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Guilt, or guilt by association? Insulin therapy in type 2 diabetes and death
Comment
People with type 2 diabetes who take insulin die sooner than people with type 2 diabetes who do not take insulin. This is accepted. What is not accepted is whether insulin is at fault. One could easily conclude that insulin shortens lives. By the same logic, one could conclude that chemotherapy causes people to die from cancer, but of course only people with cancer get chemotherapy. For people with type 2 diabetes, those who require insulin could simply have a higher risk of dying than people who do not require insulin—a plausible idea given that poor glycaemic control triggers both the need for insulin and a higher risk of cardiovascular events including death. Insulin might then seem culpable; the challenge is proving its innocence. In The Lancet Diabetes & Endocrinology, John Gamble and colleagues1 undertake the challenge of extricating the effect of insulin dose on cardiovascular disease and death. In a cohort study using routinely collected data from general practitioners in the UK, the authors studied 6072 new users of insulin; using Cox proportional hazard models to adjust for confounding, they found a positive association between insulin dose and death. Compared with patients taking less than 25 units per day, the adjusted hazard ratio (aHR) was 1·41 (95% CI 1·12–1·78) for those taking 25 to less than 50 units per day, 1·37 (1·04–1·80) for those taking 50 to less than 75 units per day, 1·85 (1·35–2·53) for those taking 75 to less than 100 units per day, and 2·16 (1·58–2·93) for those taking at least 100 units per day. However, when they used a marginal structural Cox proportional hazards model, which adjusts for time-varying confounders affected by previous insulin treatment, they did not find a significant association between insulin dose and death (aHR 1·40 [95% CI 0·99–1·99], 1·12 [0·75–1·68], 1·49 [0·93–2·38], and 1·60 [0·99–2·60] for the four insulin doses, respectively, relative to less than 25 units per day) in a model with fewer covariates. This is not the first observational study to assess the association between insulin dose and mortality in type 2 diabetes, and not even the first to do so using the Clinical Practice Research Datalink.2 Like the study from Gamble and colleagues,1 Holden and colleagues2 assessed higher doses of insulin compared with lower doses of insulin
(the exposures) and cardiovascular disease and death (the outcome) using Cox proportional hazards modelling to control for confounding. Both studies also accounted for residual confounding and found that insulin increases the risk of death. The two studies differ in other ways, including the population being studied. The study by Holden and colleagues2 included only people on insulin monotherapy, whereas the study by Gamble and colleagues1 included people who added insulin to metformin. Care guidelines in England advocate that people with type 2 diabetes remain on metformin when adding insulin3 making the study by Gamble and colleagues2 more generalisable. The study by Holden and colleagues2 analysed insulin dose by bodyweight, whereas the study by Gamble and colleagues1 consider bodyweight as a potential confounder in all analyses. An apparently fundamental analytical difference between the two studies is that the study by Gamble and colleagues1 used a marginal structural model to tackle the dual problems of time-dependent exposures (specifically, changing doses of insulin) and timedependent confounders (for example, insulin is offered to people with hyperglycaemia, which itself both changes over time and increases the risk of death).4 Moreover, glycaemia both determines future doses of insulin, and reflects previous dosages of insulin. The method uses so-called inverse probability of treatment weighting, meaning that individuals are given mathematical weights proportional to their probability of receiving their own exposure history (here, insulin treatment), and removes the association between the dose of insulin and any measured confounders.5–7 There are issues remaining with regard to the study by Gamble and colleagues. As the study design selected patients who added insulin after starting metformin monotherapy, it might or might not apply to the about 6% of the UK population with type 2 diabetes who initiate treatment with a sulfonylurea.8 Appropriately, the authors also included patients who took other diabetic drugs between metformin and insulin. Misclassification of exposure classically biases results towards finding no effect. In this regard, although the authors have not reassured
www.thelancet.com/diabetes-endocrinology Published online November 16, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30394-1
Ian Hooton/Science Photo Library
Guilt, or guilt by association? Insulin therapy in type 2 diabetes and death
Lancet Diabetes Endocrinol 2016 Published Online November 16, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30394-1 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(16)30316-3
1
Comment
the reader that their method of calculating insulin dosage based on time between prescriptions accurately reflects dosages actually taken, they acknowledge the need to validate their approach. Lastly, marginal structural models depend on assuming no unmeasured confounding, and, alas, this is not empirically verifiable.5 Why can’t this question be addressed in a randomised controlled trial where randomisation equally distributes confounders known and unknown? For one, it is considered unethical to do interventional studies using treatments hypothesised to cause harm. For another, in a blinded trial of higher versus lower doses of insulin, the patients and clinicians are unlikely to remain masked. Even the ongoing DEVOTE trial is not designed to assess the effect of insulin dosages, but instead to assess whether insulin degludec is not worse than glargine with respect to cardiovascular disease and death.9 Drugs are meant to do more good than harm. If the harms of insulin in type 2 diabetes overshadow the benefits, then the public would reasonably expect the regulatory agencies to take action. The Pharmacovigilance Risk Assessment Committee of the European Medicines Agency addressed the safety of insulin in 2014 noting ‘‘no consistent evidence of cardiovascular harm from use of insulin in patients with type 2 diabetes’’ and did not deem regulatory action to be necessary.10 The regulator will continue to monitor for cause to change its decision. Finally, what does the negative finding mean? Should patients and their doctors be reassured as the authors suggest? Simply, a negative finding could mean that no association exists or that an association does exist, but the study did not find it. The results from their marginal structural models with a subset of covariates showed no significant higher risk of death in people in any of four categories of increasing daily dosages of insulin compared with people on fewer than 25 units of insulin per day;
