![Remission Criteria
A1C criteria: see before
FPG criteria: ≤110 mg/dL for remission to normal
glucose levels or 110 to 125 mg/dL for remission to
prediabetes
OGTT criteria: both FPG [as above] and 2hPG ≤ 140
mg/dL for remission to normal glucose levels or 141
to 199 mg/dL for remission to prediabetes
Can J Diabetes46 (2022) 753 – 761](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-22-2048.jpg)
![How to start
Discussion concept of remission + should meet the
specified criteria to eliminate the need for
antihyperglycemic therapy [Grade D, Consensus].
The approach to deprescribing antihyperglycemic agents
should be individualized [Grade D, Consensus].
Can J Diabetes46 (2022) 753 – 761](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-26-2048.jpg)
![How to Follow
If type 2 diabetes remission criteria are
met, A1C (or, if A1C unreliable, FPG or
OGTT) should be performed at a
minimum interval of every 6 months to
assess persistence of diabetes remission
or relapse of diabetes [Grade D,
Consensus].
If, at 6 months, remission criteria have
not been met, reinitiation of
antihyperglycemic agents should be
considered.
Can J Diabetes46 (2022) 753 – 761
The Journal of Clinical Endocrinology & Metabolism. 2022 Jan;107(1):1-9.](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-29-2048.jpg)
![Cut it down
Bariatric surgery should be recommended
to nonpregnant adults with type 2
diabetes and a BMI ≥35 kg/m2 as an
option to potentially induce type 2
diabetes remission [Grade A, Level 1A]](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-32-2048.jpg)
![Health Behavioral
Interventions
• Low calorie diets (800-850
cal/day) with meal
replacement products for 3-
5 months aimed at
achieving >15kg weight loss,
followed by a structured
food reintroduction program
and increased physical
activity (for people with BMI
27-45) [Grade A, Level 1A].
Can J Diabetes46 (2022) 753 – 761](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-34-2048.jpg)
![Health Behavioral Interventions (cont.)
• Exercise training (240-420
min/week) with a calorie
restricted diet (for people
with BMI >25, and with a
lower level of evidence for
this option) [Grade C, Level
2]
Can J Diabetes46 (2022) 753 – 761](https://image.slidesharecdn.com/diabetesremissionandpreventionf-230118234900-46fc568a/75/Diabetes-Remission-and-Prevention-35-2048.jpg)
Uploaded byUsama Ragab
Diabetes Remission and Prevention
This document summarizes key findings from the IDF Diabetes Atlas 2021: 1) An estimated 537 million adults aged 20-79 have diabetes globally in 2021, representing 1 in 10 adults. 6.7 million deaths are attributed to diabetes each year. 2) The top 10 countries for number of adults with diabetes are China, India, USA, Brazil, Pakistan, Indonesia, Mexico, Egypt, Italy, and Bangladesh. The top countries for diabetes healthcare expenditure are USA, China, Japan, Germany, and India. 3) Diabetes prevalence is increasing worldwide, with the majority (75%) of people with diabetes living in low and middle income countries. Cardiovascular disease is the leading cause of death for people
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Diabetes Remission and Prevention
- 2. 2 | IDFDiabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Highlights In 2021, IDF estimates show that: 1 in 2 Adults is undiagnosed 240 million people 11.5% Of global health expenditure spent on diabetes (USD 966 billion) 1 in 10 Adults (20-79 years) has diabetes 537 million people 1 in 6 Live births (21 million) affected by hyperglycaemia in pregnancy, 80% have mothers with GDM 6.7 million Deaths attributed to diabetes 1 in 18 Adults (20-79 years) has impaired fasting glucose 319 million people 1 in 9 Adults (20-79 years) has impaired glucose tolerance 541 million people 1.2 million Children and adolescents below 20 years have type 1 diabetes 3 in 4 People with diabetes live in low and middle-income countries
- 3. 3 | IDFDiabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Number of people with diabetes Aged 20–79 years globally and by IDF region
- 4. 4 | IDFDiabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Top 10 countries with diabetes In adults aged 20–79 years and diabetes-related health expenditure, 2021
- 5. Represents 2 millionpeople. Diabetes is mostly (85–95%) T2D.1 • T2D approximately doubles the risk of death2 • Diabetes caused 4.9 million deaths in 20141 • CVD is the principal cause of death in T2D2,3 1.76 1.85 1 1.5 2.0 T2D is increasingly prevalent and CVD is the leading cause of death in this population 5 1. IDF Diabetes Atlas, 2019. 9th Edition. http://www.idf.org/diabetesatlas. 2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 3. Morrish et al. Diabetologia 2001;44(suppl 2):S14–21. • Globally, 463 million people are living with diabetes1 • Rising to 700 million by 20451 Relative risk for all-cause mortality Relative risk for CV mortality
- 6. The “common soil”from which type 2 diabetes and cardiovascular disease arise
- 7. Diabetes is ASCVD risk equivalent NEngl J Med 1998;339:229-34.
- 8. Modifiable CV riskfactors are common in patients with T2D1,2 8 Almost a third of diabetes patients were current smokers2 1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.
- 10. Copyright ADA/EASD 2022 WardZJ et al; NEJM 2019; 381: 2440-2450 https://www.worldobesity.org/resources/resource-library/world-obesity-atlas-2022, Accessed 04 June, 2022 https://www.cdc.gov/obesity/data/prevalence-maps.html, Accessed 04 June, 2022
- 11. Copyright ADA/EASD 2022 WeightReduction as a Targeted Intervention • Weight reduction → improve glycemic management and reduce ABCD. • Weight loss of 5-15% should be a primary target in T2DM. • More is better • Loss of 5-10% = metabolic improvement • Loss of 10-15% = disease-modifying effect + lead to remission of diabetes. • Weight loss → improve risk factors for cardiometabolic disease and QoL DaviesMJ,ArodaVR,CollinsBS,GabbayRA,GreenJ,MaruthurNM,RosasSE,DelPratoS,MathieuC,MingroneG,RossingP,TankovaT,TsapasA,BuseJB DiabetesCare2022;https://doi.org/10.2337/dci22-0034.Diabetologia2022;https://doi.org/10.1007/s00125-022-05787-2.
