 2012: 57. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010; 362: 1090–101. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci 2013; 1281: 64–91. Kong AP, Xu G, Brown N, So WY, Ma RC, Chan JC. Diabetes and its comorbidities-where East meets West. Nat Rev Endocrinol 2013; 9: 537–47. Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, noninferiority randomised trial. Lancet Diabetes Endocrinol 2013; published online Oct 18. http://dx.doi.org/10.1016/S2213-8587(13)70021-4. Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol 1995; 30: 892–96. Zhu Q, Tong Y, Wu T, Li J, Tong N. Comparison of the hypoglycemic effect of acarbose monotherapy in patients with type 2 diabetes mellitus consuming an eastern or western diet: a systematic meta-analysis. Clin Ther 2013; 35: 880–99. Henry CJ, Lightowler HJ, Newens K, et al. Glycaemic index of common foods tested in the UK and India. Br J Nutr 2008; 99: 840–45.
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Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 2012; 153: 3613–19. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, Flum DR, Belle SH, et al. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med 2009; 361: 445–54.
9
Still CD, Wood GC, Benotti P, et al. Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study. Lancet Diabetes Endocrinol 2013; published online Sept 13. http://dx.doi.org/10.1016/S2213-8587(13)70070-6.
Acarbose: an alternative to metformin for first-line treatment in type 2 diabetes? Published Online October 18, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70107-4 See Articles page 46
6
Most guidelines currently recommend metformin as the first-line treatment for type 2 diabetes1–3 on the basis of data mostly generated in European populations. Asia represents the region with the largest number of patients with diabetes worldwide, with more than 90 million in China alone.4 Asians with type 2 diabetes can have several characteristics in terms of pathophysiology and pattern of complications that might therefore need a slightly different approach to treatment.5,6 Nevertheless, large-scale randomised controlled trials in different ethnic groups are scarce, and most current national or regional treatment guidelines are largely based on those of the USA or Europe. In The Lancet Diabetes & Endocrinology, Wenying Yang and colleagues7 report the findings of a randomised controlled trial that compared the α-glucosidase inhibitor acarbose with metformin as initial treatment for type 2 diabetes. Investigators in the MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) trial recruited 788 Chinese patients aged 30–70 years who were newly diagnosed with type 2 diabetes.7 Patients were randomly assigned to receive metformin (up to 1500 mg sustained release preparation) or acarbose (titrated gradually up to a maximum of 100 mg three times a day). At the end of the 48-week study period, acarbose was found to be non-inferior to metformin in terms of its HbA1clowering effect (least-squares mean difference 0·01% [95% CI –0·12 to 0·14; p=0·8999]), and both treatment regimens achieved weight loss, although patients in the acarbose group lost slightly more weight (–0·63 kg [–1·15 to –0·10; p=0·0194]). Patients assigned to the acarbose group also had a more favourable lipid profile, with improved HDL and lower triglycerides at 48 weeks. As expected, treatment with acarbose was associated with less postprandial hyperinsulinaemia than with metformin.
Of particular note is the detailed characterisation of changes in gastrointestional hormones during treatment. Although both treatments show similar patterns of changes in glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucagon levels, there were also important differences (figure). Both metformin and acarbose showed a significant rise in GLP-1 concentrations from 24 weeks onwards, although the decreases in glucagon seen in both groups were apparent mainly from 24 weeks onwards and occurred earlier with acarbose than with metformin. Further studies to investigate these changes would be of interest. The increase in GLP-1 concentrations after acarbose is a marker of delayed and more distal intestinal absorption of carbohydrate.8 Gastrointestinal adverse effects were reported in 27% of patients receiving acarbose and 29% of those receiving metformin. The low incidence of gastrointestinal intolerance seen in the acarbose group could be partly related to the “start low, go slow” approach adopted, with gradual weekly titration from 50 mg a day during the first week to 100 mg three times a week over a 4-week period. The authors concluded that although metformin should still be considered the first-line treatment, in patients with a marked postprandial glucose excursion or with a body-mass index similar to those recruited in the current study, acarbose would be a worthy alternative. α-glucosidase inhibitors remain most popular in countries such as China and Japan, where rice forms a major component of the diet and the dietary contribution of carbohydrate is high. In the MARCH study, the mean contribution of carbohydrates for energy intake was more than 65%, which was higher than what was recommended in international guidelines (45–65%) and guidelines in China (up to 65%). The results of this large study indicate that the efficacy of acarbose could be related to the carbohydrate content in the patients’ diet, www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
