Correspondence
SGLT inhibition in patients with type 1 diabetes Inhibitors of sodium–glucose cotransporters (SGLT) have shown some advantages for patients with type 1 diabetes. 1–5 These benefits include oral route of administration, reduced insulin requirements, improved glycaemic control, reduced cardiovascular risk, and weight loss. However, this therapeutic approach might also increase risk for development of euglycaemic diabetic ketoacidosis (ie, diabetic ketoacidosis that is dissociated from hyperglycaemia). Euglycaemic diabetic ketoacidosis is a potentially fatal, metabolic acidosis state that is not necessarily less severe than diabetic ketoacidosis with hyperglycaemia. The risk of euglycaemic diabetic ketoacidosis in patients with type 1 diabetes after SGLT inhibition is linked to the underlying pathophysiology of diabetes and the many mechanisms of action for this drug class. The insulinindependent removal of glucose from the body might enable glycaemic control concurrent with either an absolute or relative deficiency of insulin. Additionally, SGLT inhibition has been associated with increased glucagon concentration in patients with type 2 diabetes. 4,5 Although insulinopenia is implicated indirectly in ketogenesis, glucagon is implicated directly and is potently lipolytic and ketogenic. Investigators of at least one study have reported an increased incidence of ketonuria among patients with type 1 diabetes treated with an SGLT inhibitor.1 The previously mentioned risks might be aggravated by nonadherence to existing treatments—for example, some patients with type 1 diabetes intentionally omit insulin for weight control. Further, the decreased frequency of long-acting basal insulin administration paradoxically increases the ketogenic effect of even a single
omission, which might be greater in the presence of SGLT inhibition. In these cases, the avoidance of hyperglycemia through SGLT inhibition could mask the most obvious indicator of insulin non-compliance. Patients and healthcare providers might be oblivious to the development of a potentially life-threatening state, distracted by a false sense of euglycaemic security. Thus, use of SGLT inhibitors in patients with type 1 diabetes warrants a cautious approach. I am an employee of Celerion, a contract research organisation that potentially participates in the investigation of any antidiabetic drug class.
Clayton A Dehn [email protected] Metabolic Diseases, Celerion, Tempe, AZ 85283, USA 1
2
3
4
5
Henry RR, Rosenstock J, Chalamandris A-G, Kasichayanula S, Bogle A, Griffen SC. Exploring the potential of dapagliflozin in type 1 diabetes: phase 2a pilot study. 73rd American Diabetes Association Scientific Sessions; Chicago, IL, USA; June 21–25, 2013; 70-LB. Perkins BA, Cherney DZ, Partridge H, et al. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves glycemic control in patients with type 1 diabetes: a single-arm clinical trial. 73rd American Diabetes Association Scientific Sessions; Chicago, IL, USA; June 21–25, 2013; 1074-P. Lexicon Pharmaceuticals. LX4211 achieves positive results in type 1 diabetes clinical trial. 2013. Press release. http://www.lexgen.com/ news/press-releases/2321-lx4211-achievespositive-results-in-type-1-diabetes-clinicaltrial.html (accessed April 29, 2014. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium–glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124: 499–508. Mervoci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124: 509–14.
Cardiovascular outcomes in the Da Qing Diabetes Prevention Study In their Article in The Lancet Diabetes & Endocrinology (May 24), Li and colleagues1 report that a 6 year lifestyle intervention in people with impaired glucose tolerance had positive effects on cardiovascular mortality and all-cause mortality
www.thelancet.com/diabetes-endocrinology Vol 2 July 2014
after 23 years. They describe how a difference between the groups started to emerge 12 years after the study began, how this difference had increased at 20 years, and how it had finally reached significance after 23 years.1 However, these results should be interpreted with caution. First, trials that stop early are likely to show more dramatic treatment effects than do trials that go on for the full planned period2 because results are subject to substantial random fluctuations. An interim result substantial enough to stop a trial will most likely show an unrepresentatively large difference by chance.3 Whether this effect is also present in post-interventional follow-up studies, as for that analysed by Li and colleagues, is not as clear, but a random fluctuation can still be expected. If analyses are repeated again and again, effects will sometimes seem more pronounced. The Kaplan-Meyer plots for mortality outcomes in the Da Qing study are particularly steep during year 21, more so than during the rest of the study period.1 This observation might indicate that the differences in statistical significance seen between 20 years and 23 years are, at least partly, random. Second, repeated testing is a general statistical problem for trials. Together, in the 20 year follow-up and the 23 year follow-up, the authors specify at least 13 primary analyses, and a number of post-hoc analyses with different multivariate models.4 Although these calculations were done with the best of intentions, the number in itself poses a threat to the statistical validity of the results.3 Third, the interpretation is difficult for the subgroup analyses that showed greater reductions in all-cause and cardiovascular mortality in women. The results were almost completely confined to the cardiovascular analysis, which consists of only 22 events. In very small cohorts, again, the impact of chance will increase. Also, differences
Published Online June 9, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70112-3
539
Correspondence
between individuals at baseline will start to have possible effects on the results. The conclusion that lifestyle interventions for people with impaired glucose tolerance lowers diabetesrelated deaths, and that these effects are true in women especially, thus seem somewhat premature. I declare no competing interests.
