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Prediabetes

Definition, risk factor, pathogenesis, diagnosis and treatment

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Prediabetes

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  1. Diabetes PreventionTime To Act

  2. PATIENT CASE STUDY (1)Pre-Diabetic MEDICAL RECORDS – NOT TO BE REMOVED – 01 02 03 04

  3. Female , 38 years of age History • Female with prediabetes for 3 months • Follow up visit after 3 months • Lifestyle Modification suggested • Both parents have a history of type 2 diabetes. • History of GDM 3 years back • Presents to you for diabetes assessment • Current Medications: none MEDICAL RECORDS – NOT TO BE REMOVED – INFORMATION IN THIS RECORD IS CONFIDENTAL – NOT TO BE REMOVED – 01 02 03 04

  4. Key Vitals and Laboratory Test Results From Most Recent Visit • BP= 130/80 mmHg • BMI = 31 kg/m2 • HbA1c = 5.9% • Creatinine = 86 • eGFR = 90 mL/min/1.73 m2, • Urine ACR = normal • LDL= 2.6 mmol/L History MEDICAL RECORDS – NOT TO BE REMOVED – INFORMATION IN THIS RECORD IS CONFIDENTAL – NOT TO BE REMOVED – 01 02 03 04

  5. Remember... the vast majority of people with type 2 diabetes are already overweight or obese ≥80% have metabolic syndrome3 . 1. World Health Organization. Fact sheet: Obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/media/en/gsfs_obesity.pdf. Accessed: 26 June 2013; 2. Marchesini G, et al. Diabet Med 2004;21:383–7. 3. Alexander et al. Diabetes. 52:1210 –1214, 2003

  6. 537 million people have diabetes in the world and 73 million people in the MENA Region; by 2045 this will rise to 135.7 million1 Prevalence of diabetes in the gulf countries in 2022 UAE1 KSA2 Bahrain3 Qatar4 Kuwait5 Oman6 11.8% 12.3% 17.7% 25.5% 16.4% 9% 1. members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/49-united-arab-emirates.html> [Accessed 9 February 2022]. 2. members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/46-saudi-arabia.html> [Accessed 9 February 2022].3.members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/33-bahrain.html> [Accessed 9 February 2022]. 4. members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/45-qatar.html> [Accessed 9 February 2022]. 5. members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/38-kuwait.html > [Accessed 9 February 2022]. 6. members, R. and Africa, M., 2022. IDF MENA Members. [online] Idf.org. Available at: <https://idf.org/our-network/regions-members/middle-east-and-north-africa/members/42-oman.html> [Accessed 9 February 2022].

  7. What is Prediabetes? Diabetes Mellitus Diabetes Mellitus Diabetes Mellitus Prediabetes Impaired GlucoseTolerance Prediabetes Prediabetes Impaired Fasting Glucose Normal Normal Normal Hemoglobin A1C Fasting Plasma Glucose 2-hour Plasma Glucose On OGTT 6.5% 126 mg/dL 200 mg/dL 140 mg/dL 5.7% 100 mg/dL Any abnormality must be repeated and confirmed on a separate day The diagnosis of diabetes can also be made based on unequivocal symptoms and a random glucose >200 mg/dL Adapted from: American Diabetes Association. Diabetes Care. 2014;37 Suppl 1:S81-90.

  8. Insulin resistance Insulin secretion Natural History Of Prediabetes and Diabetes Years from diagnosis 10 5 15 –10 –5 0 Extreme variability in rates of progression among adults and adolescents /youth Diagnosis Onset Metabolic Stress Pre-diabetes” “Cardio-Metabolic Syndrome” “Metabesity PLASMA GLUCOSE Normal : 99mg/dl or less Pre Diabetes: 100-125 mg/dL Diabetes ≥126 mg/dL (fasting; ≥200 mg/dl; (post prandial) Postprandial glucose Fasting glucose Figure courtesy of CADRE. Adapted from Holman RR. Diabetes Res ClinPract. 1998;40(suppl):S21-S25;Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258 Prediabetes Type 2 diabetes Figure courtesy of CADRE. Adapted from Holman RR. Diabetes Res ClinPract. 1998;40(suppl):S21-S25;Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258

  9. Pathophysiology of prediabetes Ref:Brannick B, Dagogo-Jack S. Prediabetes and Cardiovascular Disease: Pathophysiology and Interventions for Prevention and Risk Reduction. EndocrinolMetabClin North Am. 2018 Mar;47(1):33-50. doi: 10.1016/j.ecl.2017.10.001. PMID: 29407055; PMCID: PMC5806140..