- 12. Copyright ADA/EASD 2022 KeyKnowledge Gaps Study conduct Greater attention to subgroups, in particular vulnerable populations Youth, frailty, >75 years of age Gender balance A minimal first step to enhancing health justice Weight management Comparative effectiveness Targets: A1c, TIR, weight, remission Cardiorenal protection Comparative effectiveness, Combination therapy, Cost effectiveness in low/moderate risk population DaviesMJ,ArodaVR,CollinsBS,GabbayRA,GreenJ,MaruthurNM,RosasSE,DelPratoS,MathieuC,MingroneG,RossingP,TankovaT,TsapasA,BuseJB DiabetesCare2022;https://doi.org/10.2337/dci22-0034.Diabetologia2022;https://doi.org/10.1007/s00125-022-05787-2.
- 13. Potential goals and approaches for type2 diabetes Diabetes Prevention Diabetes Remission Prediabetes Schematic representation Adapted from Raccah et al. Diabetes Metab Res Rev 2007; 23: 257–264 S. Jin et al. / Can J Diabetes 46 (2022) 762e774
- 14. Diabetes care. 2009Nov 1;32(11):2133-5.
- 15. 2021 Definition • Majordiabetes journals published consensus-based remission definitions, authored by representatives from the ADA, the EASD, Diabetes UK, the Endocrine Society and the Diabetes Surgery Summit • A1C <6.5% without use of antihyperglycemic medications for at least the 3 prior months. The Journal of Clinical Endocrinology & Metabolism. 2022 Jan;107(1):1-9.
- 17. First of all,it is a consensus not a guideline We make a consensus to agree on something that doesn’t have enough evidence to be written in guidelines So they agree to not agree So grades of new recommendations are D Bariatric surgery and healthy behavioral intervention have the greatest evidence A
- 18.
- 19. Don’t be afraid butbe cautious
- 20. Bottomline for terminology Remission NotReversal or Regression Not Cure
- 21. New Definitions • Type2 diabetes remission with no antihyperglycemic medication for at least 3 consecutive months and achieving an A1C threshold as listed below: • Remission categories: remission to normal glucose levels (A1C <6.0%) remission to prediabetes (A1C between 6.0% and 6.4%) • Type 2 diabetes relapse (subsequent A1C ≥6.5%) • Pharmacologically-managed diabetes (if currently on antihyperglycemic medication/s) Can J Diabetes46 (2022) 753 – 761
- 22. Remission Criteria A1C criteria:see before FPG criteria: ≤110 mg/dL for remission to normal glucose levels or 110 to 125 mg/dL for remission to prediabetes OGTT criteria: both FPG [as above] and 2hPG ≤ 140 mg/dL for remission to normal glucose levels or 141 to 199 mg/dL for remission to prediabetes Can J Diabetes46 (2022) 753 – 761
- 23. The impact ofthe concept of diabetes remission on A1C targets Can J Diabetes46 (2022) 753 – 761
- 24.
- 25. 3 Categories 1. Howto Start 2. How to Follow 3. Options available
- 26. How to start Discussionconcept of remission + should meet the specified criteria to eliminate the need for antihyperglycemic therapy [Grade D, Consensus]. The approach to deprescribing antihyperglycemic agents should be individualized [Grade D, Consensus]. Can J Diabetes46 (2022) 753 – 761
- 27. Remission is more likely forpeople: diagnosed with diabetes for a shorter time (6 years or less) with overweight or obesity, who are ‘able or inclined’ to lose weight with blood sugars that are not that elevated who do not take insulin
- 28. Other considerations inissue of remission without significant eating disorders or mental health disorders (present challenges in adhering to strategies to achieve diabetes remission long term) without cardiovascular disease, heart failure, or chronic kidney disease (because of potential GLP1 RA and/or SGLT2i continuation)
- 29. How to Follow Iftype 2 diabetes remission criteria are met, A1C (or, if A1C unreliable, FPG or OGTT) should be performed at a minimum interval of every 6 months to assess persistence of diabetes remission or relapse of diabetes [Grade D, Consensus]. If, at 6 months, remission criteria have not been met, reinitiation of antihyperglycemic agents should be considered. Can J Diabetes46 (2022) 753 – 761 The Journal of Clinical Endocrinology & Metabolism. 2022 Jan;107(1):1-9.
- 30.
- 31. Approaches to Type2 Diabetes Remission 1. Surgical interventions (+/- others below) 2. Pharmacological interventions (+/- others below) 3. Health behavioral interventions (diet and/or physical activity not include the addition of new pharmacological agents or surgery). 4. Digital technology interventions Can J Diabetes46 (2022) 753 – 761
- 32. Cut it down Bariatricsurgery should be recommended to nonpregnant adults with type 2 diabetes and a BMI ≥35 kg/m2 as an option to potentially induce type 2 diabetes remission [Grade A, Level 1A]
- 33. Copyright ADA/EASD 2022 Mingroneet al. The Lancet. 2021 23;397:293-304 Weight Management: Metabolic Surgery
- 34. Health Behavioral Interventions • Lowcalorie diets (800-850 cal/day) with meal replacement products for 3- 5 months aimed at achieving >15kg weight loss, followed by a structured food reintroduction program and increased physical activity (for people with BMI 27-45) [Grade A, Level 1A]. Can J Diabetes46 (2022) 753 – 761
- 35. Health Behavioral Interventions(cont.) • Exercise training (240-420 min/week) with a calorie restricted diet (for people with BMI >25, and with a lower level of evidence for this option) [Grade C, Level 2] Can J Diabetes46 (2022) 753 – 761
- 36.
- 37.
- 38. DiRECT (Diabetes Remission Clinical Trial) •First time randomized trial shows remission of T2DM with dietary and lifestyle intervention Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet 2017
- 39. Background & Objectives •T2DM management is focused on pharmacological treatment • Caloric restriction is beneficial for T2DM patients, but not tested in routine primary care. • The DiRECT study was designed to assess whether intensive weight management can produce sustained remission of T2DM in the primary care setting.
