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Artigo joga dúvidas sobre a necessidade/ ou mesmo contraindicação de insulina em DM2. A hiperinsulinemia que precede a clínica do DM, quando associada à aplicação exógena do hormônio pode trazer efeitos adversos. O artigo põe em dúvida a aplicação de insulina no DM.

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  1. 1. The safety profile of exogenous insulin in people with type 2 diabetes: justification forconcernCraig J. Currie, PhDReader in Diabetes Pharmacoepidemiology, School of Medicine, Cardiff University, Cardiff,United KingdomJeffrey A. Johnson, PhDProfessor and Canada Research Chair, School of Public Health, University of Alberta, Edmonton,CanadaAbstractThere is no doubt about the value of exogenous insulin for people with type 1diabetes. The purpose of this commentary is to discuss emerging evidence thatthis may not be the case for the majority of people with type 2 diabetes.This is an Accepted Article that has been peer-reviewed and approved for publication in theDiabetes, Obesity and Metabolism, but has yet to undergo copy-editing and proof correction.Please cite this article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01469.x 1 )
  2. 2. In general, exogenous insulin is a good thing. It has enjoyed a long history as alife-saving therapy for innumerable patients with type 1 diabetes. Insulin’sintroduction revolutionised the management of these patients, and over thepast 90 years it has saved countless organs, limbs and lives1. But is this true for allpatients with diabetes? Every drug has both benefits and risks, and therapy isindicated when the former outweighs the latter. Insulin, whether in its humanform or as an analogue, is no different. While the benefits clearly outweigh therisks in the management of type 1 diabetes, emerging evidence suggests thismay not be the case for all people with type 2 diabetes.The market for insulin continues its rapid expansion2 due in large part to theincreasing prevalence of type 2 diabetes, and a focus on intensifying glycaemiccontrol. Insulin is the most effective therapy for reducing hyperglycaemia, andtherefore remains high amongst the choices of add-on therapy for thosepatients whose HbA1c remains above recommended targets3,4. A lower HbA1cis much easier to achieve when using insulin-based regimens, and in aglucocentric culture of ‘treatment-to-target’5,6, insulin represents an attractivetreatment preference.Nevertheless, the strategy of such intensive glucose control for type 2 diabetes isrightly being questioned because of emerging evidence suggesting a lack of 2 )
  3. 3. substantial benefit in the face of potential risks7,8. In this regard, the glucose-lowering benefit of insulin is generally weighed against the acute risks ofhypoglycaemia (postulated to cause arrhythmia, “dead-in-bed” syndrome, andother cardiovascular sequelea9), weight gain, and the underappreciateddisutility and distress patients with type 2 diabetes experience with insulininjections and glucose self-monitoring. It is important; however, to consider aneven broader risk profile for insulin.A hallmark of type 2 diabetes is resistance to insulin action10. What is becomingclearer though, is that the insulin resistance of type 2 diabetes is largely limited tomuscle and adipose tissues, whereas other tissues or organs either retain normalsensitivity or become hypersensitive to insulin actionError! Bookmark not defined..And furthermore, the broader negative clinical consequences of insulinresistance are―for the most part―a result of compensatoryhyperinsulinaemiaError! Bookmark not defined.. This being the case, it wouldplausibly seem counter-productive to add to the problem with exogenous insulintherapy.What is the evidence for these broader clinical consequences of insulinresistance and hyperinsulinaemia? From the physiologic perspective, insulinplays a major regulatory role in many tissuesError! Bookmark not defined.. Thekidneys remain sensitive to insulin, and compensatory hyperinsulinaemia leads to 3 )
  4. 4. increased retention of salt, water and uric acid, contributing to increased risk ofcardiovascular disease11. Hyperinsulinaemia also increases sympathetic nervoussystem activity, which may further contribute to increased blood pressureError!Bookmark not defined.. Finally, there has been a re-focusing of attentionrecently on insulin’s well-established role on cell growth, differentiation andproliferation12,13. In the face of insulin resistance, endogenous or exogenoushyperinsulinaemia results in an exacerbation of insulin’s mitogenic andatherogenic effectsError! Bookmark not defined..If these physiologic effects of insulin resistance and compensatoryhyperinsulinaemia are of clinical concern, we might also expect to seeincreased risk of cardiovascular events and cancer, and then a correspondingincreased risk of mortality. Could it be that these more long-term clinicaloutcomes of insulin therapy in type 2 diabetes have been somewhatoverlooked? There could be a number of reasons if this is the case. Forexample, people with type 2 diabetes are in a complex, heterogeneous, multi-morbid state. Furthermore, there is an overt glucocentric view of diabetesmanagement and, potentially, a blind over-confidence in making widerinference from data characterising the benefit-to-risk ratio observed in type 1diabetes. We believe there is, in fact, accumulating evidence that these risksmay be real and a cause for concern. 4 )
