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Algorithms for Diabetes Management for Students

Usama Ragab, profile picture
Usama Ragab

This document discusses type 2 diabetes and cardiovascular disease. It provides the following key points: 1. Type 2 diabetes significantly increases the risk of cardiovascular disease, which is the leading cause of death in people with type 2 diabetes. Even modest reductions in blood sugar levels through treatment can substantially reduce cardiovascular risks. 2. Multiple modifiable risk factors like hypertension, dyslipidemia, and smoking are common in people with type 2 diabetes and contribute to increased cardiovascular risk. A multifactorial treatment approach targeting these risk factors alongside blood sugar control is recommended to reduce complications. 3. Incretin-based therapies that target the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide pathways

Health & Medicine
Related topics:
Type 2 Diabetes
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Email: usamaragab@medicine.zu.edu.eg, Usama.ragab.zu@gmail.com SlideShare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863
Agenda • Type 2 Diabetes 101 • Incretin based therapy • Algorithms of management Dr. Usama Ragab Youssif 2
3 | IDF Diabetes 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
5 | IDF Diabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Number of people with diabetes Aged 20–79 years globally and by IDF region
Diabetes in Middle-East and North Africa Dr. Usama Ragab Youssif 6
7 | IDF Diabetes 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 10
Top 10 countries or territories for number of adults (20–79 years) with diabetes in 2021 and 2045 Dr. Usama Ragab Youssif 8
Represents 2 million people. Diabetes is mostly (85–95%) T2D.1 • T2D approximately doubles the risk of death2 • Diabetes caused 6.7 million deaths in 20211 • 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 9 1. IDF Diabetes Atlas, 2021. 10th 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, 537 million people are living with diabetes1 • Rising to 783 million by 20451 Relative risk for all-cause mortality Relative risk for CV mortality Dr. Usama Ragab Youssif
Key manifestations of CV disease 10 1. World Health Organization 2015: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1 2. http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp# Peripheral arterial disease Disease of blood vessels supplying arms and legs1 Coronary heart disease Disease of blood vessels supplying heart muscle1 Stroke Caused by disruption of blood supply to the brain1 Heart failure Failure of the heart to pump blood with normal efficiency (sometimes called congestive heart failure)2 Dr. Usama Ragab Youssif
Diabetes is ASCVD risk equivalent N Engl J Med 1998;339:229-34. Dr. Usama Ragab Youssif 11
Modifiable CV risk factors are common in patients with T2D1,2 12 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. Dr. Usama Ragab Youssif
Progression of Type 2 Diabetes and Related Complications1 (1) Conceptual representation Insulin level Insulin resistance Hepatic glucose production Postprandial glucose Fasting plasma glucose Beta-cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier. Dr. Usama Ragab Youssif 13
Reduction in The Risk of Diabetes Related Complications Stratton IM1, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000 Aug 12;321(7258):405-12. Any End point Related to Diabetes Death Related to Diabetes Stroke Microvascular End points Amputation or Death form Peripheral Vascular Disease Heart Failure Myocardial Infarction -21 % -14 % -16% -12% -37% -43% -21% 1% Reduction in HbA1C 1% Dr. Usama Ragab Youssif 14
Progression from NGT to T2DM Blood Test levels for Diagnosis of Diabetes & Prediabetes (1) FBG (mg/dL) 2-H PG (mg/dL) HbA1c (%) Diabetes ≥126 ≥200 ≥6.5 Prediabetes 100-125 140-199 5.7-6.4 Normal <100 <140 <5.7 2 15 NGT: Normal Glucose Tolerance T2DM: Type 2 Diabetes Mellitus IGT: Impaired Glucose Tolerance Ref. DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 The Diabetes Risk Score A practical tool to predict type 2 diabetes risk Dr. Usama Ragab Youssif
How to approach 16 Dr. Usama Ragab Youssif
What would your ideal diabetes drug do? • Effective in lowering HbA1c • No hypoglycemia • No effect on weight/ weight loss? • Not CV harmful or to be beneficial • Safe with few/no side effects • Comorbidities • Patient preference • Cost • Others 17 There is no one size fits all Dr. Usama Ragab Youssif
Pharmacotherapy Options Traditional Commonly used Biguanides SU TZDs Insulin Not Commonly used AGIs Glinides Newer Commonly used DPP4i GLP1 RA SGLT2i Not Commonly used Dopamine agonist Amylin mimetics BAS Dr. Usama Ragab Youssif 18
From diabetes triumvirate Dr. Usama Ragab Youssif 19
The Ominous Octet ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288. Adapted from DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Slide credit: clinicaloptions.com Liver α-cells β-cells Brain Intestine Kidney Fat HYPERGLYCEMIA Muscle
Current Antihyperglycemic Medications Slide credit: clinicaloptions.com ADA. Diabetes Care. 2018;41:S73. Amylin Mimetics Suppress glucagon -Glucosidase Inhibitors Slow intestinal carbohydrate absorption Colesevelam Sequesters intestinal bile acids DPP-4 Inhibitors Increase insulin secretion, suppress glucagon SGLT2 Inhibitors Block renal glucose reabsorption Insulin Replacement Therapy Bromocriptine Modulates hypothalamic regulation of metabolism Biguanides Reduce hepatic glucose production GLP-1 Analogues Increase insulin secretion TZDs Increase insulin sensitivity Sulfonylureas Increase insulin secretion Multiple mechanisms of action Glinides Increase insulin secretion
120 60 0 100 120 140 140 80 360 300 240 The Pathogenesis of Type 2 Diabetes: Contributions of Insulin and Glucagon Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com Carbohydrate Meal -60 120 180 240 Time (min) Insulin (µU/mL) Glucagon (pg/mL) Glucose (mg/dL) Healthy Subjects (n = 14) 60 0 Type 2 Diabetes (n = 12)
120 60 0 100 120 140 140 80 360 300 240 The Pathogenesis of Type 2 Diabetes: Contributions of Insulin and Glucagon Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com Carbohydrate Meal -60 120 180 240 Time (min) Insulin (µU/mL) Glucagon (pg/mL) Glucose (mg/dL) Healthy Subjects (n = 14) Type 2 Diabetes (n = 12) 60 0
Incretin Concept: 1906 “[T]he internal secretion of the pancreas might be stimulated and initiated … by a substance of the nature of a hormone or secretin yielded by the duodenal mucous membrane.” Intestinal Secretion of Insulin Moore. Biochem J. 1906;1:28. Slide credit: clinicaloptions.com
The Incretin Effect Is Diminished in Persons With Type 2 Diabetes Oral glucose load Time, min Control Subjects (n = 8) Insulin, mU/L Normal Incretin Effect Subjects With Type 2 Diabetes (n = 14) Diminished Incretin Effect Time, min Insulin, mU/L Nauck. Diabetologia. 1986;29:46. Slide credit: clinicaloptions.com Intravenous glucose infusion 80 60 40 20 0 180 60 120 0 80 60 40 20 0 180 60 120 0
Role of Incretins in Glucose Homeostasis Release Active GLP-1 and GIP ↑ Glucose uptake by muscles Decreased blood glucose ↓ Glucose production  ↑ Glucose-dependent insulin release, ↑ -cell regeneration? (GLP-1 and GIP)  ↓ Glucose-dependent glucagon release from -cells (GLP-1) Inactive ↓ gut motility DPP-4 ↑ Satiety ↓ appetite Adapted from Drucker. Cell Metab. 2006;3:153. Nauck. Am J Med. 2011;124:S3. Slide credit: clinicaloptions.com Pancreas
Dr. Usama Ragab Youssif 28 Glucose Regulation Jabbour SA. Postgrad Med 2014;126:111-17. Gerich JE. Diabet Med 2010;27:136-42. Meyer C, et.al. Am J Physiol Endocrinol Metab 2002;282:E419-E27.
