- Email: [email protected]
Mortality and metformin use in patients with advanced chronic kidney disease
Correspondence
is against the basic principles of our profession. It also raises the question of why longacting analogues are recommended as a first-line option for patients with type 1 diabetes (in the current draft NICE guideline),2 but denied to people with type 2 diabetes. Primary care doctors and nurses, in particular, are struggling to look after growing numbers of patients with type 2 diabetes. These healthcare professionals need clear, sensible guidance, based on evidence (and cost), but most importantly on safety. We strongly recommend that in further revisions to the NICE guideline, repaglinide is withdrawn as a first-line treatment, the prominence given to sulphonylureas at all stages of intensification is reduced, the BMI restrictions and stopping rules for GLP-1 receptor agonists are redrawn, and the SGLT-2 inhibitors are fully included. Furthermore, individualised care for insulin management should mean just that, rather than restricting choice on the basis of cost. Finally, the promotion of the waiting-for-failure approach should be reviewed. JPO’H receives lecture fees and advisory honoraria from Sanofi and Novo Nordisk. DM-J has received personal fees from Novo Nordisk, AstraZeneca, Janssen,Takeda, Lilly, MSD, and Sanofi for lectures and advisory boards. WH is chair of the South Asian Health Foundation, and receives grants, personal fees, and non-financial support from Novo Nordisk, Boerhinger Ingelhiem, and Sanofi; grants and personal fees from Astra Zeneca; grants, personal fees, and non-financial support from Jansen and Merck; and grants from Takeda, outside the submitted work. DH has worked on advisory boards for Novo Nordisk, Lilly, AstraZeneca, MSD, Abbott, Janssen, Roche, and BD, and has provided presentations at conferences sponsored by the pharmaceutical industry. RDL has worked on advisory boards for Novo Nordisk, GSK, Diamyd, and Hyperion, and has stocks and shares in GSK. SCB has received grants and honoraria from Abbott, AstraZeneca/BMS, Boehringer Ingelheim, Eli Lily, GSK, MSD, Janssen, Novartis, Novo Nordisk, Sanofi, Takeda, Servier, Roche, and Pfizer. AHB has received honoraria and lecture fees from AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Novartis, Janssen, Eli Lilly, Sanofi, and Novo Nordisk.
J Paul O’Hare*, David Millar-Jones, Wasim Hanif, Debbie Hicks, R David Leslie, Stephen C Bain, Anthony H Barnett [email protected]
680
University of Warwick Medical School, Coventry and University Hospitals, Coventry and Warwickshire NHS Trust, Coventry CV4 7AL, UK (JPO’H); Royal Gwent Hospital and Oak Street Surgery, Cwmbran, UK (DM-J); University Hospital Birmingham, Birmingham, UK (WH); Barnet, Enfield and Harringey Mental Health Trust, London,UK (DH); Queen Mary, University of London, and St Bartholomews Hospital, London, UK (RDL); Swansea University and Abertawe Bro Morgannwg University Health Board, Swansea, UK (SCB); and University of Birmingham and Heart of England NHS Foundation Trust, Birmingham, UK (AHB) 1
2
3
4
5
6
7
8
9
10
NICE. Type 2 diabetes: guideline consultation. https://www.nice.org.uk/guidance/ indevelopment/gid-cgwave0612 (accessed June 30, 2015). Barnett AH. NICE draft type 2 diabetes guidelines: a cause for concern. Lancet Diabetes Endocrinol 2015; 3: 403–05. Saleem K, Ali Yasin M, Asrar A, Qamar S. Comparison of repaglinide with glibenclamide in the reduction of HbA1C of type 2 diabetic patients. Pakistan J Med Health Sci 2011; 5: 23–26. Hussain Shah Z, Saleem K, Mahboob F, Jibran R. A comparative study of repaglinide with glibenclamide in type 2 diabetic patients. Pakistan J Med Health Sci 2011; 5: 476–79 Fang FS, Gong YP, Li CL, et al. Comparison of repaglinide and metformin monotherapy as an initial therapy in Chinese patients with newly diagnosed type 2 diabetes mellitus. Eur J Endocrinol 2014; 170: 901–08. Actos Tablets. Summary of product characteristics. https://www.medicines.org.uk/ emc/medicine/4236 (accessed July 21, 2015). Altaf QA, Barnett AH, Tahrani AA. Novel therapeutics for type 2 diabetes: insulin resistance. Diabetes Obes Metab 2015; 17: 319–34. Thong KY, Gupta PS, Cull ML, et al. GLP-1 receptor agonists in type 2 diabetes: NICE guidelines versus clinical practice. Br J Diabetes Vasc Dis 2014; 14: 52–5. Care Quality Commission. Regulation 20: duty of candour, March 2015. http://www.cqc.org. uk/sites/default/files/20150327_duty_of_ candour_guidance_final.pdf (accessed July 20, 2015). Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2008; 81: 184–89.