  10. Dedifferentiation of b-cells in Response to Hyperglycemia • Dedifferentiated β-cells reverted to progenitor-like cells • Some β-cells adopted the α-cell fate, resulting in hyperglucagonemia. • Treatment of β-cell dysfunction should restore differentiation Talchai C, Accili D et al. Cell. 2012; 150(6): 1223–1234

  11. Prevention of T2D: Selected Trials • NNT, number needed to treat; RRR, relative risk reduction; T2D, type 2 diabetes. • DPP Research Group. N Engl J Med. 2002;346:393-403. Eriksson J, et al. Diabetologia. 1999;42:793-801.Li G, et al. Lancet. 2008;371:1783-1789. Lindstrom J, et al. Lancet. 2006;368:1673-1679.

  12. Type 2 Diabetes – dysglycaemic continuum Visceral obesity Free fatty acids Hepatic Fat Proinsulin Glucose Insulin Normal Glucose tolerance Impaired Glucose tolerance Diabetes IFG Tuomilehto, J. and P.E.H. Schwarz, 2016. / Schwarz, P. et al.,. Diabetes & Metabolism, 2012. / Schwarz, P.E.H., et al., JCEM, 2009 modifiziertnach: DeFronzo RA et al., Diabetes Care 1998

  13. TYPE 2 DIABETES DYSGLYCAEMIC CONTINUUM Diagnosis Diabetes Visceral obesity Free fatty acids Hepatic fat Proinsulin Glucose Insulin Normal glucose tolerance Impaired glucose tolerance Diabetes IFG Tuomilehto, J. and P.E.H. Schwarz, 2016. / Schwarz, P. et al.,. Diabetes & Metabolism, 2012. / Schwarz, P.E.H., et al., JCEM, 2009..

  14. Prediabetesis an earlystageofthediabetescontinuum In prediabetes,glucose serum levels and/or HbA1C are increased, but still below the threshold of overt type 2 diabetes1 1. Prediabetes (followinginsulinresistance) 3. 2. Diabetes Severe Diabetes withcomplications Monotherapy is no longer sufficient. Dual, triple and finally insulin therapy are needed to counter severe hyperglycemia. Cardiovascular and renal complications are usually present. Despite high insulin con-centration, euglycemia can no longer be maintained and blood glucose rises both in fasting state and postprandially. β-cells start to fail. The insulin action/ efficacy starts to decline. Counter-reactive hyperinsulinism keeps blood glucose in a moderately elevated stage The Diabetes continuum is the patient journey from normoglycemia over insulin resistance, prediabetesto early and late stages of overt type 2 diabetes with increasing micro- and macrovascular complications As definedby ADA 2023 • 1. Rett 2019, DOI 10.1080/03007995.2019.1601455 2. ADA 2023, DOI 10.2337/dc23-S003

  15. DIAGNOSIS Prediabetes1 ORALGLUCOSETOLERANCETEST: 140 - 199mg/dl FASTINGPLASMA GLUCOSE: 100 - 125mg/dl HEMOGLOBIN A1c: 5.7% - 6.4% Normal1 Diabetes1 ORALGLUCOSE TOLERANCETEST: <140mg/dl FASTINGPLASMA GLUCOSE:<100mg/dl ORALGLUCOSETOLERANCETEST: >200mg/dl FASTINGPLASMA GLUCOSE:>126mg/dl HEMOGLOBINA1c: >6.5% HEMOGLOBINA1c: <5.7% 1. Diabetes.org. 2022. Diagnosis | ADA. Available at: https://www.diabetes.org/diabetes/a1c/diagnosis[Accessed 16 March 2022].

  16. WHY SHOULD WECARE ABOUTIT? 400 470million by20301 >80% don’t know they have it2 million haveprediabetesworldwide Risk forcomorbidities are the same fordiabetes and prediabetes.1 1. Brannick, B. and Dagogo-Jack, S., 2018. Prediabetes and cardiovasculardisease: pathophysiologyand interventions forprevention and riskreduction. Endocrinology and Metabolism Clinics,47(1), pp.33-50. 2.Centers fordisease control and prevention. CDC 2022. Prediabetes. Available at: https://www.cdc.gov/diabetes/basics/prediabetes.html#:~:text=Prediabetes%20is%20a%20serious%20health,t%20know%20they%20have%20it.[Accessed 16 March 2022].