Na+ SGLT2 inhibitor1 *Loss of ~80 g/day of glucose =320 cal/day GLUT2; glucose transporter 2 1. Bakris GL et al. Kidney Int 2009;75:1272; 2. Jardiance® (empagliflozin) summary of product characteristics SGLT2 inhibitors enhance the excretion of glucose, sodium and water into the urine 29 SGLT2 inhibitors reduce glucose and sodium reabsorption in the proximal tubule, leading to urinary glucose excretion,* natriuresis and osmotic diuresis1,2 Filtered glucose (~180 g/day) and sodium1 Na+ Glucose K+ Na+ SGLT2 Proximal tubular cells SGLT2 inhibitor Glucose GLUT2 Blood Lumen ~80 g/day of glucose2 Na+ Na+ SmPC updated
To Address Complexity of T2D, Consider Targeting Therapies to Complementary Pathophysiologic Defects ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288. Slide credit: clinicaloptions.com INSULIN TZD MET SGLT2i SFU GLP-1 RA DPP-4i Liver α-cells β-cells Brain Intestine Kidney Fat HYPERGLYCEMIA Muscle
Factors Affecting Pt Adherence to Glucose- Lowering Medications  Hypoglycemia  Weight gain  GI adverse events  Inconvenience  Aversion to injections  Costs  Stigma Slide credit: clinicaloptions.com Hauber AB, et al. Diabet Med. 2009;26:416-424. Peyrot M, et al. Curr Med Res Opin. 2009;25:1985-93. Fabunmi R, et al. Curr Med Res Opin. 2009;25:777-786.
Hypoglycemia risk and drugs Dr. Usama Ragab Youssif 33
1. NHS. Shared decision-making. https://www.england.nhs.uk/wp-content/uploads/2019/01/shared-decision-making-summary-guide-v1.pdf (accessed Feb 2023); 2. American Diabetes Association. Diabetes Care 2023;46:S1; 3. Nelson LA et al. Diabetes Res Clin Pract 2018;142:374 Shared decision making can improve disease outcomes and treatment adherence1,2 34 Adherence is key but remains suboptimal among people with T2D3 Shared decision making2 Clinician: Practical steps to manage risk factors and reduce the risk of complications Person: Needs and preferences Review and assess laboratory results Joint evidence-based decision on treatment plan Shared decision making is a collaborative process that supports a person and their healthcare professional to work together to reach a joint decision1
Guidelines and society recommendations endorse a multifactorial approach in people with early T2D to manage risk factors and reduce their risk of complications1–3 35 • Overweight/obese • Hypertension • Dyslipidaemia • Smoking4–6 • β-cell dysfunction • Insulin resistance • Hyperglycaemia7,8 A1C: blood glucose control3 A BP: blood pressure control3 B Cholesterol control3 C Drugs to protect the heart/kidneys3 D Exercise/diet/achieve a healthy body weight3 E Screening for complications, smoking cessation and stress management3 S Leading hypotheses shown; additional factors may contribute to progression of complications 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Cosentino F et al. Eur Heart J 2020;7:255; 3. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42:S1; 4. Leon BM & Maddox TM. World J Diabetes 2015;6:1246; 5. Sposito AC et al. Cardiovasc Diabetol 2018;17:157; 6. Cade WT. Phys Ther 2008;88:1322; 7. Marwick TH et al. J Am Coll Cardiol 2018;71:339; 8. DeFronzo RA et al. Diabetes 2009;58:773; 9. Fowler MJ. Clinical Diabetes 2011;29:116; 10. Song MK et al. J Diabetes Res 2014;2014:e313718; 11. Bugger H & Abel ED. Diabetologia 2014;57:660; 12. Galicia-Garcia U et al. Int J Mol Sci 2020;21:6275; 13. Hayden MR et al. Cardiorenal Med 2013;3:265; 14. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 15. McCullough PA et al. Contrib Nephrol 2013;182:82; 16. Chen Y et al. Kidney Dis 2020;6:225 Neuropathy9 Retinopathy9 Metabolic10,11 and haemodynamic changes Atherosclerosis12 CV and kidney complications14,15 Stroke12 Dementia13 Nephropathy6,10,16 CV disease12 MI10 Heart failure10,11
Glucose-Centric Algorithm for Glycemic Control Endocrine Practice 29 (2023) 305e340 Dr. Usama Ragab Youssif 36
Complication-Centric Algorithm for Glycemic Control Endocrine Practice 29 (2023) 305e340 Dr. Usama Ragab Youssif 37
ADA 2023 Standards of Medical Care recommends a multifactorial approach to reduction in the risk of diabetes complications 38 Reduction in diabetes complications Glycaemic management Blood pressure management* Lipid management Agents with CV and kidney benefit† Lifestyle modifications and diabetes education *Blood pressure should be measured at every routine clinical visit. When possible, individuals found to have elevated blood pressure (120–129/<80 mmHg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension. Hypertension is defined as ≥130/≥80 mmHg based on ≥2 measurements obtained on ≥2 occasions. Individuals with blood pressure ≥180/110 mmHg and CV disease could be diagnosed with hypertension at a single visit. All hypertensive people with diabetes should monitor their blood pressure at home, targets should be individualised through a shared decision-making process that addresses CV risk, potential adverse effects of antihypertensive medications and person preferences; †Risk reduction interventions to be applied as individually appropriate American Diabetes Association. Diabetes Care 2023;46:S1
Identify barriers to goals if HbA1c is above target Figure adapted from the ADA-EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for full recommendations, please refer to the reference. TZD, thiazolidinedione. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753 ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2: Goal – achievement and maintenance of glycaemic and weight management goals There are several treatment options ranked by level of efficacy for glycaemic and weight management for people with T2D 39 Efficacy for weight loss To avoid therapeutic inertia reassess and modify treatment regularly (3–6 months) Efficacy for glucose lowering Very high: Dulaglutide (high dose), semaglutide, tirzepatide Insulin, combination oral, combination injectable (GLP-1 RA/insulin) High: GLP-1 RA (not listed above), metformin, SGLT2 inhibitor, sulphonylurea, TZD Intermediate: DPP-4i Very high: Semaglutide, tirzepatide High: Dulaglutide, liraglutide Intermediate: GLP-1 RA (not listed above), SGLT2 inhibitor Neutral: DPP-4i, metformin Achievement and management of weight-management goals Set individualised weight-management goals and consider: Consider a glucose-lowering regimen with high-to-very-high dual glucose and weight efficacy Glycaemia management: choose approaches that provide the efficacy to achieve goals Metformin OR agent(s) including combination therapy that provide adequate efficacy to achieve and maintain goals Consider avoidance of hypoglycaemia a priority in high-risk individuals Lifestyle advice Weight-management programme Medication for weight loss Metabolic surgery