  5. 5. Recent studies provide support for the biological plausibility of adverse effectsrelating to hyper-insulinisation in patients with type 2 diabetes. Data that firstraised questions about negative outcomes of higher versus more standard dosesof insulin in type 2 diabetes were published from a pilot, randomised trial in199714. Consistent with this virtually ignored trial were data from a large,population-based cohort study where a dose-response relationship wasobserved between increasing insulin use and all-cause mortality in people withtype 2 diabetes15. This study reported an almost three-fold increase in risk ofdeath in the highest insulin exposure group, in an insulin-dose-dependentpattern. Similarly, in an epidemiologic study of patients with type 2 diabetestreated in a UK primary-care setting, those treated with insulin-based regimenshad a 50% increased risk of dying than did comparable patients treated with acombination therapy of metformin plus sulfonylureas16. More recently, datafrom the randomised controlled trial DIGAMI-2 suggest that intensified insulintreatment was associated with increased risk of non-fatal cardiovascular events,with a corresponding trend for increased cardiovascular mortality17. A 2.5-foldincreased risk of cardiac events in those with type 2 diabetes treated with insulinwas reported from another recent, large, observational study from the US18.Insulin has been found to be associated with worse cardiovascular diseaseoutcome in people with type 2 diabetes19, and independently in people withheart failure20. 5 )
  6. 6. There is also accumulating evidence of increased risk of malignancy withincreased use of insulin in patients with type 2 diabetes. Yang and colleaguesfirst reported an increased risk of colorectal cancer in people treated withinsulin, observing an escalating risk with longer duration of insulin use21.Increased risks of liver22 and pancreatic23,24,25 cancers have also beenassociated with insulin use, but there is likely to be some degree of “reversecausality” in these relationships. Insulin use in type 2 patients has also beenassociated with increased risk of overall cancer incidence26 and cancermortality27. Interestingly, the recently published extended follow-up fromDIGAMI-2 also demonstrated that insulin treatment was associated with anincreased risk of cancer mortalityError! Bookmark not defined..The counter argument to the above intelligence favouring the use of insulin inpeople with type 2 diabetes is largely based upon a lack of any convincingadverse-event signals from large randomised controlled trials such as theUKPDS28,29. Unfortunately, while insulin therapy was one of the options forintensified glycaemic control in the UKPDS, it is important to recognise that theoverarching aim of the study was achievement of lower HbA1c, as it is in allrecent large randomised trials of intensified glycaemic control. In these trials,objectives were typically pursued with protocol-driven treatment escalation―or‘rescue therapy’―resulting in the post-randomisation addition of multiple oralagents to insulin30. This sort of design makes it difficult to discern the effect of 6 )
  7. 7. individual drug therapies, since the risk associated with any one agent would belargely confounded by exposures to other glucose-lowering agents; mostnotably metformin, which is associated with reduced risk of macrovascularevents or cancer outcomes31. Finally, company-sponsored regulatory trials forinsulin products are typically short-term trials and inevitably compare insulinproduct versus another insulin product, thus data from commercial sponsorsgenerally offer little to this debate.The ongoing ORIGIN trial intends to assess whether early initiation of treatmentwith insulin glargine will reduce cardiovascular events32, but it too allows for theuse of other glucose-lowering agents at the discretion of local investigators, andtherefore it is unlikely to clarify any unique benefits or risks relating to insulintherapy. In general, published RCT data can only suggest that overallimprovements in glycaemic control achieved through combination glucose-lowering therapies do not appear to decrease the risk of all-cause orcardiovascular mortality33 or cancer34.So where do we go from here? From the research perspective, there is a clearneed to better understand the existing data on the safety and benefits of insulintherapy in patients with type 2 diabetes (including, if possible, unpublishedcompany trial data). However, if current RCT data are inadequate due tocomplex therapeutic regimens and epidemiological data are always open to 7 )
