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Insulin Therapy in Guidelines An Overview

This article provides an overview of insulin therapy in the treatment of type 2 diabetes mellitus, discussing the evolving evidence and guidelines. It explores the benefits and limitations of glycemic control, cardiovascular outcomes, and the design of clinical trials. The article highlights the importance of shared decision-making and individualized treatment approaches for patients.

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Insulin Therapy in Guidelines An Overview

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  1. Insulin Therapy in GuidelinesAn Overview F. Hadaegh Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, ShahidBeheshtiUniversity of Medical Sciences August 2017 Tehran

  2. Glycemic Control for Patients With Type 2 Diabetes Mellitus Our Evolving Faith in the Face of Evidence (Circ Cardiovasc Qual Outcomes. 2016;9:504-512)René Rodríguez-Gutiérrez et al

  3. Glycemic Control for Patients With Type 2 Diabetes Mellitus Our Evolving Faith in the Face of Evidence (Circ Cardiovasc Qual Outcomes. 2016;9:504-512) René Rodríguez-Gutiérrez et al

  4. Glycemic Control for Patients With Type 2 Diabetes Mellitus Our Evolving Faith in the Face of Evidence (Circ Cardiovasc Qual Outcomes. 2016;9:504-512) René Rodríguez-Gutiérrez et al cardiovascular disease-specific mortality (RR, 1.11; 95% [CI], 0.86–1.43) or all-cause mortality (RR, 1.04; 95% CI, 0.91–1.19), calling into question the reliability and significance of the reduced risk in nonfatal MIs.3

  5. Kasia J. Lipska, MD, MHS JAMA Published online January 26, 2017 the improvement in cardiovascular mortality in both of these trials emerged far earlier than expected (within the first 3 months for empagliflozin and 6 months for liraglutide) given the natural history of the progression of atherosclerosis attributable to hyperglycemia there was only a modest reduction in HbA1c of 0.4

  6. Kasia J. Lipska, MD, MHS JAMA Published online January 26, 2017

  7. Implications for Design of Trials • The FDA does not require post marketing studies to ensure that drugs used for the treatment of T2D do not increase (and instead hopefully reduce) microvascular events. • In fact, the FDA advises that drugs that lower HbA1c levels can be “reasonably expected to reduce the long-term risk of microvascular complications” and, therefore, “reliance on HbA1c remains an acceptable primary efficacy endpoint for approval of drugs seeking an indication to treat hyperglycemia secondary to T2D. Kasia J. Lipska, MD, MHS JAMA Published online January 26, 2017

  8. Any drug that lowers glucose levels may not predictably reduce the risk of microvascularcomplications • Empagliflozinreduced the risk of several kidney outcomes despite minimal differences in glycemic control between study groups. • Semaglutidealso improved nephropathy end points, but increased the risk of retinopathy • In the ongoing CanagliflozinCardiovascularAssessment Study(CANVAS) clinical trial the independent data monitoring committee identified an increased risk of leg and foot amputationsassociated with canagliflozin use, which is currently under investigation. Kasia J. Lipska, MD, MHS JAMA Published online January 26, 2017

  9. Kasia J. Lipska, MD, MHS JAMA Published online January 26, 2017

  10. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  11. 1.Absolute estimates of benefit: What are the absolute (and not relative) benefits of a particular therapy for patient-centered outcomes? • 2. Time horizon to benefit: How long must a patient be on a particular therapy to reap the potential benefit in comparison with their current life expectancy? • 3. Balance of benefits versus harms: Do the potential absolute benefits outweigh the potential harms of therapy for the specific patient under consideration? • 4. Shared decision making: Is the decision to treat consistent with the patient’s values and preferences? MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  12. if the risk of myocardial infarction for those prescribed drug X is only 1% and the risk in the placebo group is only 1.5%, the RR remains a deceptively impressive impressive 0.67 (1/1.5) ; But the ARR is now only 0.5%, and the NNT is 200 (1/0.5), indicating a minimally effective therapy. Thus, reports of the RR or RRR do not provide physicians any information on the magnitude of treatment benefit. ARR and NNT provide limited information to guide treatment decisions beyond the duration reported in clinical studies. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  13. What Are the Estimated Benefits of IntensiveGlycemic Control in Type 2 Diabetes? • Large Relative Benefits in Preventing (Mostly Surrogate) Outcomes MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  14. HbA1C :(6.4% -7.0 ) VS. (7.9% and 8.4%) • In the landmark UKPDS trial, the relative benefits of 10 years of intensive glycemic control for individuals with newly diagnosed diabetes were only demonstrated for intermediate markers of microvascular complications ; but not for actual meaningful clinical manifestations of microvascular disease (ie, vision loss, symptomatic neuropathy, amputation, or end-stage renal disease requiring dialysis). Other trials have similarly failed to show improvement in these more clinically meaningful end points. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  15. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  16. The potential for intensive glycemic control to prevent more meaningful microvascular outcomes (ie, vision loss or ESRD requiring dialysis) is estimated to take ≥2 decades to manifest. Even with an additional 10 years of follow-up in the UKPDS trial (for a total of 25 years), improvements in these end points have not yet been reported. Consequently, a pragmatic approach to avoiding the harms of overtreatment would be to defer intensive glycemic control in individuals with a life expectancy that is clearly <9 years. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  17. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  18. MakamAN, Nguyen OK Circulation. 2017 Jan 10; 135(2):180-195.