Figure adapted from ADA–EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for full recommendations, please refer to the reference. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753 Please see speaker notes for footnotes and abbreviations ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2: Goal – cardio-renal risk reduction in high-risk people with T2D*† SGLT2 inhibitors are recommended as a first-line treatment option in the management of people with T2D at high risk of cardio-renal events 40 +ASCVD/indicators of high risk‡ To avoid therapeutic inertia, reassess and modify treatment regularly (3–6 months) +HF SGLT2 inhibitor¶ with proven benefit in this population People with HF Preferably SGLT2 inhibitor¶ with primary evidence of reducing CKD progression Use SGLT2 inhibitor in people with an eGFR ≥20 ml/min per 1.73 m2; once initiated, should be continued until dialysis or transplantation GLP-1 RA with proven CV benefit if SGLT2 inhibitor not tolerated or contraindicated Or People with CKD (on maximally tolerated dose of ACEi/ARB) If HbA1c above target, for individuals on SGLT2 inhibitor, consider incorporating a GLP-1 RA or vice versa +CKD People with ASCVD/indicators of high risk GLP-1 RA§ with proven CVD benefit • For individuals on a GLP-1 RA consider adding SGLT2 inhibitor with proven CVD benefit or vice versa • TZD** If HbA1c above target SGLT2 inhibitor¶ with proven CVD benefit Either/ or Identify barriers to goals if additional cardio-renal risk reduction or glycaemic-lowering needed
(A) refers to the level of evidence in the ADA evidence grading system. To consult the ADA evidence grading system 2023, please refer to page 9 of the reference *For SGLT2 inhibitors, CV/renal outcomes trials demonstrate their efficacy in reducing the risk of composite MACE, CV death and ACM, MI, HHF and renal outcomes in individuals with T2D with established/high risk of CVD ACEi, angiotensin-converting enzyme inhibitors; ACM, all-cause mortality; ARB, angiotensin receptor blockers; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DKD, diabetic kidney disease; MRA, mineralocorticoid receptor antagonist American Diabetes Association. Diabetes Care 2023;46:S1 ADA 2023 Standards of Medical Care in Diabetes: adults with T2D and CKD ADA 2023 Standards of Medical Care includes several treatment options for people with T2D and CKD 41 11.5a For people with T2D and DKD, use of an SGLT2 inhibitor is recommended to reduce CKD progression and CV events in people with an eGFR rate ≥20 ml/min/1.73 m2 and urinary albumin ≥200 mg/g creatinine. A 11.5c In people with T2D and DKD, consider use of SGLT2 inhibitors (if eGFR rate is ≥20 ml/min/1.73 m2), or a GLP-1 RA or non-steroidal MRA (if eGFR ≥25 ml/min/1.73 m2) additionally for CV risk reduction. A 11.5d In people with CKD and albuminuria who are at increased risk for CV events or CKD progression, a non-steroidal MRA shown to be effective in clinical trials is recommended to reduce CKD progression and CV events. A Preferably SGLT2 inhibitor* with primary evidence of reducing CKD progression Use SGLT2 inhibitor in people with an eGFR ≥20 ml/min per 1.73 m2; once initiated, should be continued until dialysis or transplantation GLP-1 RA with proven CV benefit if SGLT2 inhibitor not tolerated or contraindicated Or People with CKD (on maximally tolerated dose of ACEi/ARB) If HbA1c above target, for individuals on SGLT2 inhibitor, consider incorporating a GLP-1 RA or vice versa +CKD
See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease ASCVD, atherosclerotic cardiovascular disease American Diabetes Association. Diabetes Care 2023;46:S1 What factors should be considered when selecting metformin for people with T2D? 42 Neutral Kidney effects Route of administration Oral • No increased risk of hypoglycaemia • Gastrointestinal side effects (diarrhoea, nausea) common Safety considerations HbA1c efficacy High Weight Neutral (potential for modest loss) Metabolism effects* HF Neutral Effect on MACE Potential benefit CV effects
See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *Evidence is lacking on the effect of sulphonylureas on blood pressure; †Beyond glucose lowering effects ASCVD, atherosclerotic cardiovascular disease American Diabetes Association. Diabetes Care 2023;46:S1 What factors should be considered when selecting a second-generation sulphonylurea as an add-on treatment for people with T2D? 43 Neutral† Kidney effects Route of administration Oral Increased risk of hypoglycaemia Safety considerations HbA1c efficacy High Weight Increase Metabolism effects* HF Neutral† Effect on MACE Neutral† CV effects
See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *A meta-analysis concluded that thiazolidinediones appear to decrease blood pressure, although this effect is small and may not be clinically significant2; †Beyond glucose lowering effects. ASCVD, atherosclerotic cardiovascular disease; NASH, nonalcoholic steatohepatitis 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Qayyum R & Adomaityte J. J Clin Hypertens (Greenwich) 2006;8:19 What factors should be considered when selecting a thiazolidinedione as an add-on treatment for people with T2D? 44 Neutral† Kidney effects1 HbA1c efficacy1 High Weight1 Increase Metabolism effects* HF1 Increased risk Effect on MACE1 Potential benefit: pioglitazone CV effects Route of administration1 Oral • No increased risk of hypoglycaemia • Possible congestive HF (pioglitazone, rosiglitazone) • Fluid retention (oedema, HF), benefit in NASH, risk of bone fractures Safety considerations1
See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *The effect of DPP-4 inhibitors on blood pressure, beyond glucose-lowering effects, is neutral2–4; †Beyond glucose-lowering effects. ASCVD, atherosclerotic cardiovascular disease. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al. Front Endocrinol 2017;8:6; 4. Rosenstock J et al. JAMA 2019;322:1155 What factors should be considered when selecting a DPP-4 inhibitor as an add-on treatment for people with T2D? 45 Neutral† Kidney effects1 • No increased risk of hypoglycaemia • Pancreatitis has been reported in clinical trials but causality has not been established. Discontinue if suspected • Joint pain • Bullous pemphigoid (postmarking). Discontinue if suspected Safety considerations1 HbA1c efficacy1 Intermediate Weight1 Neutral† Metabolism effects* HF1 Potential risk with saxagliptin Effect on MACE1 Neutral† CV effects Route of administration1 Oral
See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *Aside from lowering blood glucose, GLP-1 RAs have blood pressure-lowering effects2–5; †Beyond glucose-lowering effects. ‡Reduction in meal size, mindful eating practices (e.g. stop eating once full), decreasing intake of high-fat or spicy food. ASCVD, atherosclerotic cardiovascular disease; GI, gastrointestinal. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al. Front Endocrinol 2017;8:6; 4. Vilsbøll T et al. Diabetes Care 2007;30:1608; 5. Reid T. Clinical Diabetes 2012;30:3 What factors should be considered when selecting a GLP-1 RA for people with T2D? 46 Albuminuria benefit in CVOTs, kidney outcome study ongoing Kidney effects1 • No increased risk of hypoglycaemia • Counsel persons on potential for GI side effects and their typically temporary nature; provide guidance on dietary modifications to mitigate GI side effects‡; consider slower dose titration for people experiencing GI challenges • Pancreatitis has been reported in clinical trials but causality has not been established. Discontinue if suspected • Risk of thyroid C-cell tumours in rodents; human relevance not determined • Evaluate for gallbladder disease if cholelithiasis or cholecystitis is suspected Safety considerations1 HbA1c efficacy1 High Weight1 Reduction Metabolism effects* HF1 Neutral† Effect on MACE1 Benefit: dulaglutide, liraglutide, semaglutide; neutral: exenatide, lixisenatide CV effects Route of administration1 Injectable; oral (semaglutide)