Mortality and metformin use in patients with advanced chronic kidney disease Szu-Chun Hung and colleagues’ study1 investigating mortality in patients with diabetes and stage 5 chronic kidney disease who were taking metformin raises several issues. The
researchers provide little information about the course of chronic kidney disease in their study population. Although the patients’ chronic kidney disease is reported as corresponding to stage 5, the low prevalence of retinopathy (30%) and the short duration of diabetes (<6 years) are suggestive of an aggressive kidney disease (rather than end-stage diabetic nephropathy).2 Because patients with advanced chronic kidney disease are clinically unstable, an episode of dehydration, sepsis, or hypoxia could precipitate a further worsening of renal function. Compared with well-matched patients not taking metformin, investigators noted increased mortality in patients who received the highest cumulative defined daily dose and the highest prescribed daily dose (>1000 mg per day). However, for patients with severe renal failure, these doses are not compliant with present guidelines.3 Metformin is eliminated by the kidney (filtrationsecretion range 380-640 mL); hence, in advanced chronic kidney disease, doses higher than 1000 mg per day will rapidly result in high blood metformin concentrations.4 Hung and colleagues do not provide data for the duration of metformin treatment, the number of antidiabetes drugs used, the HbA1c concentrations, the number of comorbidities. Furthermore, the researchers do not provide information about the causes of mortality. What about pathologies unrelated to metformin (sepsis, cancer, haemorrhage, thromboembolism, trauma, and so on)? Throughout the report, lactic acidosis is mentioned as the major risk in patients with renal failure. However, the incidence of metabolic acidosis was no higher in metformin users than in non-users. No information about blood lactate concentrations was provided. In view of the fact that Hung and colleagues’ findings are not in agreement with other data from the
www.thelancet.com/diabetes-endocrinology Vol 3 September 2015
Correspondence
scientific literature,5 we suggest that metformin can be given to patients with stage 3 chronic kidney disease provided that the dose is adjusted, but that treatment should be withdrawn in unstable patients with stage 4–5 chronic kidney disease. J-DL has received personal fees from AstraZeneca, Lilly, Pierre Fabre, Janssen, Novo Nordisk, Novartis, Sanofi, and Merck Serono for speaking. FK has received personal fees from Merck Serono, and Sanofi for speaking. MdB has received personal fees from Shire for consulting. PA declares no competing interests.
*Jean-Daniel Lalau, Farshad Kajbaf, Paul Arnouts, Marc de Broe [email protected] Department of Endocrinology-Nutrition, University Hospital, F-80054 Amiens, France (J-DL, FK); INSERM Unit 1088, University of Picardie Jules Verne, Amiens, France (J-DL, FK); Department of Nephrology-Hypertension, Sint Jozefziekenhuis, Turnhout, Belgium (PA); Laboratory of Pathophysiology, University Hospital, Antwerpen, Belgium (MdB) 1
2
3
4
5
Hung S-C, Chang Y-K, Liu J-S, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3: 605–14. Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 (suppl 1): S30–33. Kajbaf F, Arnouts P, de Broe M, Lalau J. Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal from around the world. Pharmacoepidemiol Drug Saf 2013; 22: 1027–35. Kajbaf F, Lalau JD, Azzoug M, Lemaire-Hurtel AS, De Broe ME. Metformin therapy at different stages of chronic kidney disease. J Am Soc Nephrol 2014; 25 (abstract edition): 76A. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2: e001076.