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however all four categories generated hazard ratios greater than 1·0. Therefore, it seems possible that a bigger study would find significant associations suggesting harm, but also that residual confounding would remain. Only when confounding does not interfere and the study is big enough, can one confidentially conclude that insulin is not harmful to people with type 2 diabetes. Crucially, when this occurs, one could also wonder why more insulin does not make people with type 2 diabetes live any longer. Amanda I Adler Wolfson Diabetes and Endocrine Clinic, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK [email protected] I declare no competing interests. 1
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Gamble J-M, Chibrikov E, Twells LK, et al. Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study. Lancet Diabetes Endocrinol 2016; published online Nov 16. http://dx. doi.org/10.1016/S2213-8587(16)30316-3. Holden SE, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ. Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes Metab 2015; 17: 350–62. McGuire H, Longson D, Adler A, Farmer A, Lewin I, for the Guideline Development Group. Management of type 2 diabetes in adults: summary of updated NICE guidance. BMJ 2016; 353: i1575. Hernan MA, Brumback BA, Robins JM. Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures. Stat Med 2002; 21: 1689–709. Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008; 168: 656–64. Brookhart MA, Wyss R, Layton JB, Stürmer T. Propensity score methods for confounding control in nonexperimental research. Circ Cardiovasc Qual Outcomes 2013; 6: 604–11. Sugihara M. Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score. Pharm Stat 2010; 9: 21–34. Sharma M, Nazareth I, Petersen I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open 2016; 6: e010210. Marso SP, McGuire DK, Zinman B, et al. Design of DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events)—DEVOTE 1. Am Heart J 2016; 179: 175–83. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of the meeting on March 3–6, 2014. http://www.ema.europa.eu/docs/en_GB/document_library/ Minutes/2014/04/WC500165698.pdf (accessed Nov 4, 2016).
www.thelancet.com/diabetes-endocrinology Published online November 16, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30394-1
People with type 2 diabetes who take insulin die sooner than people with type 2 diabetes who do not take insulin. This is accepted. What is not accepted is whether insulin is at fault. One could easily conclude that insulin shortens lives. By the same logic, one could conclude that chemotherapy causes people to die from cancer, but of course only people with cancer get chemotherapy. For people with type 2 diabetes, those who require insulin could simply have a higher risk of dying than people who do not require insulin—a plausible idea given that poor glycaemic control triggers both the need for insulin and a higher risk of cardiovascular events including death. Insulin might then seem culpable; the challenge is proving its innocence. In The Lancet Diabetes & Endocrinology, John Gamble and colleagues1 undertake the challenge of extricating the effect of insulin dose on cardiovascular disease and death. In a cohort study using routinely collected data from general practitioners in the UK, the authors studied 6072 new users of insulin; using Cox proportional hazard models to adjust for confounding, they found a positive association between insulin dose and death. Compared with patients taking less than 25 units per day, the adjusted hazard ratio (aHR) was 1·41 (95% CI 1·12–1·78) for those taking 25 to less than 50 units per day, 1·37 (1·04–1·80) for those taking 50 to less than 75 units per day, 1·85 (1·35–2·53) for those taking 75 to less than 100 units per day, and 2·16 (1·58–2·93) for those taking at least 100 units per day. However, when they used a marginal structural Cox proportional hazards model, which adjusts for time-varying confounders affected by previous insulin treatment, they did not find a significant association between insulin dose and death (aHR 1·40 [95% CI 0·99–1·99], 1·12 [0·75–1·68], 1·49 [0·93–2·38], and 1·60 [0·99–2·60] for the four insulin doses, respectively, relative to less than 25 units per day) in a model with fewer covariates. This is not the first observational study to assess the association between insulin dose and mortality in type 2 diabetes, and not even the first to do so using the Clinical Practice Research Datalink.2 Like the study from Gamble and colleagues,1 Holden and colleagues2 assessed higher doses of insulin compared with lower doses of insulin