See labels of individual agents for CV outcomes data, kidney dose considerations and information regarding use in people with kidney disease/assessment of kidney function prior to initiation *Ertugliflozin is not approved for HF; †Benefit demonstrated for ertugliflozin for a pre-specified exploratory kidney outcome (40% reduction in eGFR, KRT, or death from kidney causes) but not for its key kidney outcome (death from kidney causes, KRT, doubling of serum creatinine);6,7 ‡Discontinue, evaluate, and treat promptly if suspected. Be aware of predisposing risk factors and clinical presentation (including euglycemic DKA), discontinue before scheduled surgery (e.g., 3–4 days), during critical illness, or during prolonged fasting to mitigate potential risk. ASCVD, atherosclerotic cardiovascular disease; DKA, diabetic ketoacidosis; KRT, kidney replacement therapy. See slide notes for references What factors should be considered when selecting an SGLT2 inhibitor for people with T2D? 47 Benefit:† canagliflozin, empagliflozin, dapagliflozin Kidney effects1 • Hypoglycaemia when in combination with insulin or secretagogues (an adjustment of these agents may be necessary to reduce the risk of hypoglycaemia)2─5 • DKA risk, rare in T2D‡ • Increased risk of genital mycotic infections • Necrotising fasciitis of the perineum (Fournier gangrene), rare reports: institute prompt treatment if suspected • Attention to volume status, blood pressure; adjust other volume-contracting agents as applicable Safety considerations1 HbA1c efficacy1 Intermediate Weight1 Reduction Metabolism effects HF1 Benefit: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin* Effect on MACE1 Benefit: empagliflozin, canagliflozin CV effects Route of administration1 Oral
Copyright ADA/EASD 2022 Glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist (tirzepatide) • Glucose-lowering mechanism of action: GIP receptor and GLP-1 receptor agonist; enhances first and second-phase insulin secretion, and reduces glucagon levels, both in a glucose- dependent manner • Clinical Efficacy profile: Very high glycaemic efficacy; low inherent risk of hypoglycaemia; weight loss (high); cardiorenal effects unknown (trials in progress) 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.
Copyright ADA/EASD 2022 Clinical Inertia Clinical inertia: failure of healthcare providers to initiate or intensify therapy when indicated, due to: •overestimation of care provided •use of “soft” reasons to avoid intensification of therapy •lack of education, training, and practice organisation aimed at achieving therapeutic goals 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. .
Treat to Failure Traditional stepwise approach versus early intervention approach to diabetes management, adapted from Del Prato S, et al. A stepwise approach often leads to unacceptable delays in achieving and maintaining glycemic goals. An early intervention approach can be considered a ‘proactive’ approach versus the ‘reactive’ stepwise approach and is suggested to provide better and more rapid glycemic control. OAD, oral antidiabetic drug. 1. Khunti K, et al. Prim Care Diabetes 2017;11:3–12; 2. Khunti K, et al. Diabetes Care 2013;36:3411‒7; 3. Del Prato S, et al. Int J Clin Pract. 2005;59:1345–55. Early intervention approach (conceptual data) 10 HbA 1c % 9 8 7 6 2.9 years 7.2 years 6.7 years Time 8.5% OAD monotherapy 9.7% Insulin 8.7% OAD dual combination 9.1% OAD triple combination Traditional stepwise treatment approach (actual data) Dr. Usama Ragab Youssif 50
Dr. Usama Ragab Youssif The 2022 ADA–EASD consensus report recommends that combination therapy should be tailored to the individual 51 Combination therapy has several potential advantages including: 1) Increased durability of the glycaemic effect, addressing therapeutic inertia 2) Simultaneous targeting of the multiple pathophysiological processes characterised by T2D 3) Impact on medication burden, medication-taking behaviour, adherence and treatment persistence 4) Complementary clinical benefits (e.g. on glycaemic control, weight and CV risk profiles and additional cardio-renal risk reduction*) Glycaemic management: choose approaches that provide the efficacy to achieve goals: Metformin OR agent(s) including COMBINATION therapy that provide adequate EFFICACY to achieve and maintain treatment goals Consider avoidance of hypoglycaemia a priority in high-risk individuals
Elderly Dr. Usama Ragab Youssif 52
Treatment recommendations for elderly = Simplify Simplify Simplify Simplify Avoid strict glycemic target to avoid hypo Metformin is first line if tolerated not CI DPP4i is safe tolerable Assess adherence avoid polypharmacy Dr. Usama Ragab Youssif 53
 High risk of hypoglycemia: sulfonylureas; meal-time insulin 1. ADA. Diabetes Care. 2021;44:S168. 2. pro.aace.com/disease-state-resources/diabetes/guidelines. Medications With Low Risk of Hypoglycemia Oral Metformin Pioglitazone DPP-4 inhibitors SGLT2 inhibitors Injection GLP-1 RA Basal insulin Slide credit: clinicaloptions.com
Patients with CKD Dr. Usama Ragab Youssif 55
Choice of treatment https://doi.org/10.1016/j.kint.2020.06.019 Dr. Usama Ragab Youssif 56
eGFR values are ml/min per 1.73 m2. *For agent-specific recommendations, please refer to the manufacturers’ prescribing information. KDIGO, Kidney Disease: Improving Global Outcomes; TZD, thiazolidinedione. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int 2022;102:S1 KDIGO 2022 treatment algorithm for selecting glucose-lowering drugs for people with T2D and CKD Lifestyle therapy in addition to first-line therapy is the cornerstone of glycaemic management for people with T2D and CKD (2/4) 57 GLP-1 RA (preferred) DPP-4 inhibitor Insulin Sulphonylurea TZD Alpha-glucosidase inhibitor • Guided by individual preferences, comorbidities, eGFR and cost • Includes people with eGFR <30 ml/min/1.73 m2 or those treated with dialysis Metformin eGFR <45 eGFR <30 Dialysis Discontinue Reduce dose Discontinue SGLT2 inhibitor eGFR <20* Dialysis Do not initiate Discontinue Lifestyle therapy First-line therapy Additional drug therapy as needed for glycaemic control Physical activity, nutrition and weight loss
Patient factors influencing the selection of glucose-lowering drugs other than SGLT2i and metformin in T2D and CKD Dr. Usama Ragab Youssif 58 Kidney International. 2022 Nov 1;102(5):S1-27.