Authors’ reply We appreciate the comments by Jean-Daniel Lalau and colleagues on our study.1 Our conclusion in the report was actually in line with their contention that metformin treatment should be withdrawn in unstable patients with stage 4–5 chronic kidney disease. Additionally, we further indicated that the risk of metabolic acidosis, a major medical concern, did not differ between metformin users and non-users. Our results are
in agreement with those of previous studies2 and systematic reviews.3 We estimated the duration of diabetes from Taiwan’s National Health Insurance Research Database from 1998 onwards. Therefore, we might have underestimated the true duration of diabetes. The prevalence of diabetic retinopathy in our study was 35%, which is in agreement with previously published Taiwanese epidemiological data,4 and confirms that the population studied is representative. We agree with Lalau and colleagues that metformin might accumulate in patients with chronic kidney disease. However, cutoff values for serum creatinine and maximum metformin daily dose recommended in existing guidelines are based on opinion rather than evidence. What would constitute an unsafe serum creatinine concentration is not really known. In fact, clinicians often need to check and find a balance between achieving glycaemic control and limiting adverse effects of metformin within the constraints of rigid guidelines. Interestingly, the proportion of patients using metformin despite having an estimated glomerular filtration rate lower than 30 mL/min per 1·73 m², at which metformin use is discouraged, remained as high as 18% in a recent study examining National Health and Nutrition Examination Survey data from 2007 to 2012 in the USA.5 The mean number of antidiabetes drugs used per patient was 1·6 in the overall study cohort. We measured patient comorbidity with the Charlson Comorbidity Index. We did not account for the actual duration of metformin treatment because of methodological limitations in the design of the study. We acknowledge that the paucity of information about HbA1c concentration might be detrimental to the analysis. However, in a study of patients with longstanding type 2 diabetes,6 intensive glucose control to achieve a target HbA1c did not provide a survival benefit. Finally, we focused mainly on all-cause death
www.thelancet.com/diabetes-endocrinology Vol 3 September 2015
because this is the most robust and relevant outcome. Although causes of death were not available in our administrative database, we noted that metformin use compared with no use was associated with a significantly higher risk of hospital admission for cardiovascular disease, the leading cause of death in patients with diabetes. In our study,1 we aimed to assess the safety of metformin in patients with diabetes and advanced chronic kidney disease. Although randomised controlled trials are needed to provide a definite answer, in the meantime registry-based studies such as ours make an important contribution to the evidence base regarding the use of metformin in these patients. We declare no competing interests.
Szu-Chun Hung, Yu-Kang Chang, Jia-Sin Liu, Chih-Cheng Hsu, Der-Cherng Tarng* [email protected] Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan (S-CH); Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan (Y-KC, J-SL, C-CH); Institutes of Clinical Medicine (C-CH, D-CT) and Physiology (D-CT), National Yang-Ming University, Taipei City, Taiwan; and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (D-CT) 1
2
3
4
5
6
Hung S-C, Chang Y-K, Liu J-S, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3: 605–14. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2: e001076. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312: 2668–75. Chang CJ, Lu FH, Yang YC, et al. Epidemiologic study of type 2 diabetes in Taiwan. Diabetes Res Clin Pract 2000; 50 (suppl 2): S49–59. Flory JH, Hennessy S. Metformin use reduction in mild to moderate renal impairment: possible inappropriate curbing of use based on Food and Drug Administration contraindications. JAMA Intern Med 2015; 175: 458–59. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372: 2197–206.