Comment
which suggests that acarbose would be more effective in populations with a high carbohydrate intake. In a recent meta-analysis of 46 studies,9 the glucose-lowering effects of acarbose did seem greater in patients with type 2 diabetes consuming an eastern Asian diet than in those on a western diet (including patients in Europe and North America). The mean HbA1c reduction in studies from eastern Asia was significantly lower at 1·54% (SD 2·0%) compared with 0·52% (1·2%) in studies of patients on a western diet.9 Whether this difference in efficacy is driven entirely by the higher carbohydrate content in eastern diets is not clear. Another study has suggested that Asian patients had greater glycaemic responses to the same foods than did white patients.10 Other potential factors that could contribute to the difference in efficacy in different populations include underlying genetic factors and the composition of the gut microbiome. With the advent of newer agents including GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, α-glucosidase inhibitors might have moved down in the list of preferred choices of glucose-lowering treatment. Nevertheless, there is also the increasing appreciation that the choice of treatment agents, as well as glycaemic targets, should be individualised on the basis of patient characteristics.1 In the recent glycaemic control algorithm developed by the American Association of Clinical Endocrinologists, newer agents including DPP4 inhibitors, GLP-1 receptor agonists, and α-glucosidase inhibitors have been proposed as alternative first-line treatments to metformin.3 Although these important results from the MARCH study provide evidence to support acarbose as a useful alternative to metformin as first-line treatment, there are currently little medium-term data for the other agents being compared with metformin as monotherapy. Additional data for the medium-term and long-term outcome of patients receiving these newer agents compared with metformin are eagerly awaited. Metformin has been linked with beneficial cardiovascular outcomes, as well as decreased risk of cancer in type 2 diabetes. The long-term cardiovascular effect of acarbose will be addressed in the Acarbose Cardiovascular Evaluation (ACE) Trial (NCT00829660, ISRCTN91899513), which is examining the cardiovascular outcome in patients with established cardiovascular disease or acute coronary syndrome who also have impaired glucose tolerance. www.thelancet.com/diabetes-endocrinology Vol 2 January 2014
↓VLDL synthesis ↓Triglyceride
Meal ingestion
↓Hyperinsulinaemia ↓Glucagon
Reduced postprandial glucose excursion
ACARBOSE
α-glucosidase
Delayed distal intestinal absorption of carbohydrates
Altered gut microbiome
↑ GLP-1
Delayed gastric emptying
Decreased appetite Weight loss
Figure: Mechanisms of action of acarbose
The MARCH trial has provided invaluable information about the efficacy and benefits of acarbose compared with metformin. MARCH represents an applaudable contribution and important step towards the development of evidence-based and population-specific treatment guidelines for type 2 diabetes. Ronald CW Ma Department of Medicine and Therapeutics, Prince of Wales Hospital; The Li Ka Shing Institute of Health Sciences; and Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China [email protected] I have received speaker honoraria or consultancy fees from BoehringerIngelheim, Eli Lilly, Bayer, Danone, Nestle, Pfizer, and Takeda, and research support for clinical studies and trials from Astra Zeneca and Merck Sharp and Dohme. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research. 1
2 3 4 5
6 7
8
9
10
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577–96. The International Diabetes Federation. Global guidelines for type 2 diabetes. Brussels: International Diabetes Federation, 2012: 57. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010; 362: 1090–101. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci 2013; 1281: 64–91. Kong AP, Xu G, Brown N, So WY, Ma RC, Chan JC. Diabetes and its comorbidities-where East meets West. Nat Rev Endocrinol 2013; 9: 537–47. Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, noninferiority randomised trial. Lancet Diabetes Endocrinol 2013; published online Oct 18. http://dx.doi.org/10.1016/S2213-8587(13)70021-4. Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol 1995; 30: 892–96. Zhu Q, Tong Y, Wu T, Li J, Tong N. Comparison of the hypoglycemic effect of acarbose monotherapy in patients with type 2 diabetes mellitus consuming an eastern or western diet: a systematic meta-analysis. Clin Ther 2013; 35: 880–99. Henry CJ, Lightowler HJ, Newens K, et al. Glycaemic index of common foods tested in the UK and India. Br J Nutr 2008; 99: 840–45.
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