Algorithms for Diabetes Management for Students
Final bottom-line Dr. Usama Ragab Youssif 60
Profiles of Antihyperglycemic Medications MET GLP-1 RA SGLT2i DPP4i AGi TZD (moderate dose) COLSVL BCR-QR INSULIN PRAML HYPO Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral Moderate to severe Neutral WEIGHT Slight loss Loss Loss Neutral Neutral Gain Gain Neutral Neutral Gain Loss RENAL/GU Contra- indicated if eGFR <30 mL/min/1.73 m2 Exenatide not indicated CrCl <30 Not indicated for eGFR <45 mL/min/1.73 m2 Dose adjustment necessary (except linagliptin) effective in reducing albuminuria Neutral Neutral More hypo risk Neutral Neutral More hypo risk Neutral See #1 Genital mycotic infections Potential benefit of LA GLP-1 RA Potential CKD Benefit; See #1 GI Sx Moderate Moderate Neutral Neutral Moderate Neutral Neutral Mild Moderate Neutral Moderate CHF CARDIAC ASCVD Neutral Neutral Prevent Hf hospitalization manage HFrEF; see #2 See #4 HHF with saxagliptin Neutral Moderate Neutral Neutral Neutral CHF risk Neutral Possible ASCVD risk Lowers LDL-C Safe Neutral Potential benefit of LA GLP-1 RA May reduce stroke risk See #3 BONE Neutral Neutral Neutral Neutral Neutral Moderate fracture risk Neutral Neutral Neutral Neutral Neutral KETOACIDOSIS Neutral Neutral DKA can occur in various stress settings Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral SU GLN Severe Mild Few AEs or possible benefits Use with caution Likelihood of AEs 1. Canagliflozin indicated for eGFR ≥30 mL/min/1.73 m2 in patients with CKD 3 + albuminuria. 2. Dapagliflozin–potential primary prevention of HF hospitalization and demonstrated efficacy in HFrEF. 3. Empagliflozin–FDA approved to reduce CV mortality. Canagliflozin– FDA approved to reduce MACE events. 4. Possible increased hospitalizations for heart failure with alogliptin and saxagliptin. Slide credit: clinicaloptions.com American Association of Clinical Endocrinology. Endo Pract. 2020;26:139.
Thank You Dr. Usama Ragab Youssif 62

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Algorithms for Diabetes Management for Students

  • 1. Email: usamaragab@medicine.zu.edu.eg, Usama.ragab.zu@gmail.com SlideShare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863
  • 2. Agenda • Type 2 Diabetes 101 • Incretin based therapy • Algorithms of management Dr. Usama Ragab Youssif 2
  • 3. 3 | IDF Diabetes 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
  • 4. 5 | IDF Diabetes Atlas 2021– 10th edition www.idf.org @IntDiabetesFed Number of people with diabetes Aged 20–79 years globally and by IDF region
  • 5. Diabetes in Middle-East and North Africa Dr. Usama Ragab Youssif 6
  • 6. 7 | IDF Diabetes 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 10
  • 7. Top 10 countries or territories for number of adults (20–79 years) with diabetes in 2021 and 2045 Dr. Usama Ragab Youssif 8
  • 8. Represents 2 million people. Diabetes is mostly (85–95%) T2D.1 • T2D approximately doubles the risk of death2 • Diabetes caused 6.7 million deaths in 20211 • 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 9 1. IDF Diabetes Atlas, 2021. 10th 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, 537 million people are living with diabetes1 • Rising to 783 million by 20451 Relative risk for all-cause mortality Relative risk for CV mortality Dr. Usama Ragab Youssif
  • 9. Key manifestations of CV disease 10 1. World Health Organization 2015: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1 2. http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp# Peripheral arterial disease Disease of blood vessels supplying arms and legs1 Coronary heart disease Disease of blood vessels supplying heart muscle1 Stroke Caused by disruption of blood supply to the brain1 Heart failure Failure of the heart to pump blood with normal efficiency (sometimes called congestive heart failure)2 Dr. Usama Ragab Youssif
  • 10. Diabetes is ASCVD risk equivalent N Engl J Med 1998;339:229-34. Dr. Usama Ragab Youssif 11
  • 11. Modifiable CV risk factors are common in patients with T2D1,2 12 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. Dr. Usama Ragab Youssif
  • 12. Progression of Type 2 Diabetes and Related Complications1 (1) Conceptual representation Insulin level Insulin resistance Hepatic glucose production Postprandial glucose Fasting plasma glucose Beta-cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier. Dr. Usama Ragab Youssif 13
  • 13. Reduction in The Risk of Diabetes Related Complications Stratton IM1, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000 Aug 12;321(7258):405-12. Any End point Related to Diabetes Death Related to Diabetes Stroke Microvascular End points Amputation or Death form Peripheral Vascular Disease Heart Failure Myocardial Infarction -21 % -14 % -16% -12% -37% -43% -21% 1% Reduction in HbA1C 1% Dr. Usama Ragab Youssif 14
  • 14. Progression from NGT to T2DM Blood Test levels for Diagnosis of Diabetes & Prediabetes (1) FBG (mg/dL) 2-H PG (mg/dL) HbA1c (%) Diabetes ≥126 ≥200 ≥6.5 Prediabetes 100-125 140-199 5.7-6.4 Normal <100 <140 <5.7 2 15 NGT: Normal Glucose Tolerance T2DM: Type 2 Diabetes Mellitus IGT: Impaired Glucose Tolerance Ref. DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 The Diabetes Risk Score A practical tool to predict type 2 diabetes risk Dr. Usama Ragab Youssif