Mattias Brunström [email protected] Department of Public Health and Clinical Medicine, Division of Medicine, Umea University, Umea 901 87-SE, Sweden 1
2
3
4
Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Bassler D, Montori VM, Briel M, et al. Reflections on meta-analyses involving trials stopped early for benefit: Is there a problem and if so, what is it? Stat Methods Med Res 2013; 22: 159–68. Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet 2005; 365: 1657–61. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371: 1783–89.
Authors’ reply We thank Mattias Bronström for his interest in our Article.1 The Da Qing Diabetes Prevention Study was not terminated prematurely, but ran the planned full course of 6 years of intervention.2 Subsequently, 20 years after the initial randomisation, we designed and implemented an observational follow-up study with prespecified outcomes and reported the results on the macrocomplications and microcomplications of diabetes.3,4 Because of potentially very important, but non-significant, trends in mortality seen in the 20 year followup, a subsequent follow-up at 23 years was specifically designed to determine whether the death rates between the lifestyle intervention and control groups continued to diverge.1 The observation of a greater effect of lifestyle intervention in women, which was the result of a post-hoc 540
analysis, was not anticipated and the explanations remain unclear. Given its level of statistical significance, we believe that this result needed to be reported. However, we do share some of Bronström’s hesitation to accept its magnitude at face value. More importantly, as the first report of a randomised controlled trial to show statistically significant reduction in mortality rates after lifestyle intervention in patients with impaired glucose tolerance,1 replication of the findings from continuing studies such as The Diabetes Prevention Program Outcomes Study (DPPOS)5 will be important to determine the extent to which our results can be generalised. We declare no competing interests.
*Guangwei Li, Ping Zhang, Edward W Gregg, Michael M Engelgau, Peter H Bennett [email protected] Department of Endocrinology, China–Japan Friendship Hospital, Beijing 100029, China (GL); Center of Endocrinology and Cardiovascular Disease, National Center of Cardiology and Fuwai Hospital, Beijing, China (GL); Division of Diabetes Translation (PZ, EWG) and Center for Global Health (MME), Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; and Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA (PHB) 1
2
3
4
5
Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–44. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371: 1783–89. Gong Q, Gregg EW, Wang J, et al. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Diabetologia 2011; 54: 300–07. Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374: 1677–86.
Vitamin D and falls In their Article in The Lancet Diabetes & Endocrinology (April 24), Bolland and colleagues1 conclude that “at present, there is little justification for prescribing vitamin D supplements to prevent falls”. The authors’ key underpinning assumption rests on their belief that a threshold risk reduction of 15% “is the smallest effect that is clinically relevant for an individual”. In our view, this statement naturally warrants examination in context. We are carrying out an economic evaluation of alternative public health strategies with regards to vitamin D supplementation. A simple 5 year budget impact model using UK inputs for outcomes2 and costs, taking into account institutional care for older adults,3 suggests that even if the effect of vitamin D supplementation (800 IU every day) on falls was as little as a 6% relative risk reduction, use of this intervention in individuals older than 75 years would save costs for the UK National Health Service. In this conservative scenario, more than 6000 deaths would be avoided and a further 7000 older adults could remain living independently (with a higher quality of life). Usefully, the work of Bolland’s group in Auckland does show the substantial heterogeneity between the few trials available. Some specific subgroups might benefit, but traditional aggregate data meta-analysis is poorly placed to detect these benefits reliably. The statistical power of aggregate data meta-analysis in simulation studies4 can be dramatically and consistently lower than that in equivalent individual patient data meta-analyses, with little agreement between the estimates obtained from the two methods. Only in meta-analyses of large numbers of large trials does meta-regression detect differential treatment effects between risk groups with any consistency. Therefore, while meta-analysis of summary data might be adequate to estimate a single pooled treatment
www.thelancet.com/diabetes-endocrinology Vol 2 July 2014