681
is against the basic principles of our profession. It also raises the question of why longacting analogues are recommended as a first-line option for patients with type 1 diabetes (in the current draft NICE guideline),2 but denied to people with type 2 diabetes. Primary care doctors and nurses, in particular, are struggling to look after growing numbers of patients with type 2 diabetes. These healthcare professionals need clear, sensible guidance, based on evidence (and cost), but most importantly on safety. We strongly recommend that in further revisions to the NICE guideline, repaglinide is withdrawn as a first-line treatment, the prominence given to sulphonylureas at all stages of intensification is reduced, the BMI restrictions and stopping rules for GLP-1 receptor agonists are redrawn, and the SGLT-2 inhibitors are fully included. Furthermore, individualised care for insulin management should mean just that, rather than restricting choice on the basis of cost. Finally, the promotion of the waiting-for-failure approach should be reviewed. JPO’H receives lecture fees and advisory honoraria from Sanofi and Novo Nordisk. DM-J has received personal fees from Novo Nordisk, AstraZeneca, Janssen,Takeda, Lilly, MSD, and Sanofi for lectures and advisory boards. WH is chair of the South Asian Health Foundation, and receives grants, personal fees, and non-financial support from Novo Nordisk, Boerhinger Ingelhiem, and Sanofi; grants and personal fees from Astra Zeneca; grants, personal fees, and non-financial support from Jansen and Merck; and grants from Takeda, outside the submitted work. DH has worked on advisory boards for Novo Nordisk, Lilly, AstraZeneca, MSD, Abbott, Janssen, Roche, and BD, and has provided presentations at conferences sponsored by the pharmaceutical industry. RDL has worked on advisory boards for Novo Nordisk, GSK, Diamyd, and Hyperion, and has stocks and shares in GSK. SCB has received grants and honoraria from Abbott, AstraZeneca/BMS, Boehringer Ingelheim, Eli Lily, GSK, MSD, Janssen, Novartis, Novo Nordisk, Sanofi, Takeda, Servier, Roche, and Pfizer. AHB has received honoraria and lecture fees from AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Novartis, Janssen, Eli Lilly, Sanofi, and Novo Nordisk.
J Paul O’Hare*, David Millar-Jones, Wasim Hanif, Debbie Hicks, R David Leslie, Stephen C Bain, Anthony H Barnett [email protected]
680
University of Warwick Medical School, Coventry and University Hospitals, Coventry and Warwickshire NHS Trust, Coventry CV4 7AL, UK (JPO’H); Royal Gwent Hospital and Oak Street Surgery, Cwmbran, UK (DM-J); University Hospital Birmingham, Birmingham, UK (WH); Barnet, Enfield and Harringey Mental Health Trust, London,UK (DH); Queen Mary, University of London, and St Bartholomews Hospital, London, UK (RDL); Swansea University and Abertawe Bro Morgannwg University Health Board, Swansea, UK (SCB); and University of Birmingham and Heart of England NHS Foundation Trust, Birmingham, UK (AHB) 1
2
3
4
5
6
7
8
9
10
NICE. Type 2 diabetes: guideline consultation. https://www.nice.org.uk/guidance/ indevelopment/gid-cgwave0612 (accessed June 30, 2015). Barnett AH. NICE draft type 2 diabetes guidelines: a cause for concern. Lancet Diabetes Endocrinol 2015; 3: 403–05. Saleem K, Ali Yasin M, Asrar A, Qamar S. Comparison of repaglinide with glibenclamide in the reduction of HbA1C of type 2 diabetic patients. Pakistan J Med Health Sci 2011; 5: 23–26. Hussain Shah Z, Saleem K, Mahboob F, Jibran R. A comparative study of repaglinide with glibenclamide in type 2 diabetic patients. Pakistan J Med Health Sci 2011; 5: 476–79 Fang FS, Gong YP, Li CL, et al. Comparison of repaglinide and metformin monotherapy as an initial therapy in Chinese patients with newly diagnosed type 2 diabetes mellitus. Eur J Endocrinol 2014; 170: 901–08. Actos Tablets. Summary of product characteristics. https://www.medicines.org.uk/ emc/medicine/4236 (accessed July 21, 2015). Altaf QA, Barnett AH, Tahrani AA. Novel therapeutics for type 2 diabetes: insulin resistance. Diabetes Obes Metab 2015; 17: 319–34. Thong KY, Gupta PS, Cull ML, et al. GLP-1 receptor agonists in type 2 diabetes: NICE guidelines versus clinical practice. Br J Diabetes Vasc Dis 2014; 14: 52–5. Care Quality Commission. Regulation 20: duty of candour, March 2015. http://www.cqc.org. uk/sites/default/files/20150327_duty_of_ candour_guidance_final.pdf (accessed July 20, 2015). Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2008; 81: 184–89.