  • 15. How to approach 16 Dr. Usama Ragab Youssif
  • 16. What would your ideal diabetes drug do? • Effective in lowering HbA1c • No hypoglycemia • No effect on weight/ weight loss? • Not CV harmful or to be beneficial • Safe with few/no side effects • Comorbidities • Patient preference • Cost • Others 17 There is no one size fits all Dr. Usama Ragab Youssif
  • 17. Pharmacotherapy Options Traditional Commonly used Biguanides SU TZDs Insulin Not Commonly used AGIs Glinides Newer Commonly used DPP4i GLP1 RA SGLT2i Not Commonly used Dopamine agonist Amylin mimetics BAS Dr. Usama Ragab Youssif 18
  • 18. From diabetes triumvirate Dr. Usama Ragab Youssif 19
  • 19. The Ominous Octet ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288. Adapted from DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Slide credit: clinicaloptions.com Liver α-cells β-cells Brain Intestine Kidney Fat HYPERGLYCEMIA Muscle
  • 20. Current Antihyperglycemic Medications Slide credit: clinicaloptions.com ADA. Diabetes Care. 2018;41:S73. Amylin Mimetics Suppress glucagon -Glucosidase Inhibitors Slow intestinal carbohydrate absorption Colesevelam Sequesters intestinal bile acids DPP-4 Inhibitors Increase insulin secretion, suppress glucagon SGLT2 Inhibitors Block renal glucose reabsorption Insulin Replacement Therapy Bromocriptine Modulates hypothalamic regulation of metabolism Biguanides Reduce hepatic glucose production GLP-1 Analogues Increase insulin secretion TZDs Increase insulin sensitivity Sulfonylureas Increase insulin secretion Multiple mechanisms of action Glinides Increase insulin secretion
  • 21. 120 60 0 100 120 140 140 80 360 300 240 The Pathogenesis of Type 2 Diabetes: Contributions of Insulin and Glucagon Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com Carbohydrate Meal -60 120 180 240 Time (min) Insulin (µU/mL) Glucagon (pg/mL) Glucose (mg/dL) Healthy Subjects (n = 14) 60 0 Type 2 Diabetes (n = 12)
  • 22. 120 60 0 100 120 140 140 80 360 300 240 The Pathogenesis of Type 2 Diabetes: Contributions of Insulin and Glucagon Müller. N Engl J Med. 1970;283:109. Slide credit: clinicaloptions.com Carbohydrate Meal -60 120 180 240 Time (min) Insulin (µU/mL) Glucagon (pg/mL) Glucose (mg/dL) Healthy Subjects (n = 14) Type 2 Diabetes (n = 12) 60 0
  • 23. Incretin Concept: 1906 “[T]he internal secretion of the pancreas might be stimulated and initiated … by a substance of the nature of a hormone or secretin yielded by the duodenal mucous membrane.” Intestinal Secretion of Insulin Moore. Biochem J. 1906;1:28. Slide credit: clinicaloptions.com
  • 24. The Incretin Effect Is Diminished in Persons With Type 2 Diabetes Oral glucose load Time, min Control Subjects (n = 8) Insulin, mU/L Normal Incretin Effect Subjects With Type 2 Diabetes (n = 14) Diminished Incretin Effect Time, min Insulin, mU/L Nauck. Diabetologia. 1986;29:46. Slide credit: clinicaloptions.com Intravenous glucose infusion 80 60 40 20 0 180 60 120 0 80 60 40 20 0 180 60 120 0
  • 25. Role of Incretins in Glucose Homeostasis Release Active GLP-1 and GIP ↑ Glucose uptake by muscles Decreased blood glucose ↓ Glucose production  ↑ Glucose-dependent insulin release, ↑ -cell regeneration? (GLP-1 and GIP)  ↓ Glucose-dependent glucagon release from -cells (GLP-1) Inactive ↓ gut motility DPP-4 ↑ Satiety ↓ appetite Adapted from Drucker. Cell Metab. 2006;3:153. Nauck. Am J Med. 2011;124:S3. Slide credit: clinicaloptions.com Pancreas
  • 26. Dr. Usama Ragab Youssif 28 Glucose Regulation Jabbour SA. Postgrad Med 2014;126:111-17. Gerich JE. Diabet Med 2010;27:136-42. Meyer C, et.al. Am J Physiol Endocrinol Metab 2002;282:E419-E27.
  • 27. Na+ SGLT2 inhibitor1 *Loss of ~80 g/day of glucose =320 cal/day GLUT2; glucose transporter 2 1. Bakris GL et al. Kidney Int 2009;75:1272; 2. Jardiance® (empagliflozin) summary of product characteristics SGLT2 inhibitors enhance the excretion of glucose, sodium and water into the urine 29 SGLT2 inhibitors reduce glucose and sodium reabsorption in the proximal tubule, leading to urinary glucose excretion,* natriuresis and osmotic diuresis1,2 Filtered glucose (~180 g/day) and sodium1 Na+ Glucose K+ Na+ SGLT2 Proximal tubular cells SGLT2 inhibitor Glucose GLUT2 Blood Lumen ~80 g/day of glucose2 Na+ Na+ SmPC updated
  • 28. To Address Complexity of T2D, Consider Targeting Therapies to Complementary Pathophysiologic Defects ADA. Diabetes Care. 2021;44:S1. Ferrannini. Eur Heart J. 2015;36:2288. Slide credit: clinicaloptions.com INSULIN TZD MET SGLT2i SFU GLP-1 RA DPP-4i Liver α-cells β-cells Brain Intestine Kidney Fat HYPERGLYCEMIA Muscle
  • 29. Factors Affecting Pt Adherence to Glucose- Lowering Medications  Hypoglycemia  Weight gain  GI adverse events  Inconvenience  Aversion to injections  Costs  Stigma Slide credit: clinicaloptions.com Hauber AB, et al. Diabet Med. 2009;26:416-424. Peyrot M, et al. Curr Med Res Opin. 2009;25:1985-93. Fabunmi R, et al. Curr Med Res Opin. 2009;25:777-786.