  19. We should abandon the notion that HbA1c levels ≤7% are well controlled and levels > 7% are uncontrolled. • This arbitrary dichotomy does not adequately portray whether we are optimizing the benefits of treatment, quality of life, and value for individuals, because most people with diabetes in the uncontrolled range (ie, HbA1c >7%) are nonetheless asymptomatic • Achieving tight glycemic control does not meaningfully reduce cardiovascular complications. • An EBM approach would consist of treating to achieve adequate glycemic control to prevent symptomatic disease (eg,polyuria, polydipsia), followed by further consideration of more intensive treatment if a clinical assessment suggests that the potential absolute benefits outweigh the harms, as with any other cardiovascular risk factor MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  20. This assessment would encompass a thorough understanding of the patient’s risks, prognosis (ie, age, comorbidities, and functional status), and socio-personal context (eg, lifestyle, social support, workload capacity), as well as engaging with the patient to elicit perceived or experienced treatment burden, and values and preferences for care. • it is imperative for physicians to remember that the fundamental goal is to help individuals who have diabetes make the best therapeutic decision to improve their overall health and quality of life, not to prevent diabetes-related complications by any means possible. MakamAN, Nguyen OK Circulation. 2017 Jan 10;135(2):180-195.

  21. Max:0.5 IU/kg

  22. At the end of 24 weeks, the two approaches were shown to be clinically equivalent. Over 32 weeks, participants initiated with the stepwise plan had a similar A1C with significantly lower hypoglycemia and better patient satisfaction compared to the group who initiated three bolus injections per day.

  23. Over-basalization occurs when the basal dose is increased, but glycemic targets are not achieved

  24. Key Message • Our analyses suggest that there is no clinically relevant difference in the efficacy of basal-bolus versus premixed insulin regimens for HbA1c decrease in type 2 diabetic patients who intensified their insulin therapy.

  25. ADA 2017

  26. ADA 2017

  27. Consider different proportions in Mixed Insulin (75/25, 50/50) Changing to Human Insulin ???

  28. Fixed combinations of GLP-1 receptoragonists with long-acting insulin, • Compared with insulin alone, these products such as insulin Degludec +Liraglutide (Xultophy )or insulin Glargine +lixisenatide(Soliqua100/33 )are associated with less hypoglycaemiaand weight gain, as well as reduced insulin doses. • Findings from head-to-head studies of basal insulin and GLP-1 receptor agonist combinations indicated that the drugs are as effective as basal bolus insulin regimens, possibly because GLP-1 receptor agonists reduce postprandial glucose excursions. Type 2 Diabetes Sudensa Chat terjee, KamleshKhunti, Melanie J Davies www.thelancet Vol389 June3, 3017

  29. J Diabetes Investig. 2017 May • we analyzed data of a cohort of Japanese patients with diabetes from a large-scale single-center registry to investigate the association between different methods of insulin therapy in real-life clinical settings and subsequent changes in glycemic control in patients with type 2 diabetes.

  30. Challenges in optimisationand maintenance of glycaemiccontrol • Major difficulties in optimisingglucose-lowering therapies are clinical inertia and treatment non-adherence. • Clinical inertia is the reluctance of health-care professionals to initiate and titrate therapy appropriately to reach glycaemic targets and is associated with : • 1-lack of knowledge, • 2- Fear of adverse effects such as hypoglycaemia, • 3-and a perception that patients will not accept treatment intensification,

  31. Challenges in optimisation and maintenance of glycaemic control • Treatment non-adherence places considerable financial burden on health-care economies with billions of US$ wasted on medication that is prescribed but not consumed. • Patients can get help to adhere to treatment through structured education and self-management programmes, which have been shown to improve personal responsibility and should be emphasisedfor all medications, including anti-hypertensive and lipid-lowering therapies

  32. Take Home Message • Different recommendations in different guidelines, in part, can be explained by various contextual variables • In our country with limited resources, we need to develop a new national evidence based guideline • Considering difficulties in guideline development, and as an easier task, customizing existing guidelines seems to be more practical

  33. Take Home Message • Clinicians should discuss treatment options with patients using a shared decision-making approach that considers • individual health status, • Resources, • Life context; • Tools are available to support this process • evidence-based medicine approach can be used to individualize glycemic goals and prevent OVERTREATMENT,

  34. Thanks for your patience, dear colleagues!

  35. Case Studies

  36. Mrs. M. 52 year old housewife with T2DM from 10 years ago, admitted for control of diabetes. She has inactive life but obey diet under observation of a dietician. Clinical history: PMH: HTN form 5 years ago FH:DM + DH : Tab. Metformin 2000 mg /D Tab. Gliclazide 80 mg/BD GI intolerance to Liraglutide Tab. ASA 80 mg /D Tab. Atorvastatin 10 mg /D Tab. Valsartan 80 mg/ BD

  37. Ph/Ex:no End organ damage BMI:26 kg/m2 SMBG SBP:130 DBP:75mmHg Lab data:

  38. Recommendation •  Metformin 3000 mg/D & Gliclazide 320 mg/D • Adding Sitagliptin 100 mg/D • Adding Pioglitazone 30 mg/D • Adding basal Insulin 12 U/D 5) Starting basal/prandial Insulin Analogues

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