- 40. Study design (1) Inclusion Criteria •T2DM diagnosis within the previous 6 years(*) • age 20–65 years • BMI: 27 - 45 kg/m2 Exclusion Criteria • current insulin use • HbA1c >12% • weight loss of >5 kg within the past 6 months • recent eGFR <30 mL/min/1.73m2 • severe or unstable HF (*) most recent HbA1c value > 6.0%, if HbA1c <6.5% antidiabetic medication was continued
- 41. Study design (2) ITTpopulation (N=298) Control Group (N=149) best-practice care by guidelines for up to 52 weeks Intervention Group (N=149) stop anti-diabetic and anti-hypertensive medications Lean MEJ, et al. Lancet 2017 Total Diet Replacement 12-20 weeks Food Reintroduction 2-8 weeks Weight Loss Maintenance up to 52 weeks ITT: Intention-to-treat; Total Diet Replacement: 825-853 kcal/day formula;
- 42. Main results (1/2) IG:Intervention group; CG: Control group; DM: Diabetes Mellitus; (*) Additionally, 5% in the CG started antidiabetic medications Lean MEJ, et al. Lancet 2017 24% 46% 74% 0% 4% 18% 0% 10% 20% 30% 40% 50% 60% 70% 80% weight loss 15kg or more DM remission drug discontinuation(*) IG CG Percentages of patients in each group
- 43. Main results (2/2) -10 -1 -12 -10 -8 -6 -4 -2 0 IGCG Mean change in weight (kg) P<0.0001 -0.9 0.1 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 IG CG Mean change in HbA1c (%) P<0.0001 IG: Intervention group; CG: Control group; Lean MEJ, et al. Lancet 2017
- 44. DiRECT trial 12-monthBottom-line Diabetes remission may occur in T2DM of up to 6 years’ duration with help of an evidence-based structured weight management. Almost a quarter of participants who followed the intervention achieved at least 15 kg of weight loss at 12 months. Almost half of patients (46%) in the IG showed remission of diabetes and stopped antidiabetic Rx.
- 45. The 24 monthfollow up
- 47. 24-month DiRECT trialbottom-line 36% of intervention participants had sustained remission at 24 months HbA1c was significantly reduced in the intervention group, with 50% reduction in use of diabetes medications
- 48.
- 49. My Doctor told methat diabetes has gone
- 50. My Diabetes hasnot gone
- 51.
- 52. Benefits are notonly to stop drugs… • Substantial weight loss is associated with reduced liver and pancreatic fat, and with restoration of pancreatic morphology and β-cell insulin secretory capacity = glycemic benefits of loosing weight • CV benefits of loosing weight • Obesity itself is a disease, you must deal with it whether or whether not achieving remission Lancet Diabetes Endocrinol. 2020; 8: 939-948 Lancet Diabetes Endocrinol. 2019; 7: 726-736
- 53. Do not negativelyimpact your patient • Sometimes it its difficult, you may not achieve this • Weight loss may be difficult, and if occurred its • maintenance is difficult “on lifestyle alone” • Remission is one target, lowering A1C is the classic most important one • Don’t underestimate the 1% reduction in A1c
- 54. Message for thosewho are on remission • You carry risk, you are always at risk • You have to see your caregiver every now and then • A1c (or others) at 3 month interval
- 55. Dilemma • Insulin duringremission • Starting GLP-1 & SGLT2i for non glycemic indications • Diabetes beyond 6 years (what about 7) • If not obese at the start • Blood sugar that not that elevated
- 56. Copyright ADA/EASD 2022 WeightManagement in Type 2 Diabetes Davies M et al; Lancet 2021; 397: 971-84 Frías JP et al. N Engl J Med 2021;385:503-515
- 57. Bottom-line for diabetesremission • Diabetes remission may be occurring more often due to advances in treatment • More research is needed. • Individualize deprescription • A1c reduction is enough sometimes • Remission is one of treatment targets, not the only one
- 58.
- 59.
- 60. Potential goals and approaches for type2 diabetes Diabetes Prevention Prediabetes Schematic representation Adapted from Raccah et al. Diabetes Metab Res Rev 2007; 23: 257–264 S. Jin et al. / Can J Diabetes 46 (2022) 762e774
- 61. 61 | IDFDiabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Highlights In 2021, IDF estimates show that: 1 in 2 Adults is undiagnosed 240 million people 11.5% Of global health expenditure spent on diabetes (USD 966 billion) 1 in 10 Adults (20-79 years) has diabetes 537 million people 1 in 6 Live births (21 million) affected by hyperglycaemia in pregnancy, 80% have mothers with GDM 6.7 million Deaths attributed to diabetes 1 in 18 Adults (20-79 years) has impaired fasting glucose 319 million people 1 in 9 Adults (20-79 years) has impaired glucose tolerance 541 million people 1.2 million Children and adolescents below 20 years have type 1 diabetes 3 in 4 People with diabetes live in low and middle-income countries
- 62. β-Cell Volume inPatients With IFG and Patients With T2D Butler AE et al. Diabetes 2003;52:102-10
- 63. Don’t let the “pre”fool you
- 64. Heatlh Risks Associated With Prediabetes 64 Prediabetes todiabetes: 4-6% for isolated IGT, for isolated IFG 6-9% and for both IGT and IFG was 15-19% CKD and early nephropathy Neuropathies Retinopathy ASCVD (prediabetes or diabetes or IR) Diabetes Res Clin Pract. 2007 Dec; 78(3):305-12. Diabetes Care. 2000 Aug; 23(8):1113-8. Diabetes Care. 2010 Oct; 33(10):2285-93. Diabet Med. 2007 Feb; 24(2):137-44. Lancet. 2010 Jun 26; 375(9733):2215-22. World J Diabetes. 2015 Mar 15; 6(2): 296–303.