SGLT inhibition in patients with type 1 diabetes Inhibitors of sodium–glucose cotransporters (SGLT) have shown some advantages for patients with type 1 diabetes. 1–5 These benefits include oral route of administration, reduced insulin requirements, improved glycaemic control, reduced cardiovascular risk, and weight loss. However, this therapeutic approach might also increase risk for development of euglycaemic diabetic ketoacidosis (ie, diabetic ketoacidosis that is dissociated from hyperglycaemia). Euglycaemic diabetic ketoacidosis is a potentially fatal, metabolic acidosis state that is not necessarily less severe than diabetic ketoacidosis with hyperglycaemia. The risk of euglycaemic diabetic ketoacidosis in patients with type 1 diabetes after SGLT inhibition is linked to the underlying pathophysiology of diabetes and the many mechanisms of action for this drug class. The insulinindependent removal of glucose from the body might enable glycaemic control concurrent with either an absolute or relative deficiency of insulin. Additionally, SGLT inhibition has been associated with increased glucagon concentration in patients with type 2 diabetes. 4,5 Although insulinopenia is implicated indirectly in ketogenesis, glucagon is implicated directly and is potently lipolytic and ketogenic. Investigators of at least one study have reported an increased incidence of ketonuria among patients with type 1 diabetes treated with an SGLT inhibitor.1 The previously mentioned risks might be aggravated by nonadherence to existing treatments—for example, some patients with type 1 diabetes intentionally omit insulin for weight control. Further, the decreased frequency of long-acting basal insulin administration paradoxically increases the ketogenic effect of even a single
omission, which might be greater in the presence of SGLT inhibition. In these cases, the avoidance of hyperglycemia through SGLT inhibition could mask the most obvious indicator of insulin non-compliance. Patients and healthcare providers might be oblivious to the development of a potentially life-threatening state, distracted by a false sense of euglycaemic security. Thus, use of SGLT inhibitors in patients with type 1 diabetes warrants a cautious approach. I am an employee of Celerion, a contract research organisation that potentially participates in the investigation of any antidiabetic drug class.
Clayton A Dehn [email protected] Metabolic Diseases, Celerion, Tempe, AZ 85283, USA 1
2
3
4
5
Henry RR, Rosenstock J, Chalamandris A-G, Kasichayanula S, Bogle A, Griffen SC. Exploring the potential of dapagliflozin in type 1 diabetes: phase 2a pilot study. 73rd American Diabetes Association Scientific Sessions; Chicago, IL, USA; June 21–25, 2013; 70-LB. Perkins BA, Cherney DZ, Partridge H, et al. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves glycemic control in patients with type 1 diabetes: a single-arm clinical trial. 73rd American Diabetes Association Scientific Sessions; Chicago, IL, USA; June 21–25, 2013; 1074-P. Lexicon Pharmaceuticals. LX4211 achieves positive results in type 1 diabetes clinical trial. 2013. Press release. http://www.lexgen.com/ news/press-releases/2321-lx4211-achievespositive-results-in-type-1-diabetes-clinicaltrial.html (accessed April 29, 2014. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium–glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124: 499–508. Mervoci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124: 509–14.
Cardiovascular outcomes in the Da Qing Diabetes Prevention Study In their Article in The Lancet Diabetes & Endocrinology (May 24), Li and colleagues1 report that a 6 year lifestyle intervention in people with impaired glucose tolerance had positive effects on cardiovascular mortality and all-cause mortality
www.thelancet.com/diabetes-endocrinology Vol 2 July 2014
after 23 years. They describe how a difference between the groups started to emerge 12 years after the study began, how this difference had increased at 20 years, and how it had finally reached significance after 23 years.1 However, these results should be interpreted with caution. First, trials that stop early are likely to show more dramatic treatment effects than do trials that go on for the full planned period2 because results are subject to substantial random fluctuations. An interim result substantial enough to stop a trial will most likely show an unrepresentatively large difference by chance.3 Whether this effect is also present in post-interventional follow-up studies, as for that analysed by Li and colleagues, is not as clear, but a random fluctuation can still be expected. If analyses are repeated again and again, effects will sometimes seem more pronounced. The Kaplan-Meyer plots for mortality outcomes in the Da Qing study are particularly steep during year 21, more so than during the rest of the study period.1 This observation might indicate that the differences in statistical significance seen between 20 years and 23 years are, at least partly, random. Second, repeated testing is a general statistical problem for trials. Together, in the 20 year follow-up and the 23 year follow-up, the authors specify at least 13 primary analyses, and a number of post-hoc analyses with different multivariate models.4 Although these calculations were done with the best of intentions, the number in itself poses a threat to the statistical validity of the results.3 Third, the interpretation is difficult for the subgroup analyses that showed greater reductions in all-cause and cardiovascular mortality in women. The results were almost completely confined to the cardiovascular analysis, which consists of only 22 events. In very small cohorts, again, the impact of chance will increase. Also, differences
Published Online June 9, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70112-3
539
Correspondence
between individuals at baseline will start to have possible effects on the results. The conclusion that lifestyle interventions for people with impaired glucose tolerance lowers diabetesrelated deaths, and that these effects are true in women especially, thus seem somewhat premature. I declare no competing interests.