(the exposures) and cardiovascular disease and death (the outcome) using Cox proportional hazards modelling to control for confounding. Both studies also accounted for residual confounding and found that insulin increases the risk of death. The two studies differ in other ways, including the population being studied. The study by Holden and colleagues2 included only people on insulin monotherapy, whereas the study by Gamble and colleagues1 included people who added insulin to metformin. Care guidelines in England advocate that people with type 2 diabetes remain on metformin when adding insulin3 making the study by Gamble and colleagues2 more generalisable. The study by Holden and colleagues2 analysed insulin dose by bodyweight, whereas the study by Gamble and colleagues1 consider bodyweight as a potential confounder in all analyses. An apparently fundamental analytical difference between the two studies is that the study by Gamble and colleagues1 used a marginal structural model to tackle the dual problems of time-dependent exposures (specifically, changing doses of insulin) and timedependent confounders (for example, insulin is offered to people with hyperglycaemia, which itself both changes over time and increases the risk of death).4 Moreover, glycaemia both determines future doses of insulin, and reflects previous dosages of insulin. The method uses so-called inverse probability of treatment weighting, meaning that individuals are given mathematical weights proportional to their probability of receiving their own exposure history (here, insulin treatment), and removes the association between the dose of insulin and any measured confounders.5–7 There are issues remaining with regard to the study by Gamble and colleagues. As the study design selected patients who added insulin after starting metformin monotherapy, it might or might not apply to the about 6% of the UK population with type 2 diabetes who initiate treatment with a sulfonylurea.8 Appropriately, the authors also included patients who took other diabetic drugs between metformin and insulin. Misclassification of exposure classically biases results towards finding no effect. In this regard, although the authors have not reassured
www.thelancet.com/diabetes-endocrinology Published online November 16, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30394-1
Ian Hooton/Science Photo Library
Guilt, or guilt by association? Insulin therapy in type 2 diabetes and death
Lancet Diabetes Endocrinol 2016 Published Online November 16, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30394-1 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(16)30316-3
1
Comment
the reader that their method of calculating insulin dosage based on time between prescriptions accurately reflects dosages actually taken, they acknowledge the need to validate their approach. Lastly, marginal structural models depend on assuming no unmeasured confounding, and, alas, this is not empirically verifiable.5 Why can’t this question be addressed in a randomised controlled trial where randomisation equally distributes confounders known and unknown? For one, it is considered unethical to do interventional studies using treatments hypothesised to cause harm. For another, in a blinded trial of higher versus lower doses of insulin, the patients and clinicians are unlikely to remain masked. Even the ongoing DEVOTE trial is not designed to assess the effect of insulin dosages, but instead to assess whether insulin degludec is not worse than glargine with respect to cardiovascular disease and death.9 Drugs are meant to do more good than harm. If the harms of insulin in type 2 diabetes overshadow the benefits, then the public would reasonably expect the regulatory agencies to take action. The Pharmacovigilance Risk Assessment Committee of the European Medicines Agency addressed the safety of insulin in 2014 noting ‘‘no consistent evidence of cardiovascular harm from use of insulin in patients with type 2 diabetes’’ and did not deem regulatory action to be necessary.10 The regulator will continue to monitor for cause to change its decision. Finally, what does the negative finding mean? Should patients and their doctors be reassured as the authors suggest? Simply, a negative finding could mean that no association exists or that an association does exist, but the study did not find it. The results from their marginal structural models with a subset of covariates showed no significant higher risk of death in people in any of four categories of increasing daily dosages of insulin compared with people on fewer than 25 units of insulin per day;
2
however all four categories generated hazard ratios greater than 1·0. Therefore, it seems possible that a bigger study would find significant associations suggesting harm, but also that residual confounding would remain. Only when confounding does not interfere and the study is big enough, can one confidentially conclude that insulin is not harmful to people with type 2 diabetes. Crucially, when this occurs, one could also wonder why more insulin does not make people with type 2 diabetes live any longer. Amanda I Adler Wolfson Diabetes and Endocrine Clinic, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK [email protected] I declare no competing interests. 1
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Gamble J-M, Chibrikov E, Twells LK, et al. Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study. Lancet Diabetes Endocrinol 2016; published online Nov 16. http://dx. doi.org/10.1016/S2213-8587(16)30316-3. Holden SE, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ. Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes Metab 2015; 17: 350–62. McGuire H, Longson D, Adler A, Farmer A, Lewin I, for the Guideline Development Group. Management of type 2 diabetes in adults: summary of updated NICE guidance. BMJ 2016; 353: i1575. Hernan MA, Brumback BA, Robins JM. Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures. Stat Med 2002; 21: 1689–709. Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol 2008; 168: 656–64. Brookhart MA, Wyss R, Layton JB, Stürmer T. Propensity score methods for confounding control in nonexperimental research. Circ Cardiovasc Qual Outcomes 2013; 6: 604–11. Sugihara M. Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score. Pharm Stat 2010; 9: 21–34. Sharma M, Nazareth I, Petersen I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open 2016; 6: e010210. Marso SP, McGuire DK, Zinman B, et al. Design of DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events)—DEVOTE 1. Am Heart J 2016; 179: 175–83. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of the meeting on March 3–6, 2014. http://www.ema.europa.eu/docs/en_GB/document_library/ Minutes/2014/04/WC500165698.pdf (accessed Nov 4, 2016).
www.thelancet.com/diabetes-endocrinology Published online November 16, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30394-1