  17. Both Prediabetes&Diabetes IncreasetheRisk of MacrovascularComplications1,2 34 28 2655 64 74 80 70 60 50 40 30 20 10 0 Increaseindeathfrom differentcauses CVD CHD Stroke CVD CHD Stroke Diabetes IGT 2-HourGlucoseCriteria IGT is astrongerpredictorofCVD andtotal mortalitythanIFG.1,2 IGT: Impaired Glucose Tolerance;IFG:Impaired Fasting Glucose;NGT:Normal Glucose Tolerance. 1.MilmanS et al. Mechanisms of vascular complications in prediabetes. Med Clin North Am. 2. 2011.2.DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med . 3. 2001.

  18. A1C Level andFutureIncreased Riskof Diabetes1 5X 20X 2X 25 20 15 10 5 0 Relative risk vs. HbA1cof5.0% 5.5% to6.0% 6.0% to6.5% 5.0% to5.5% HbA1c Range (%) 1.Zhang X. Gregg EW. et al. A1C Level and Future Risk of Diabetes: A Systematic Review. Diabetes Care. 33:1665–1673, 2010.

  19. Asymptomatic Individualsat Riskof T2DShouldBe Tested for Prediabetes1 1. Perform tests in overweight or obese adults who have one or more of the following risk factors: First – degree relative with diabetes High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) History of cardiovascular disease (CVD) Hypertension (≥140/90 mmHg or on therapy for hypertension) HDL-C <0.90 mmol/L (35 mg/dL) and/or a TG >2.82 mmol/L (250 mg/dL) Women with polycystic ovary syndrome Physical inactivity Other clinical conditions association with insulin resistance (e.g., severe obesity, acanthosis nigricans) CriteriaforTesting forDiabetesor Prediabetesin AsymptomaticAdults 2. Test Patients with prediabetes yearly (A1C ≥5.7% [39 mmol/mol], IGT, or IFG) Women diagnosed with GDM should have lifelong testing at least every 3 years For all other patients, testing should begin at age 35 years If results are normal, repeat tests at a minimum of 3-year intervals, depending on initial results and risk status Reference: 1.American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022.Diabetes Care 2022;45(Suppl. 1):S17–S38.

  20. Prediabetes is an early stage of the diabetes continuum This model shows how we cannot ignore the fact that with diabetes we face a continuum of stages starting with insulin resistance, prediabetes, type 2 diabetes and cardiorenal disease as consequence of hyperglycemia Prediabetes is not an isolated diagnostic entity, but a stage of the spectrum adaptedfromMechanick 2018 • 1. Mechanick 2018, DOI 10.4158/PS-2018-0139

  21. Prediabetes is already linked to complications • Individuals with prediabetes are at high risk for developing type 2 diabetes (T2DM)1,2 • 11% of individuals with prediabetes will go on to develop T2DM on an annual basis if they do not sufficiently lose weight or engage in physical activity3 • Prediabetes is very often associated with other cardiovascular risk factors and leads to microvascular alterations: • Retinopathy4 • Nephropathy5 • Neuropathy6 • Clinical trials have shown that (intensive) lifestyle change, on one side, and pharmaceutical products like metformin, on the other side, can reduce the risk of T2DM7 • 1. ADA 2023, DOI 10.2337/dc23-S0032. Nathan 2007, DOI 10.2337/dc07-9920 3. Bergman 2013, DOI 10.1007/s12020-013-0017-9 4. Cheng 2009, DOI 10.2337/dc09-04405. Garg 2015, DOI 10.1007/s10157-015-1085-3 6. Ziegler 2008, DOI 10.2337/dc07-1796 7. DPPOS 2015, DOI 10.1016/S2213-8587(15)00291-0

  22. Questions to be considered Questions 1. Does this patient have pre-diabetes? 2. When should patients be screened for pre-diabetes? 3. How should pre-diabetes be treated in primary care settings?