- 65. Goals of therapy in personswith prediabetes and metabolic syndrome • Prevent progression to T2DM • Prevent progression to MAFLD • Improve CVD risk factors via aggressive control of: elevated BP dyslipidemia • Treat ABCD • Improve functionality and • QoL
- 66.
- 67. Lifestyle intervention forthe Prevention or Delay of Type 2 Diabetes 67 Study Title (country of conduct, year of publication, n) Risk eligibility criteria Duration of follow-up Intervention Risk reduction in diabetes incidence compared to control Da Qing Study (China, 1997, n=577) IGT; age ≥ 25 years 6 y Diet 31% Exercise 46% Diet + Exercise 42% Control -- Finnish Diabetes Study (Finland, 2001, n=522) IGT; age 40–65 years; BMI > 25 kg/m2 3.2 y Diet + Activity 58% Control -- Diabetes Prevention Program (US, 2002, n=3,234) GT; FPG 5.3–6.9 mmol/l (<6.9 mmol/l for Native American ancestry); age ≥ 25 years; BMI ≥ 24 kg/m2 (≥ 22 kg/m2 in Asians) 2.8 y ILS 58% Met 850 bid 31% Placebo -- Japanese IGT Study (Japan, 2005, n=458) Men with IGT 4 y Diet + Exercise 67% Control -- Indian Diabetes Prevention Program (India, 2006, n=531) IGT; age 35–55 years 30 months Lifestyle 29% Met 250 bid 26% LS + Met 28% Control -- Diabetologia . 2017 September ; 60(9): 1601–1611.
- 68. Metformin for thePrevention or Delay of Type 2 Diabetes 68 Study Title (country of conduct, year of publication, n) Risk eligibility criteria Duration of follow-up Intervention Risk reduction in diabetes incidence compared to control Diabetes Prevention Program (US, 2002, n=3,234) GT; FPG 5.3–6.9 mmol/l (<6.9 mmol/l for Native American ancestry); age ≥ 25 years; BMI ≥ 24 kg/m2 (≥ 22 kg/m2 in Asians) 2.8 y ILS 58% Met 850 bid 31% Placebo -- Indian Diabetes Prevention Program (India, 2006, n=531) IGT; age 35–55 years 30 months Lifestyle 29% Met 250 bid 26% LS + Met 28% Control -- Diabetologia. 2017 September ; 60(9): 1601–1611.
- 69.
- 70. Role in PreDiabetes DiabetesPrevention Program Metformin reduced the incidence of T2DM by 31% relative to Placebo(13) 31% RRR 58% RRR Ref. The writing group (William C. Knowler, M.D., Dr.P.H., Elizabeth Barrett- Connor, M.D., Sarah E. Fowler, Ph.D., Richard F. Hamman, M.D., Dr.P.H., John M. Lachin, Sc.D., Elizabeth A. Walker, D.N.Sc., and David M. Nathan, M.D.) takes responsibility for the content of this article. Address reprint requests to he Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852. *The members of the Diabetes Prevention Program Research Group are listed in the Appendix.
- 71. Cumulative incidence ofdiabetes and weight change Since Randomization of DPP/DPPOS 71
- 72. Essential Role inPre-Diabetes Diabetes Prevention Program Effect of Metformin was higher in Younger age groups Higher BMI Higher FPG at baseline Ref. Lancet Diabetes Endocrinol 2015; 3: 866–75 Published Online September 14, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00291-0 See Comment page 831 *Members listed in the appendix Correspondence to: Prof David M Nathan, Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD 20852, USA dppmail@bsc.gwu.edu
- 73. At 15-year follow-up(DPPOS) 73 Participants with higher FPG (>110 mg/dL) and women with history of GDM experienced high RRR with metformin Therefor, women with prior GDM are candidates for metformin in diabetes prevention
- 74.
- 75. Compared to theplacebo intervention The lifestyle intervention cost ~$1,700 more per person over 10 years but substantially improved quality-of- life = “cost-effective” The metformin intervention cost ~$100 less per person over 10 years and marginally improved quality-of- life = “cost-saving” Diabetes Care 2012;35:723-30
- 76. Intensive lifestyle was intensive •Individual lifestyle coaches and access to support staff: 1. Dietitian 2. Behavioral counselor 3. Exercise specialist • 16-session individual curriculum, covering nutrition, exercise, and behavioral self management • Kept food journals (mandatory requirement in run-in period); these were monitored • The “Toolbox”
- 77. Consider Prediabetes treatment • Prediabetes isa metabolic and vascular disorder, and clinicians should actively treat people with prediabetes in order to prevent or at least delay progression to T2D and development of CVD complications. Grade A; BEL 1
- 78. AACE endorses thehealthy lifestyle while dealing with prediabetes • The prevention of T2D can be addressed by lifestyle modifications that include a healthy meal plan, regular physical activity, and behavioral health practices and weight loss in persons with ABCD. The Mediterranean diet should be considered to reduce progression to T2D and risk of CVD. Low-fat, vegetarian, and DASH meal patterns can also be considered for prevention of T2D. (Grade A, BEL 1)
- 79. AACE endorses thehealthy lifestyle while dealing with prediabetes • Lifestyle intervention should include aerobic and resistance physical activity in all persons with prediabetes and/or metabolic syndrome. The initial aerobic prescription may require a progressive increase in the volume and intensity of exercise, and the ultimate goal should be 150 minutes/week of moderate exercise performed during 3 to 5 sessions per week (Grade A; BEL 1). Resistance exercise should consist of single-set exercises that use the major muscle groups 2 to 3 times per week (Grade A; BEL 1). An increase in non- exercise and active leisure activity should be encouraged to reduce sedentary behavior (Grade B; BEL 2).