  • 30. Hypoglycemia risk and drugs Dr. Usama Ragab Youssif 33
  • 31. 1. NHS. Shared decision-making. https://www.england.nhs.uk/wp-content/uploads/2019/01/shared-decision-making-summary-guide-v1.pdf (accessed Feb 2023); 2. American Diabetes Association. Diabetes Care 2023;46:S1; 3. Nelson LA et al. Diabetes Res Clin Pract 2018;142:374 Shared decision making can improve disease outcomes and treatment adherence1,2 34 Adherence is key but remains suboptimal among people with T2D3 Shared decision making2 Clinician: Practical steps to manage risk factors and reduce the risk of complications Person: Needs and preferences Review and assess laboratory results Joint evidence-based decision on treatment plan Shared decision making is a collaborative process that supports a person and their healthcare professional to work together to reach a joint decision1
  • 32. Guidelines and society recommendations endorse a multifactorial approach in people with early T2D to manage risk factors and reduce their risk of complications1–3 35 • Overweight/obese • Hypertension • Dyslipidaemia • Smoking4–6 • β-cell dysfunction • Insulin resistance • Hyperglycaemia7,8 A1C: blood glucose control3 A BP: blood pressure control3 B Cholesterol control3 C Drugs to protect the heart/kidneys3 D Exercise/diet/achieve a healthy body weight3 E Screening for complications, smoking cessation and stress management3 S Leading hypotheses shown; additional factors may contribute to progression of complications 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Cosentino F et al. Eur Heart J 2020;7:255; 3. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42:S1; 4. Leon BM & Maddox TM. World J Diabetes 2015;6:1246; 5. Sposito AC et al. Cardiovasc Diabetol 2018;17:157; 6. Cade WT. Phys Ther 2008;88:1322; 7. Marwick TH et al. J Am Coll Cardiol 2018;71:339; 8. DeFronzo RA et al. Diabetes 2009;58:773; 9. Fowler MJ. Clinical Diabetes 2011;29:116; 10. Song MK et al. J Diabetes Res 2014;2014:e313718; 11. Bugger H & Abel ED. Diabetologia 2014;57:660; 12. Galicia-Garcia U et al. Int J Mol Sci 2020;21:6275; 13. Hayden MR et al. Cardiorenal Med 2013;3:265; 14. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 15. McCullough PA et al. Contrib Nephrol 2013;182:82; 16. Chen Y et al. Kidney Dis 2020;6:225 Neuropathy9 Retinopathy9 Metabolic10,11 and haemodynamic changes Atherosclerosis12 CV and kidney complications14,15 Stroke12 Dementia13 Nephropathy6,10,16 CV disease12 MI10 Heart failure10,11
  • 33. Glucose-Centric Algorithm for Glycemic Control Endocrine Practice 29 (2023) 305e340 Dr. Usama Ragab Youssif 36
  • 34. Complication-Centric Algorithm for Glycemic Control Endocrine Practice 29 (2023) 305e340 Dr. Usama Ragab Youssif 37
  • 35. ADA 2023 Standards of Medical Care recommends a multifactorial approach to reduction in the risk of diabetes complications 38 Reduction in diabetes complications Glycaemic management Blood pressure management* Lipid management Agents with CV and kidney benefit† Lifestyle modifications and diabetes education *Blood pressure should be measured at every routine clinical visit. When possible, individuals found to have elevated blood pressure (120–129/<80 mmHg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension. Hypertension is defined as ≥130/≥80 mmHg based on ≥2 measurements obtained on ≥2 occasions. Individuals with blood pressure ≥180/110 mmHg and CV disease could be diagnosed with hypertension at a single visit. All hypertensive people with diabetes should monitor their blood pressure at home, targets should be individualised through a shared decision-making process that addresses CV risk, potential adverse effects of antihypertensive medications and person preferences; †Risk reduction interventions to be applied as individually appropriate American Diabetes Association. Diabetes Care 2023;46:S1
  • 36. Identify barriers to goals if HbA1c is above target Figure adapted from the ADA-EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for full recommendations, please refer to the reference. TZD, thiazolidinedione. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753 ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2: Goal – achievement and maintenance of glycaemic and weight management goals There are several treatment options ranked by level of efficacy for glycaemic and weight management for people with T2D 39 Efficacy for weight loss To avoid therapeutic inertia reassess and modify treatment regularly (3–6 months) Efficacy for glucose lowering Very high: Dulaglutide (high dose), semaglutide, tirzepatide Insulin, combination oral, combination injectable (GLP-1 RA/insulin) High: GLP-1 RA (not listed above), metformin, SGLT2 inhibitor, sulphonylurea, TZD Intermediate: DPP-4i Very high: Semaglutide, tirzepatide High: Dulaglutide, liraglutide Intermediate: GLP-1 RA (not listed above), SGLT2 inhibitor Neutral: DPP-4i, metformin Achievement and management of weight-management goals Set individualised weight-management goals and consider: Consider a glucose-lowering regimen with high-to-very-high dual glucose and weight efficacy Glycaemia management: choose approaches that provide the efficacy to achieve goals Metformin OR agent(s) including combination therapy that provide adequate efficacy to achieve and maintain goals Consider avoidance of hypoglycaemia a priority in high-risk individuals Lifestyle advice Weight-management programme Medication for weight loss Metabolic surgery
  • 37. Figure adapted from ADA–EASD consensus report. Davies MJ et al. Diabetes Care 2022;45:2753. There are additional recommendations If HbA1c remains above target; for full recommendations, please refer to the reference. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Davies MJ et al. Diabetes Care 2022;45:2753 Please see speaker notes for footnotes and abbreviations ADA 2023 Standards of Medical Care and ADA–EASD Consensus Report1,2: Goal – cardio-renal risk reduction in high-risk people with T2D*† SGLT2 inhibitors are recommended as a first-line treatment option in the management of people with T2D at high risk of cardio-renal events 40 +ASCVD/indicators of high risk‡ To avoid therapeutic inertia, reassess and modify treatment regularly (3–6 months) +HF SGLT2 inhibitor¶ with proven benefit in this population People with HF Preferably SGLT2 inhibitor¶ with primary evidence of reducing CKD progression Use SGLT2 inhibitor in people with an eGFR ≥20 ml/min per 1.73 m2; once initiated, should be continued until dialysis or transplantation GLP-1 RA with proven CV benefit if SGLT2 inhibitor not tolerated or contraindicated Or People with CKD (on maximally tolerated dose of ACEi/ARB) If HbA1c above target, for individuals on SGLT2 inhibitor, consider incorporating a GLP-1 RA or vice versa +CKD People with ASCVD/indicators of high risk GLP-1 RA§ with proven CVD benefit • For individuals on a GLP-1 RA consider adding SGLT2 inhibitor with proven CVD benefit or vice versa • TZD** If HbA1c above target SGLT2 inhibitor¶ with proven CVD benefit Either/ or Identify barriers to goals if additional cardio-renal risk reduction or glycaemic-lowering needed