Mortality and metformin use in patients with advanced chronic kidney disease Szu-Chun Hung and colleagues’ study1 investigating mortality in patients with diabetes and stage 5 chronic kidney disease who were taking metformin raises several issues. The
researchers provide little information about the course of chronic kidney disease in their study population. Although the patients’ chronic kidney disease is reported as corresponding to stage 5, the low prevalence of retinopathy (30%) and the short duration of diabetes (<6 years) are suggestive of an aggressive kidney disease (rather than end-stage diabetic nephropathy).2 Because patients with advanced chronic kidney disease are clinically unstable, an episode of dehydration, sepsis, or hypoxia could precipitate a further worsening of renal function. Compared with well-matched patients not taking metformin, investigators noted increased mortality in patients who received the highest cumulative defined daily dose and the highest prescribed daily dose (>1000 mg per day). However, for patients with severe renal failure, these doses are not compliant with present guidelines.3 Metformin is eliminated by the kidney (filtrationsecretion range 380-640 mL); hence, in advanced chronic kidney disease, doses higher than 1000 mg per day will rapidly result in high blood metformin concentrations.4 Hung and colleagues do not provide data for the duration of metformin treatment, the number of antidiabetes drugs used, the HbA1c concentrations, the number of comorbidities. Furthermore, the researchers do not provide information about the causes of mortality. What about pathologies unrelated to metformin (sepsis, cancer, haemorrhage, thromboembolism, trauma, and so on)? Throughout the report, lactic acidosis is mentioned as the major risk in patients with renal failure. However, the incidence of metabolic acidosis was no higher in metformin users than in non-users. No information about blood lactate concentrations was provided. In view of the fact that Hung and colleagues’ findings are not in agreement with other data from the
www.thelancet.com/diabetes-endocrinology Vol 3 September 2015
Correspondence
scientific literature,5 we suggest that metformin can be given to patients with stage 3 chronic kidney disease provided that the dose is adjusted, but that treatment should be withdrawn in unstable patients with stage 4–5 chronic kidney disease. J-DL has received personal fees from AstraZeneca, Lilly, Pierre Fabre, Janssen, Novo Nordisk, Novartis, Sanofi, and Merck Serono for speaking. FK has received personal fees from Merck Serono, and Sanofi for speaking. MdB has received personal fees from Shire for consulting. PA declares no competing interests.
*Jean-Daniel Lalau, Farshad Kajbaf, Paul Arnouts, Marc de Broe [email protected] Department of Endocrinology-Nutrition, University Hospital, F-80054 Amiens, France (J-DL, FK); INSERM Unit 1088, University of Picardie Jules Verne, Amiens, France (J-DL, FK); Department of Nephrology-Hypertension, Sint Jozefziekenhuis, Turnhout, Belgium (PA); Laboratory of Pathophysiology, University Hospital, Antwerpen, Belgium (MdB) 1
2
3
4
5
Hung S-C, Chang Y-K, Liu J-S, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3: 605–14. Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 (suppl 1): S30–33. Kajbaf F, Arnouts P, de Broe M, Lalau J. Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal from around the world. Pharmacoepidemiol Drug Saf 2013; 22: 1027–35. Kajbaf F, Lalau JD, Azzoug M, Lemaire-Hurtel AS, De Broe ME. Metformin therapy at different stages of chronic kidney disease. J Am Soc Nephrol 2014; 25 (abstract edition): 76A. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2: e001076.