- 80. AACE drugs forprediabetes • Obesity medications, namely phentermine/topiramate ER, liraglutide 3 mg, or weekly semaglutide 2.4 mg, in conjunction with lifestyle therapy, should be considered in persons with prediabetes and/or metabolic syndrome with ABCD, whether overweight (BMI 27 to 29.9 kg/m2) or with obesity (BMI ≥30 kg/m2), when needed to achieve and sustain 7% to 10% weight loss for prevention of T2D. (Grade A; BEL 1) • Although no medications have been approved for the treatment of prediabetes, diabetes medications including metformin, acarbose, pioglitazone, or GLP-1 RA can be considered in persons with prediabetes or in persons who also have ABCD and remain glucose-intolerant following weight loss using lifestyle and/or weight- loss medications. (Grade A; BEL 1)
- 82. • Monitor forthe development of type 2 diabetes in those with prediabetes at least annually; modify based on individual risk/benefit assessment. E • Refer adults with overweight/obesity at high risk of type 2 diabetes, as typified by the DPP, to an intensive lifestyle behavior change program to achieve and maintain a weight reduction of at least 7% of initial body weight through healthy reduced-calorie diet and ≥150 min/week of moderate intensity physical activity. A • A variety of eating patterns can be considered to prevent diabetes in individuals with prediabetes. B 82
- 83. • Prediabetes isassociated with heightened cardiovascular risk; therefore, screening for and treatment of modifiable risk factors for cardiovascular disease are suggested. B • Statin therapy may increase the risk of type 2 diabetes in people at high risk of developing type 2 diabetes. In such individuals, glucose status should be monitored regularly, and diabetes prevention approaches reinforced. It is not recommended that statins be discontinued. B • In people with a history of stroke and evidence of insulin resistance and prediabetes, pioglitazone may be considered to lower the risk of stroke or myocardial infarction. However, this benefit needs to be balanced with the increased risk of weight gain, edema, and fracture. A Lower doses may mitigate the risk of
- 84. Prediabetes as AContinuum in DCRM
- 85. Diabetes Prevention Bottom-line should actively treatpeople with prediabetes = delay diabetes + delay complications DPP intensive lifestyle DPP metformin Consider medication to treat ABCD + prediabetes Pioglitazone has its position in diabetes prevention
- 86.
Editor's Notes
- #6 5
- #7 It has traditionally been thought that type 2 diabetes is a direct risk factor for atherosclerosis and cardiovascular disease. However, there is growing evidence that both type 2 diabetes and cardiovascular disease spring from a “common soil” of metabolic antecedents, including impaired glucose tolerance, hypertension, dyslipidemia, and abdominal obesity (4–6) (see Fig. 1 ). The clustering of these cardiovascular risk factors results from an underlying insulin resistance syndrome, also known as metabolic syndrome or Syndrome X, that precedes the onset of type 2 diabetes (6–11). Reaven (7) first summarized the insulin resistance syndrome, or Syndrome X, as resistance to insulin-stimulated glucose uptake, hyperinsulinemia, impaired glucose tolerance, hyperglycemia, hypertension, elevated triglycerides, and decreased high-density lipoprotein (HDL) cholesterol. Since this initial description, multiple components of the insulin resistance syndrome, including hyperinsulinemia, impaired glucose tolerance, general and abdominal obesity, dyslipidemia (elevated triglycerides and low HDL), hypertension, elevated small dense LDL, elevated uric acid, and abnormal clotting factors, have been found to cluster in men and women in multiple ethnic groups. ------------------ The decision to make diabetes a coronary heart disease risk equivalent is supported by a landmark study by Haffner et al. in 1998, which showed that patients with diabetes who had never experienced a myocardial infarction had a comparable risk of cardiovascular disease mortality as individuals without diabetes who had experienced an infarction.
- #8 Our data suggest that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction. These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in nondiabetic patients with prior myocardial infarction.
- #9 8
- #11 Geltrude: Here’s another option to have both US and global information
- #12 Weight reduction, as a targeted intervention, has largely been viewed as a strategy to improve glycemic control, and minimize weight-related complications. 5-15% weight loss reduction is considered by some to be a viable target for those living with T2D. While more weight loss can improve outcomes and have a disease modifying effect, weight loss in general has benefits that extend well beyond glycemic control and has been associated with an improved overall quality of life. ------------- Weight reduction has mostly been seen as a strategy to improve glycaemic management and reduce the risk for weight-related complications. It was recently suggested that weight loss of 5-15% should be a primary target in management for many people living with type 2 diabetes. A higher magnitude of weight loss confers better outcomes, and a 5-10% loss confers metabolic improvement, and a loss of 10-15% or more of body weight can have a disease-modifying effect, and lead to remission of diabetes. Weight loss may exert benefits that extend beyond glycaemic management to improve risk factors for cardiometabolic disease and quality of life. I will now hand it off to Dr. Rossing…..
- #13 The tools available to prevent and treat diabetes are vastly improved However, implementation of effective innovation has lagged behind and requires fundamental changes in health care policy and societal approaches to wellness Our understanding of the basic mechanisms of diabetes, the development of complications, and the treatment of both, though continuously advancing, has highlighted how much we do not know Current therapy of overweight/obesity is clearly inadequate Lifestyle management and diabetes self-management education and support is of clear benefit, yet current paradigms on how to apply the broad approaches need to be better targeted and individualized Preserving and enhancing beta-cell function is perceived as the holy grail of diabetes and yet effective techniques are inadequately developed The promise of personalized medicine and –omics approaches addressing both personal and environmental factors and their interaction is largely unrealized in diabetes care and will require large investments and coordination to reach application in the form of enhanced biomarkers and tailored treatments There is a gap between what we know from trial data and what happens in clinical practice We need better devised trials which include measures of patient preference and patient-recorded outcome measures Better application of “real-world evidence” to complement traditional RCT evidence is needed to impact patient outcomes
- #14 People with type 2 diabetes can achieve “remission” by sustaining normal blood glucose levels for at least three months without taking diabetes medication. HbA1c (average blood glucose) level of less than 6.5% at least three months after stopping diabetes medication as the usual diagnostic criterion for diabetes remission
- #15 John B. Buse formerly held the position of President, Medicine & Science on the board of the American Diabetes Association during 2008. Buse currently serves as the Director of the Diabetes Care Center at UNC
- #16 4 major diabetes journals published consensus-based remission definitions, authored by representatives from the American Diabetes Association, the European Association for the Study of Diabetes, Diabetes UK, the Endocrine Society and the Diabetes Surgery Summit A1C <6.5% without use of antihyperglycemic medications for at least the 3 prior months.