  8. 8. criticism; then equipoise exists. There is then a need for a new, long-termrandomised trial to assess efficacy; perhaps with a simpler design of varyinginsulin doses in the absence of oral therapy changes. Regardless, since it isunethical to power a trial to characterise harm, in the absence of such a trial wewill necessarily have to rely on accumulating evidence from mechanistic andobservational studies.From a clinical perspective, there is no question that the absolute need andbenefit related to treatment with exogenous insulin in people with type 1diabetes outweighs its risks. Furthermore, there will always remain a small groupof patients who require insulin replacement therapy in type 2 diabetes. Broadlyspeaking, these people are treatment-compliant patients who are already onmaximally tolerated doses of oral agents who still have osmotic symptoms andweight loss. However, the considerations for insulin in the majority of people withtype 2 diabetes are very different. While hyperglycaemia is associated withincreased risks of death and cardiovascular disease35,36; for the vast majority ofpatients with type 2 diabetes there is no unequivocal evidence of benefit frominsulin. At the same time, hyperinsulinaemia is also associated with increased riskof deathError! Bookmark not defined., and there is mounting evidence fromboth controlled and observational studies suggesting that aggressive insulintreatment in people with type 2 diabetes may be associated withunacceptable risks. In the meantime it would seem prudent to minimise insulin 8 )
  9. 9. resistance through healthy eating, physical activity and other non-pharmacologic means, and then through non-insulin, anti-hyperglycaemicdrugs.Including the corresponding article in this edition of Diabetes, Obesity andMetabolism37, we are aware of at least one other commentaries have publisheda similar opinion suggesting that there exists good reason to challenge thesafety profile and the role of insulin in type 2 diabetes38. The order of magnitudeof the differences in event rates emanating from the epidemiological evidencequestioning insulin is such that this matter should be investigated urgently. Theregulatory agencies have a duty to investigate, and manufacturers have a dutyto prove the safety of their products.Whilst unlikely, it remains theoretically plausible that these concerns areunfounded. However, until such time that there is clear evidence of relativebenefit in the majority of people with type 2 diabetes, we should aim to use aslittle exogenous insulin as possible to achieve reasonable glycaemic control. 9 )
  10. 10. References1. Hollemann F, Gale EAM. Nice insulins, pity about the evidence. Diabetologia2007; 50: 1783–1790.2. Hauber A, Gale EA. The market in diabetes. Diabetologia 2006; 49: 247–252.3. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR Sherwin R et al.Medical management of hyperglycaemia in type 2 diabetes mellitus: aconsensus algorithm for the initiation and adjustment of therapy: a consensusstatement from the American Diabetes Association and the EuropeanAssociation for the Study of Diabetes. Diabetologia 2009; 52: 17–30.4. American Diabetes Association. Standards of medical care in diabetes—2011.Diabetes Care 2011; 34 Suppl 1: S11–S61.5. Riddle MC, Rosenstock J, Gerich J: Insulin Glargine 4002 Study Investigators.The treat-to-target trial: randomized addition of glargine or human NPH insulin tooral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080–3086.6. Holman RR, Farmer AJ, Davies MJ, et al: 4-T Study Group. Three-year efficacyof complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361: 1736–1747.7. Yudkin JS, Richter B, Gale EA. Intensified glucose lowering in type 2 diabetes:time for a reappraisal. Diabetologia 2010; 53: 2079–2085.8. Montori VM, Fernández-Balsells M. Glycemic control in type 2 diabetes: timefor an evidence-based about-face? Ann Intern Med 2009; 150: 803–808.9. Johnston SS, Conner C, Aagren M, Smith DM, Bouchard J, Brett J. Evidencelinking hypoglycemic events to an increased risk of acute cardiovascular eventsin patients with type 2 diabetes. Diabetes Care 2011;34:1164-70.10. Reaven GM. Insulin resistance: from bit player to centre stage. CMAJ 2011;183: 536–537.11. Reaven GM. The kidney: an unwilling accomplice in syndrome X. Am JKidney Dis 1997; 30: 928–931.12. Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat RevCancer 2008; 8: 915–928.13. Draznin B. Mitogenic action of insulin: friend, foe or “frenemy’? Diabetologia2010; 53: 229–233.14. Abraira C, Colwell J, Nuttall F, et al. Cardiovascular events and correlates inthe Veterans Affairs diabetes feasibility trial—Veterans Affairs Cooperative Studyon gylcemic control and complications in type II diabetes. Arch Intern Med1997; 157: 181–188.15. Gamble JM, Simpson SH, Eurich DT, Majumdar SR, Johnson JA. Insulin use andincreased risk of mortality in type 2 diabetes: a cohort study. Diabetes ObesMetab 2010; 12: 47–53.16. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA1c in peoplewith type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–489. 10 )