Authors’ reply We appreciate the comments by Jean-Daniel Lalau and colleagues on our study.1 Our conclusion in the report was actually in line with their contention that metformin treatment should be withdrawn in unstable patients with stage 4–5 chronic kidney disease. Additionally, we further indicated that the risk of metabolic acidosis, a major medical concern, did not differ between metformin users and non-users. Our results are
in agreement with those of previous studies2 and systematic reviews.3 We estimated the duration of diabetes from Taiwan’s National Health Insurance Research Database from 1998 onwards. Therefore, we might have underestimated the true duration of diabetes. The prevalence of diabetic retinopathy in our study was 35%, which is in agreement with previously published Taiwanese epidemiological data,4 and confirms that the population studied is representative. We agree with Lalau and colleagues that metformin might accumulate in patients with chronic kidney disease. However, cutoff values for serum creatinine and maximum metformin daily dose recommended in existing guidelines are based on opinion rather than evidence. What would constitute an unsafe serum creatinine concentration is not really known. In fact, clinicians often need to check and find a balance between achieving glycaemic control and limiting adverse effects of metformin within the constraints of rigid guidelines. Interestingly, the proportion of patients using metformin despite having an estimated glomerular filtration rate lower than 30 mL/min per 1·73 m², at which metformin use is discouraged, remained as high as 18% in a recent study examining National Health and Nutrition Examination Survey data from 2007 to 2012 in the USA.5 The mean number of antidiabetes drugs used per patient was 1·6 in the overall study cohort. We measured patient comorbidity with the Charlson Comorbidity Index. We did not account for the actual duration of metformin treatment because of methodological limitations in the design of the study. We acknowledge that the paucity of information about HbA1c concentration might be detrimental to the analysis. However, in a study of patients with longstanding type 2 diabetes,6 intensive glucose control to achieve a target HbA1c did not provide a survival benefit. Finally, we focused mainly on all-cause death
www.thelancet.com/diabetes-endocrinology Vol 3 September 2015
because this is the most robust and relevant outcome. Although causes of death were not available in our administrative database, we noted that metformin use compared with no use was associated with a significantly higher risk of hospital admission for cardiovascular disease, the leading cause of death in patients with diabetes. In our study,1 we aimed to assess the safety of metformin in patients with diabetes and advanced chronic kidney disease. Although randomised controlled trials are needed to provide a definite answer, in the meantime registry-based studies such as ours make an important contribution to the evidence base regarding the use of metformin in these patients. We declare no competing interests.
Szu-Chun Hung, Yu-Kang Chang, Jia-Sin Liu, Chih-Cheng Hsu, Der-Cherng Tarng* [email protected] Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan (S-CH); Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan (Y-KC, J-SL, C-CH); Institutes of Clinical Medicine (C-CH, D-CT) and Physiology (D-CT), National Yang-Ming University, Taipei City, Taiwan; and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (D-CT) 1
2
3
4
5
6
Hung S-C, Chang Y-K, Liu J-S, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3: 605–14. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2: e001076. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312: 2668–75. Chang CJ, Lu FH, Yang YC, et al. Epidemiologic study of type 2 diabetes in Taiwan. Diabetes Res Clin Pract 2000; 50 (suppl 2): S49–59. Flory JH, Hennessy S. Metformin use reduction in mild to moderate renal impairment: possible inappropriate curbing of use based on Food and Drug Administration contraindications. JAMA Intern Med 2015; 175: 458–59. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372: 2197–206.
681