- #19 The term “remission” is commonly used in oncology to describe the non-detection of cancer after treatment. Inherent in the concept of cancer remission is that recurrence may develop as risk remains. ---------------------- We learnt this word “remission” from oncology, nephrology & rheumatology They consider non detection of the original disease as remission But still there are is a risk of recurrence “exacerbation” We need to closely follow them Same apply for diabetes remission It emphasises the future possibility of relapse even after a prolonged period of normoglycaemia and ensures continuous surveillance for relapse and for occurrence of diabetes complications.
- #20 لا تخافوا ولكن أحذروا
- #21 Some people want to use the word reversal, but then when you use reversal, does this really give us the true nature of what happens in people with diabetes? And some people thought it’s a cure, but did we really cure diabetes? So they needed to come up with a term that made clinical sense, that is closer to reality and closer to what actually happens in our bodies. The word “remission” was favored over “reversal” or “regression” to signify the potentially temporary nature of glucose improvement, which may or may not impact the long-term deterioration of beta cells. And remission does a really good job of conveying, similar to cancer, it means you don’t have cancer right now, but it could come back. Versus cure implies you’re never going to deal with this again. Absolutely. Because the word cure was tricky because some people, for example, who had surgery, bariatric surgery to lose weight. They would say cure, but we’ve seen in some studies that not everyone has a durable effect. Many don’t years down the line. So remission is, I think, a more appropriate term. And that’s why this group gave us this consensus statement.
- #22 The consensus was to categorize remission of type 2 diabetes based on the achieved A1C level: remission to prediabetes (A1C between 6.0% and 6.4%) and remission to normal glucose concentrations (A1C <6.0%). Both remission subclasses require that an individual in remission not be taking any antihyperglycemic medications for a minimum of 3 months. If, after achieving remission with either definition, the A1C subsequently rises above the specified threshold of 6.4%, the individual with remission would be considered to have relapsed with type 2 diabetes. Furthermore, if antihyperglycemic agents are added back or continued, even if prescribed only for the purpose of cardiovascular and/or renal protection and/or weight control, the individual’s type 2 diabetes would not be considered as being in remission, but would be considered as pharmacologically-managed diabetes, regardless of A1C.
- #23 Primary criterion: Meeting A1C thresholds, as listed above. If the primary criterion for defining remission cannot be used (e.g. unreliable value), secondary criteria may include: Meeting FPG thresholds on 2 separate occasions (FPG ≤110 mg/dL for remission to normal glucose levels or 110 to 125 mg/dL for remission to prediabetes) or Meeting both OGTT thresholds (both FPG [as above] and 2hPG ≤ 140 mg/dL for remission to normal glucose levels or 141 to 199 mg/dL for remission to prediabetes)
- #27 Following a thorough discussion outlining the concept of remission and its limitations, a therapeutic goal of diabetes remission may be considered for individuals with type 2 diabetes who are interested in attempting remission; do not have significant eating or mental health disorders; do not have a compelling indication for antihyperglycemic agent(s) for renal or cardiovascular benefit; and meet the specified criteria outlined in the intervention-based recommendations #4, #5 and #6, to eliminate the need for antihyperglycemic therapy [Grade D, Consensus]. The approach to deprescribing antihyperglycemic agents should be individualized and incorporate the principles of minimizing the risk for hypoglycemia and avoiding medications with potential for weight gain/regain [Grade D, Consensus].
- #28 diagnosed with diabetes for a shorter time (6 years or less – this exact duration being based on specific clinical trial data; I would suggest that clinicians do not necessarily need to consider this as a hard cutoff) with overweight or obesity, who are ‘able or inclined’ to lose weight with blood sugars that are not that elevated who do not take insulin (as the need for insulin may indicate a more tired pancreas) ---------------------------------- Stopping certain glucose-lowering medication(s) with proven benefits on reducing heart and/or kidney disease complications may not be recommended for individuals with type 2 diabetes who have a history of cardiovascular disease and/or kidney disease. Your health-care professional or diabetes care team can help you determine if type 2 diabetes remission is appropriate for you. If so, they can help you select the best therapeutic option among the available strategies to give you the best chance of remission, and make appropriate referrals.
- #29 early type 2 diabetes (6 years or less) with overweight or obesity, who are ‘able or inclined’ to lose weight without significant eating disorders or mental health disorders (reason: these were often exclusions from the referenced studies, presumably because these issues can present challenges in adhering to strategies to achieve diabetes remission long term. I would suggest that this should be interpreted/assessed very carefully and perhaps should not be categorical.) without cardiovascular disease, heart failure, or chronic kidney disease (because GLP1 receptor agonists and/or SGLT2 inhibitors should be continued even if sugars are normal, for heart and kidney protection)
- #30 In terms of A1C testing frequency for initially determining remission, whether for an individual with established type 2 diabetes stopping glucose-lowering medication(s) or after a new diagnosis of type 2 diabetes, we recommend lab evaluation (A1C or, if A1C unreliable, FPG or OGTT) at 3 and 6 months. If, at 6 months, remission criteria have not been met, reinitiation of antihyperglycemic agents should be considered. If remission criteria are met, subsequent A1C testing to monitor for persistence of remission or relapse status should be performed at least every 6 months.