  11. 11. 17. Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L, for the DIGAMI 2Investigators. Prognostic implications of glucose-lowering treatment in patientswith acute myocardial infarction and diabetes: experiences from an extendedfollow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute MyocardialInfarction (DIGAMI) 2 Study. Diabetologia 2011, published on-line 26 February2011. DOI 10.1007/s00125-011-2084.18. Colayco DC, Niu F, McCombs JS, Cheetham TC. A1C and cardiovascularoutcomes in type 2 diabetes: a nested case-control study. Diabetes Care2011;34:77-83.19. Anselmino M, Ohrvik J, Malmberg K, Standl E, Rydén L; Euro Heart SurveyInvestigators. Glucose lowering treatment in patients with coronary arterydisease is prognostically important not only in established but also in newlydetected diabetes mellitus: a report from the Euro Heart Survey on Diabetes andthe Heart. Eur Heart J 2008;29:177-8420. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associatedwith a marked increase in mortality in patients with advanced heart failure. AmHeart J 2005;149:168-7421. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer riskamong type 2 diabetes mellitus patients. Gastroenterology 2004; 127: 1044–1050.22. Donadon V, Balbi M, Zanette G. Hyperinsulinemia and risk for hepatocellularcarcinoma in patients with chronic liver diseases and Type 2 diabetes mellitus.Expert Rev Gastroenterol Hepatol 2009; 3: 465–467.23. Bonelli L, Aste H, Bovo P, et al. Exocrine pancreatic cancer, cigarettesmoking and diabetes mellitus: a case-control study in Northern Italy. Pancreas2003; 27: 143–149.24. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetictherapies affect risk of pancreatic cancer. Gastroenterology 2009; 137: 482–488.25. Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in apopulation-based case-control study in the San Francisco Bay Area, California.Cancer Epidemiol Biomarkers Prev 2006; 15: 1458–1463.26. Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapieson cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766–1777.27. Bowker SL, Yasui Y, Veugelers P, Johnson JA. Glucose-lowering agents andcancer mortality rates in type 2 diabetes: assessing effects of time-varyingexposure. Diabetologia 2010; 53: 1631–1637.28. UK Prospective Diabetes Group: Intensive blood-glucose control withsulphonylureas or insulin compared with conventional treatment and risk ofcomplications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853. 11 )
  12. 12. 29. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up ofintensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–1589.30. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea,metformin, or insulin in patients with type 2 diabetes mellitus—Progressiverequirement for multiple therapies (UKPDS 49). JAMA 1999; 281: 2005–2012.31. UK Prospective Diabetes Group: Effect of intensive blood-glucose controlwith metformin on complications in overweight patients with type 2 diabetes(UKPDS 34). Lancet 1998; 352: 854–865.32. ORIGIN Trial Investigators, Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J.Rationale, design, and baseline characteristics for a large international trial ofcardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial(Outcome Reduction with an Initial Glargine Intervention). Am Heart J 2008; 155:26–32.33. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control andmacrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288–2298.34. Johnson JA, Bowker SL. Intensive glycemic control and cancer risk in type 2diabetes: A meta-analysis of major trials. Diabetologia 2011; 54: 25–31.35. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, etal. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl JMed 2011; 364: 829–841.36. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, et al.Diabetes mellitus, fasting blood glucose concentration, and risk of vasculardisease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375: 2215–2222.37. Rensing K, et al. Reducing cardiovascular disease risk in diabetic patientswith established macrovascular disease: can insulin be too much of a goodthing? Diabetes, Obesity and Metabolism 2011 (under review)38. Nandish S, Bailon O, Wyatt J, Smith J, Stevens A, Lujan M, Chilton R.Vasculotoxic effects of insulin and its role in atherosclerosis: what is theevidence? Curr Atheroscler Rep 2011;13:123–128.Conflict of interest details: CC wrote the first draft and JJ amended the draft comprehensively.Authorship details: A statement will be made in the published mansucript. 12 )