  23. Prediabetes: risk factors Overweight or obese Emirates Consensus 2020, modified from ADA Standards of Care Age Weight Family history Previous prediabetes Lipids Blood pressure Exercise Ethnicity CV disease PCOS, GDM Insulin resistance Adults ≥30 years old • Adults of any age who are overweight or obese (BMI ≥25 or ≥23 kg/m2 if Asian descent) with ≥1 additional risk factor as listed below: − First-degree relative with diabetes − Pre-diabetes, i.e. HbA1c ≥5.7%, IGT or IFG on previous testing − Low levels of high-density lipoprotein cholesterol (<35 mg/dL [<0.90 mmol/L]) and/or high triglyceride (TG) levels (>250 mg/dL [>1.70 mmol/L]) − Hypertension (blood pressure ≥140/90 mm Hg or on treatment for hypertension) − Physical inactivity − High-risk ethnic groups − History of cardiovascular disease (CVD) − Polycystic ovary syndrome − History of gestational diabetes − Other conditions associated with insulin resistance, e.g. severe obesity or acanthosis nigricans Alawadia et al, Emirates Diabetes Society Consensus Guidelines– 2020. Dubai Diabetes Endocrinol J 2020

  24. What is the next best step ? • Metformin 500 BID Gram • Metformin 750 BID • Pioglitazone • Long acting GLP-1 • Lifestyle changes and review in 3 months

  25. PREVENTION OF TYPE 2 DIABETES LIFESTYLE MODIFICATIONS ~50% 50% Smokers are 50% more likely to develop type 2 diabetes.1 Losing 7-10% weight will cut the chance of developing type 2 diabetes in half.1 Weight Loss1 Smoking1 30% Dietary changes decreased risk of developing type 2 diabetes by 33%.2 Walking hastily for a half hour every day reduces the risk of developing type 2 diabetes by 30%.1 33% Changing Dietary Habits2 Exercising1 1. The Nutrition Source. 2022. Simple Steps to Preventing Diabetes. Available at: https://www.hsph.harvard.edu/nutritionsource/disease-prevention/diabetes-prevention/preventing-diabetes-full-story/ [Accessed 17 March 2022]. 2. Uusitupa, M., Khan, T.A., Viguiliouk, E., Kahleova, H., Rivellese, A.A., Hermansen, K., Pfeiffer, A., Thanopoulou, A., Salas-Salvadó, J., Schwab, U. and Sievenpiper, J.L., 2019. Prevention of type 2 diabetes by lifestyle changes: a systematic review and meta-analysis. Nutrients, 11(11), p.2611-2632.

  26. METFORMIN IS THE ONLY APPROVED FOR Pre-Diabetes IN ≥55 COUNTRIES WORLDWIDE1 2017 2004 2014 2015 2016 2018 2019 2020

  27. METFORMIN MECHANISM OF ACTION1 Figure adapted from reference 2 GLP-1: Glucagon-like peptide 1. 1. Baker, C., Retzik-Stahr, C., Singh, V., Plomondon, R., Anderson, V., & Rasouli, N. 2021. Should metformin remain the first-line therapy for treatment of type 2 diabetes? Therapeutic Advances in Endocrinology and Metabolism, 12, 1–13. 2. Schernthaner, G., Brand, K., & Bailey, C. J. (2022). Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism: clinical and experimental, 130, 155-160.

  28. Metformin: Extra effects in the gut • Metformin increases GLP-1secretion, in part by reducing absorption of bile acids1 Gut microbiome effects include2 • Increase in abundance of Lactobacillus by metformin upregulates GLP-1 • Increase in abundance of Akkermansia • promotes SCFA production • counters increased gut permeability • counters pro-inflammatory markers 1 Sansome 2020doi 10.1111/dom.13869 2 Lee 2021doi 10.3390/ijms22073566

  29. Emirates diabetes society consensus guidelines Intensive lifestyle Add metformin if lifestyle unsuccessful Alawadia et al, Emirates Diabetes Society Consensus Guidelines– 2020. Dubai Diabetes Endocrinol J 2020

  30. WHAT HAVE THE PREVENTION STUDIES ACHIEVED? Diagnosis Diabetes IDPP, DaQing Visceral obesity DPP, DPS Hepatic Fat FFA Proinsulin secretion Insulin Blood glucose Normal glucose tolerance Impaired glucose tolerance Diabetes IFG Modifiziertnach: DeFronzo RA et al., Diabetes Care 1998.

  31. NIDDK: National Institute of Diabetes and Digestive and Kidney Diseases. 1. Diabetes Prevention Program 2022. Diabetes Prevention Program (DPP) | NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Available at: https://www.niddk.nih.gov/about-niddk/research- areas/diabetes/diabetes-prevention-program-dpp [Accessed 17 March 2022].

  32. METFORMIN AND TYPE 2 DIABETES PREVENTION

  33. Lifestyle Intervention More Effectively Prevents Diabetes as Populations Age Diabetes Prevention Program (N=3234) 48% Diabetes Incidence per 100 Person-Years 59% 71% Age (years) *Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise . DPP Research Group. N Engl J Med. 2002;346:393-403.