Mattias Brunström [email protected] Department of Public Health and Clinical Medicine, Division of Medicine, Umea University, Umea 901 87-SE, Sweden 1
2
3
4
Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Bassler D, Montori VM, Briel M, et al. Reflections on meta-analyses involving trials stopped early for benefit: Is there a problem and if so, what is it? Stat Methods Med Res 2013; 22: 159–68. Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet 2005; 365: 1657–61. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371: 1783–89.
Authors’ reply We thank Mattias Bronström for his interest in our Article.1 The Da Qing Diabetes Prevention Study was not terminated prematurely, but ran the planned full course of 6 years of intervention.2 Subsequently, 20 years after the initial randomisation, we designed and implemented an observational follow-up study with prespecified outcomes and reported the results on the macrocomplications and microcomplications of diabetes.3,4 Because of potentially very important, but non-significant, trends in mortality seen in the 20 year followup, a subsequent follow-up at 23 years was specifically designed to determine whether the death rates between the lifestyle intervention and control groups continued to diverge.1 The observation of a greater effect of lifestyle intervention in women, which was the result of a post-hoc 540
analysis, was not anticipated and the explanations remain unclear. Given its level of statistical significance, we believe that this result needed to be reported. However, we do share some of Bronström’s hesitation to accept its magnitude at face value. More importantly, as the first report of a randomised controlled trial to show statistically significant reduction in mortality rates after lifestyle intervention in patients with impaired glucose tolerance,1 replication of the findings from continuing studies such as The Diabetes Prevention Program Outcomes Study (DPPOS)5 will be important to determine the extent to which our results can be generalised. We declare no competing interests.
*Guangwei Li, Ping Zhang, Edward W Gregg, Michael M Engelgau, Peter H Bennett [email protected] Department of Endocrinology, China–Japan Friendship Hospital, Beijing 100029, China (GL); Center of Endocrinology and Cardiovascular Disease, National Center of Cardiology and Fuwai Hospital, Beijing, China (GL); Division of Diabetes Translation (PZ, EWG) and Center for Global Health (MME), Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; and Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA (PHB) 1
2
3
4
5
Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014; 2: 474–80. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–44. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371: 1783–89. Gong Q, Gregg EW, Wang J, et al. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Diabetologia 2011; 54: 300–07. Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374: 1677–86.
Vitamin D and falls In their Article in The Lancet Diabetes & Endocrinology (April 24), Bolland and colleagues1 conclude that “at present, there is little justification for prescribing vitamin D supplements to prevent falls”. The authors’ key underpinning assumption rests on their belief that a threshold risk reduction of 15% “is the smallest effect that is clinically relevant for an individual”. In our view, this statement naturally warrants examination in context. We are carrying out an economic evaluation of alternative public health strategies with regards to vitamin D supplementation. A simple 5 year budget impact model using UK inputs for outcomes2 and costs, taking into account institutional care for older adults,3 suggests that even if the effect of vitamin D supplementation (800 IU every day) on falls was as little as a 6% relative risk reduction, use of this intervention in individuals older than 75 years would save costs for the UK National Health Service. In this conservative scenario, more than 6000 deaths would be avoided and a further 7000 older adults could remain living independently (with a higher quality of life). Usefully, the work of Bolland’s group in Auckland does show the substantial heterogeneity between the few trials available. Some specific subgroups might benefit, but traditional aggregate data meta-analysis is poorly placed to detect these benefits reliably. The statistical power of aggregate data meta-analysis in simulation studies4 can be dramatically and consistently lower than that in equivalent individual patient data meta-analyses, with little agreement between the estimates obtained from the two methods. Only in meta-analyses of large numbers of large trials does meta-regression detect differential treatment effects between risk groups with any consistency. Therefore, while meta-analysis of summary data might be adequate to estimate a single pooled treatment
www.thelancet.com/diabetes-endocrinology Vol 2 July 2014