- #32 Surgical interventions considered all interventions that included a surgery, whether or not they also involved behavioural interventions or pharmacological agents. Pharmacological interventions were classified as those which added 1 or more pharmacological agents to achieve remission, whether or not they also involved behavioural interventions. Health behavioural interventions were those that attempted to change diet and/or physical activity or other health-related behaviours, but that did not include the addition of new pharmacological agents or surgery. Digital technology interventions covered a subset of health behavioural interventions where platforms and tools, such as smartphones/watches, mobile and web/digital applications, glucose-sensing and related technologies, etc., were the central instruments used to achieve diabetes remission, but that did not include new pharmacological agents or surgery. ------------------------------------------------- The Guidelines recommend three options to potentially induce type 2 diabetes remission: bariatric surgery (for people with BMI ≥35) low calorie diets (800-850 cal/day) with meal replacement products for 3-5 months aimed at achieving >15kg (33lb) weight loss, followed by a structured food reintroduction program and increased physical activity (for people with BMI 27-45) exercise training (240-420 min/week) with a calorie restricted diet (for people with BMI >25, and with a lower level of evidence for this option)
- #33 The STAMPEDE (Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently) trial showed that metabolic surgery, when compared with intensive medical therapy (lifestyle counseling, weight management, self-monitoring of glucose, drug therapy), significantly improved outcomes for weight loss, DM remission, glycemic control, need for DM medications, lipid and BP medications, and QoL
- #35 Low-calorie (800 to 850 kcal/day) diets with meal replacement products for 3 to 5 months aimed at achieving >15 kg body weight loss, followed by structured food reintroduction and increased physical activity for weight loss maintenance, should be recommended as an option to potentially induce type 2 diabetes remission to selected nonpregnant adults with a BMI between 27 and 45 kg/m2; type 2 diabetes duration <6 years, A1C <12% and not using insulin [Grade A, Level 1A].
- #36 Exercise training (aiming for 240 to 420 min/week of structured physical activity spread over 5 days per week) combined with a calorie-restricted diet to promote modest weight loss (5% to 7% of initial body weight), may be recommended as an option to potentially induce type 2 diabetes remission to selected nonpregnant adults with a BMI >25 kg/m2, type 2 diabetes duration <10 years, A1C <9% and not using insulin [Grade C, Level 2]
- #38 The Look AHEAD and DiRECT studies attest to the powerful benefits of lifestyle interventions and weight loss in persons with T2D and ABCD. These composite data indicate that weight loss should be a primary treatment modality in persons with T2D and ABCD. The initial dietary prescription should generally be designed to produce a 500 kilocalories daily energy deficit. Very low-calorie diets and meal substitutes can be considered and have the potential for T2D remission. In clinical trials comparing bariatric surgery vs medical treatment in persons with T2D, bariatric surgery results in greater short-term and long-term lowering of A1C, including remission of T2D in some persons.
- #40 Background Current guidelines for the management of type 2 diabetes (T2DM) focus on pharmacological treatment to reduce blood glucose and the associated elevated CV risk. Life expectancy is, however, still markedly reduced in T2DM patients. There are data showing that T2DM can be returned to normal glucose control by caloric restriction, but this intervention has not been tested in routine primary care.
- #41 Study Endpoints: Weight loss ≥15 kg DM remission defined as HbA1c <6.5% (<48 mmol/mol) after 2 months without antidiabetic medications
- #42 The DiRECT study was an open-label, cluster-randomized trial at 49 primary care practices. Participants in the intervention group were asked to follow the Counterweight-Plus weight management program [9] and aim for achieving and maintaining at least 15 kg weight loss. A total diet replacement phase with a low energy formula diet (825-853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber) for 3 months was used, followed by structured food reintroduction of 2-8 weeks (about 50% carbohydrate, 25% total fat, 15% protein) and an ongoing structured program with monthly visits for long-term weight loss maintenance. All oral antidiabetic drugs were discontinued on day 1 of the program, with standard protocols for reintroduction according to national guidelines. Antihypertensive drugs were withdrawn in light of the rapid BP reductions seen upon commencement of a low energy diet. At the start of food reintroduction, physical activity strategies were introduced to help participants in the intervention group to reach and maintain their individual sustainable maximum.
- #43 - At 12 months, weight loss ≥15 kg was seen in 26 (24%) of participants in the intervention group and in no control participants (Fisher’s exact p<0·0001). - Diabetes remission was seen in 68 (46%) of intervention participants and in six (4%) of control participants (OR: 19.7, 95%CI: 7.8-49.8, P<0.0001). - At 12 months, 74% in the intervention group were taking no antidiabetic medication, compared with 18% of controls, and in the latter group 5% commenced antidiabetic medication.
- #44 - The intervention group showed on average 10.0 kg weight loss and the control group 1.0 kg (adj difference: -8.8, 95%CI: -10.3 to -7.3, P<0.0001). - Mean HbA1c reduced by -0.9% (SD: 1.4) in the intervention group, and increased with 0.1% (SD: 1.1) in the control group (adj difference: -0.85%, 95%CI: -1.10 to -0.59, P<0.0001).
- #45 T2DM of up to 6 years’ duration can be reversed by weight loss with help of an evidence-based structured weight management program delivered in a community setting, by routine primary care staff. Almost a quarter of participants who followed the intervention achieved at least 15 kg of weight loss at 12 months. Almost half of patients in the intervention group showed remission of diabetes and were off antidiabetic medication.
- #48 Was 46% in 12-month Direct trial Durable remission of short duration T2DM is attainable in a Primary Care setting
- #52 Let your patients know that if they lose enough weight, particularly during the early phases of type 2 diabetes, they will significantly lower their blood glucose, have less risk for diabetes complications, and may be able to achieve remission.
- #53 Substantial weight loss is associated with reduced liver and pancreatic fat, and with restoration of pancreatic morphology and β-cell insulin secretory capacity = glycemic benefits of loosing weight
- #54 Remission is a journey, not a destination, and authors very appropriately caution against a ‘success/failure’ approach to diabetes remission. There is potential negative mental health impact to a person who doesn’t achieve or sustain diabetes remission, as they may feel as though they have failed. Remember: people who improve their sugars and/or weight but don’t get to diabetes remission are still achieving important health improvements, and this too is a success! ----------------------------- Remission may not be a reality for many people with type 2 diabetes. Weight loss is not feasible or achievable for many people with lifestyle therapy.