  34. Effectiveness of Lifestyle Intervention for Diabetes Prevention Wanes as Weight Increases Diabetes Prevention Program (N=3234) 51% Diabetes Incidence per 100 Person-Years 61% 65% BMI (kg/m2) *Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise . DPP Research Group. N Engl J Med. 2002;346:393-403.

  35. Da Qing Diabetes Prevention Outcome Study • 577 participant • IGT • (diet, exercise, or diet + exercise) • 6 years intervention => 24 years follow-up Qiuhong Gong, Lancet Diabetes Endocrinol. 2019 

  36. Maintenance of Long-Term Weight Loss DPP Outcomes Study (N=2766) 4 5 6 7 0 1 2 3 8 9 10 Years DPP, Diabetes Prevention Program; T2D, type 2 diabetes. DPP Research Group. Lancet. 2009;374:1677-1686.

  37. Weight Loss Over 10 Years of Follow-Up in Patients with Diabetes in Real-World Clinical Practice 0 Group A -4.3% Why WAIT participants maintained 6.9% weight loss after 10 years 53% of them maintained 9.3% weight loss after 10 years Total group -5 -6.9% *** Weight Loss (%) -9.3% *** -10 *** *** *** Group B (53% of participants) *** *** *** *** *** *** -15 Baseline 3m 12m 24m 36m 48m 60m 72m 84m 96m 108m 120m Total Group n=129 Group A n=61 (Participants maintained <7% weight loss at 1 year) Group B n=68 (Participants maintained > 7% weight loss at 1 year) Duration in Months Values are mean ± SD. *p <0.05 **p <0.01 ***p <0.001 Hamdy O, et al. Presented at: ADA Annual Conference, June 2019; California, USA.

  38. 10-Year Incidence of T2D DPP Outcomes Study (N=2766) Placebo Metformin Lifestyle 4 5 6 7 0 1 2 3 8 9 10 Years DPP, Diabetes Prevention Program; T2D, type 2 diabetes. DPP Research Group. Lancet. 2009;374:1677-1686.

  39. T2D Prevention in Women With a History of GDM • Findings from the DPP • Progression to diabetes is more common in women with a history of GDM vs those without, despite equivalent degrees of IGT at baseline • Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus; IGT, impaired glucose tolerance;T2D, type 2 diabetes. Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.

  40. METFORMIN AND TYPE 2 DIABETES PREVENTION Diabetes Prevention Program (DPP) (N=3234) 12 Diabetes Incidence Per 100 Person-Years -31% 10 Results for DPP Study 8 -58% Metformin 850 mg twice daily significantly reduces the risk of diabetes by 31% vs. placebo in 3 years. 6 4 2 0 Placebo (n=1082) Metformin 850 mg BID (n=1073) Intensive Life-Style Intervention* (n=1079) Study Design: Interventional, 3234 participants, randomized parallel assignment. The study has recruited volunteers, who are at high risk of developing diabetes, at twenty-five medical centers in the United States. It is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and other Institute and corporate sponsors. Researchers will evaluate the efficacy of a lifestyle intervention and a pharmacological intervention in preventing or delaying Type 2 diabetes in persons with impaired glucose tolerance (IGT). Each person in the study will be followed for 3 to 6 years.2 *with a greater effect in those who were more obese, had a higher-fasting glucose or a history of gestational diabetes. RRR: Relative risk reduction; DPP: Diabetes prevention program; BTD: Twice a day. 1. Aroda, V. R., & Ratner, R. E. 2018. Metformin and Type 2 Diabetes Prevention. Diabetes Spectrum, 31(4), 336–342. 2. Diabetes Prevention Program - Full Text View - ClinicalTrials.gov. (n.d.). Home - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00004992.

  41. Primary Outcome-CDPP Cumulative incidence of diabetes by intervention group Lifestyle intervention alone group Metforminpluslifestyleinterventiongroup Metformin plus lifestyle intervention group had a 17% lower incidence of diabetes than the lifestyle intervention alone group 2-year incidence Numberatrisk LifestyleinterventionalonegroupMetforminpluslifestyle interventiongroup Zhang L. et al. Lancet Diabetes Endocrinol. 2023 Aug;11(8):567-577.

  42. Results, 1ry Outcome Incidence of diabetes by subgroup Zhang L. et al. Lancet Diabetes Endocrinol. 2023 Aug;11(8):567-577.

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