- #55 Genetically if you’re at risk, you remain at risk. you have to have long-term follow-up and you still have to see your healthcare team There are patients who will never achieve this. We are treating diabetes to classic targets including “remission” not only to remit them If you cannot achieve remission, remember, we always have to remember that a 1% reduction in A1C means a lot of reduction in complications. So do not underestimate that. ----------------------------- Remission is a journey, not a destination, and authors very appropriately caution against a ‘success/failure’ approach to diabetes remission. There is potential negative mental health impact to a person who doesn’t achieve or sustain diabetes remission, as they may feel as though they have failed. Remember: people who improve their sugars and/or weight but don’t get to diabetes remission are still achieving important health improvements, and this too is a success! ------------------- In terms of A1C testing frequency for initially determining remission, whether for an individual with established type 2 diabetes stopping glucose-lowering medication(s) or after a new diagnosis of type 2 diabetes, we recommend lab evaluation (A1C or, if A1C unreliable, FPG or OGTT) at 3 and 6 months. If, at 6 months, remission criteria have not been met, reinitiation of antihyperglycemic agents should be considered. If remission criteria are met, subsequent A1C testing to monitor for persistence of remission or relapse status should be performed at least every 6 months.
- #60 Prediabetes is identified by the presence of impaired fasting glucose (IFG) (100 to125mg/dL),impaired glucose tolerance (IGT),which is a PG value of 140 to 199mg/dL 2 hours after ingesting 75 g of glucose, and/or A1C value between 5.7% and 6.4%. A1C should be used only for screening for prediabetes. The diagnosis of prediabetes, which may manifest as either IFG or IGT, should be confirmed with glucose testing. Grade B; BEL 2
- #61 People with type 2 diabetes can achieve “remission” by sustaining normal blood glucose levels for at least three months without taking diabetes medication. HbA1c (average blood glucose) level of less than 6.5% at least three months after stopping diabetes medication as the usual diagnostic criterion for diabetes remission
- #63 Insu-00056817 [Source: Butler et al. Diabetes 2003;52(1):102-10. /p 105 Figure 2B, /p104/col 2/paragraph 3/sentences 1, 3 and 7; N value from Abstract] Abbreviations: IFG=Impaired fasting glucose; T2D=Type 2 diabetes Key Point: This Mayo Clinic study showed that patients with T2D and those with borderline abnormalities (IFG) have severely reduced β-cell mass. [inferred from /p103/col 1/paragraph 4/Sentence 1 and sentence 3; p/104/col 2/paragraph 2 continued to /p105/col 1/paragraph 1; /p106/col 1/paragaraph 2/sentence 1; /p109/col 2/paragraph 3/sentence 1 and 3 ] Reference: Butler AE, Janson J, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1):102-10.
- #70 DPPOS Study Design The DPPOS follow-up study started in 2002. All 3,149 surviving participants of DPP groups were eligible for the DPPOS, including those with and without diabetes. Of the 3,149 surviving participants, 2,776 (88 percent) joined the DPPOS. Similar proportions of each DPP group joined the DPPOS and remained in their original groups. There were some changes to the treatments each group received: Lifestyle Change Group –Group participants received quarterly group lifestyle change classes throughout the study and two group classes yearly to reinforce self-management behaviors for weight loss. Metformin Group – Group participants received quarterly group lifestyle change classes throughout the study. Participants continued to take metformin and were told that they were taking metformin. Placebo Group – Group participants received quarterly group lifestyle change classes throughout the study. Participants did not take a placebo pill. DPPOS participants who developed diabetes remained in the study and received additional care from their own physicians if good blood glucose control could not be maintained.
- #72 a) Cumulative incidence of diabetes and (b) weight change over 15 years in the DPP/DPPOS, in metformin (blue line) and placebo (red line) groups.
- #73 Metformin therapy for the prevention of type 2 diabetes should be considered in adults at high risk of type 2 diabetes, as typified by the Diabetes Prevention Program, especially those aged 25–59 years with BMI ≥35 kg/m2, higher fasting plasma glucose (e.g., ≥110 mg/dL), and higher A1C (e.g., ≥6.0%), and in individuals with prior gestational diabetes mellitus. A
- #79 In persons with prediabetes and/or metabolic syndrome or identified to be at high risk of T2D based on validated risk-staging instruments, the prevention of T2D can be addressed by lifestyle modifications that include a healthy meal plan, regular physical activity, and behavioral health practices and weight loss in persons with ABCD. The Mediterranean diet should be considered to reduce progression to T2D and risk of CVD. Low-fat, vegetarian, and DASH meal patterns can also be considered for prevention of T2D. Grade A, BEL 1 Lifestyle intervention should include aerobic and resistance physical activity in all persons with prediabetes and/or metabolic syndrome. The initial aerobic prescription may require a progressive increase in the volume and intensity of exercise, and the ultimate goal should be 150 minutes/week of moderate exercise performed during 3 to 5 sessions per week (Grade A; BEL 1). Resistance exercise should consist of single-set exercises that use the major muscle groups 2 to 3 times per week (Grade A; BEL 1). An increase in nonexercise and active leisure activity should be encouraged to reduce sedentary behavior (Grade B; BEL 2).
- #80 In persons with prediabetes and/or metabolic syndrome or identified to be at high risk of T2D based on validated risk-staging instruments, the prevention of T2D can be addressed by lifestyle modifications that include a healthy meal plan, regular physical activity, and behavioral health practices and weight loss in persons with ABCD. The Mediterranean diet should be considered to reduce progression to T2D and risk of CVD. Low-fat, vegetarian, and DASH meal patterns can also be considered for prevention of T2D. Grade A, BEL 1 Lifestyle intervention should include aerobic and resistance physical activity in all persons with prediabetes and/or metabolic syndrome. The initial aerobic prescription may require a progressive increase in the volume and intensity of exercise, and the ultimate goal should be 150 minutes/week of moderate exercise performed during 3 to 5 sessions per week (Grade A; BEL 1). Resistance exercise should consist of single-set exercises that use the major muscle groups 2 to 3 times per week (Grade A; BEL 1). An increase in nonexercise and active leisure activity should be encouraged to reduce sedentary behavior (Grade B; BEL 2).