  • 38. (A) refers to the level of evidence in the ADA evidence grading system. To consult the ADA evidence grading system 2023, please refer to page 9 of the reference *For SGLT2 inhibitors, CV/renal outcomes trials demonstrate their efficacy in reducing the risk of composite MACE, CV death and ACM, MI, HHF and renal outcomes in individuals with T2D with established/high risk of CVD ACEi, angiotensin-converting enzyme inhibitors; ACM, all-cause mortality; ARB, angiotensin receptor blockers; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DKD, diabetic kidney disease; MRA, mineralocorticoid receptor antagonist American Diabetes Association. Diabetes Care 2023;46:S1 ADA 2023 Standards of Medical Care in Diabetes: adults with T2D and CKD ADA 2023 Standards of Medical Care includes several treatment options for people with T2D and CKD 41 11.5a For people with T2D and DKD, use of an SGLT2 inhibitor is recommended to reduce CKD progression and CV events in people with an eGFR rate ≥20 ml/min/1.73 m2 and urinary albumin ≥200 mg/g creatinine. A 11.5c In people with T2D and DKD, consider use of SGLT2 inhibitors (if eGFR rate is ≥20 ml/min/1.73 m2), or a GLP-1 RA or non-steroidal MRA (if eGFR ≥25 ml/min/1.73 m2) additionally for CV risk reduction. A 11.5d In people with CKD and albuminuria who are at increased risk for CV events or CKD progression, a non-steroidal MRA shown to be effective in clinical trials is recommended to reduce CKD progression and CV events. A Preferably SGLT2 inhibitor* with primary evidence of reducing CKD progression Use SGLT2 inhibitor in people with an eGFR ≥20 ml/min per 1.73 m2; once initiated, should be continued until dialysis or transplantation GLP-1 RA with proven CV benefit if SGLT2 inhibitor not tolerated or contraindicated Or People with CKD (on maximally tolerated dose of ACEi/ARB) If HbA1c above target, for individuals on SGLT2 inhibitor, consider incorporating a GLP-1 RA or vice versa +CKD
  • 39. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease ASCVD, atherosclerotic cardiovascular disease American Diabetes Association. Diabetes Care 2023;46:S1 What factors should be considered when selecting metformin for people with T2D? 42 Neutral Kidney effects Route of administration Oral • No increased risk of hypoglycaemia • Gastrointestinal side effects (diarrhoea, nausea) common Safety considerations HbA1c efficacy High Weight Neutral (potential for modest loss) Metabolism effects* HF Neutral Effect on MACE Potential benefit CV effects
  • 40. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *Evidence is lacking on the effect of sulphonylureas on blood pressure; †Beyond glucose lowering effects ASCVD, atherosclerotic cardiovascular disease American Diabetes Association. Diabetes Care 2023;46:S1 What factors should be considered when selecting a second-generation sulphonylurea as an add-on treatment for people with T2D? 43 Neutral† Kidney effects Route of administration Oral Increased risk of hypoglycaemia Safety considerations HbA1c efficacy High Weight Increase Metabolism effects* HF Neutral† Effect on MACE Neutral† CV effects
  • 41. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *A meta-analysis concluded that thiazolidinediones appear to decrease blood pressure, although this effect is small and may not be clinically significant2; †Beyond glucose lowering effects. ASCVD, atherosclerotic cardiovascular disease; NASH, nonalcoholic steatohepatitis 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Qayyum R & Adomaityte J. J Clin Hypertens (Greenwich) 2006;8:19 What factors should be considered when selecting a thiazolidinedione as an add-on treatment for people with T2D? 44 Neutral† Kidney effects1 HbA1c efficacy1 High Weight1 Increase Metabolism effects* HF1 Increased risk Effect on MACE1 Potential benefit: pioglitazone CV effects Route of administration1 Oral • No increased risk of hypoglycaemia • Possible congestive HF (pioglitazone, rosiglitazone) • Fluid retention (oedema, HF), benefit in NASH, risk of bone fractures Safety considerations1
  • 42. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *The effect of DPP-4 inhibitors on blood pressure, beyond glucose-lowering effects, is neutral2–4; †Beyond glucose-lowering effects. ASCVD, atherosclerotic cardiovascular disease. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al. Front Endocrinol 2017;8:6; 4. Rosenstock J et al. JAMA 2019;322:1155 What factors should be considered when selecting a DPP-4 inhibitor as an add-on treatment for people with T2D? 45 Neutral† Kidney effects1 • No increased risk of hypoglycaemia • Pancreatitis has been reported in clinical trials but causality has not been established. Discontinue if suspected • Joint pain • Bullous pemphigoid (postmarking). Discontinue if suspected Safety considerations1 HbA1c efficacy1 Intermediate Weight1 Neutral† Metabolism effects* HF1 Potential risk with saxagliptin Effect on MACE1 Neutral† CV effects Route of administration1 Oral
  • 43. See labels of individual agents for kidney dose considerations and information regarding use in people with kidney disease *Aside from lowering blood glucose, GLP-1 RAs have blood pressure-lowering effects2–5; †Beyond glucose-lowering effects. ‡Reduction in meal size, mindful eating practices (e.g. stop eating once full), decreasing intake of high-fat or spicy food. ASCVD, atherosclerotic cardiovascular disease; GI, gastrointestinal. 1. American Diabetes Association. Diabetes Care 2023;46:S1; 2. Inzucchi S et al. Diabetes Care 2015;38:140; 3. Chaudhury A et al. Front Endocrinol 2017;8:6; 4. Vilsbøll T et al. Diabetes Care 2007;30:1608; 5. Reid T. Clinical Diabetes 2012;30:3 What factors should be considered when selecting a GLP-1 RA for people with T2D? 46 Albuminuria benefit in CVOTs, kidney outcome study ongoing Kidney effects1 • No increased risk of hypoglycaemia • Counsel persons on potential for GI side effects and their typically temporary nature; provide guidance on dietary modifications to mitigate GI side effects‡; consider slower dose titration for people experiencing GI challenges • Pancreatitis has been reported in clinical trials but causality has not been established. Discontinue if suspected • Risk of thyroid C-cell tumours in rodents; human relevance not determined • Evaluate for gallbladder disease if cholelithiasis or cholecystitis is suspected Safety considerations1 HbA1c efficacy1 High Weight1 Reduction Metabolism effects* HF1 Neutral† Effect on MACE1 Benefit: dulaglutide, liraglutide, semaglutide; neutral: exenatide, lixisenatide CV effects Route of administration1 Injectable; oral (semaglutide)
  • 44. See labels of individual agents for CV outcomes data, kidney dose considerations and information regarding use in people with kidney disease/assessment of kidney function prior to initiation *Ertugliflozin is not approved for HF; †Benefit demonstrated for ertugliflozin for a pre-specified exploratory kidney outcome (40% reduction in eGFR, KRT, or death from kidney causes) but not for its key kidney outcome (death from kidney causes, KRT, doubling of serum creatinine);6,7 ‡Discontinue, evaluate, and treat promptly if suspected. Be aware of predisposing risk factors and clinical presentation (including euglycemic DKA), discontinue before scheduled surgery (e.g., 3–4 days), during critical illness, or during prolonged fasting to mitigate potential risk. ASCVD, atherosclerotic cardiovascular disease; DKA, diabetic ketoacidosis; KRT, kidney replacement therapy. See slide notes for references What factors should be considered when selecting an SGLT2 inhibitor for people with T2D? 47 Benefit:† canagliflozin, empagliflozin, dapagliflozin Kidney effects1 • Hypoglycaemia when in combination with insulin or secretagogues (an adjustment of these agents may be necessary to reduce the risk of hypoglycaemia)2─5 • DKA risk, rare in T2D‡ • Increased risk of genital mycotic infections • Necrotising fasciitis of the perineum (Fournier gangrene), rare reports: institute prompt treatment if suspected • Attention to volume status, blood pressure; adjust other volume-contracting agents as applicable Safety considerations1 HbA1c efficacy1 Intermediate Weight1 Reduction Metabolism effects HF1 Benefit: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin* Effect on MACE1 Benefit: empagliflozin, canagliflozin CV effects Route of administration1 Oral
  • 45. Copyright ADA/EASD 2022 Glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist (tirzepatide) • Glucose-lowering mechanism of action: GIP receptor and GLP-1 receptor agonist; enhances first and second-phase insulin secretion, and reduces glucagon levels, both in a glucose- dependent manner • Clinical Efficacy profile: Very high glycaemic efficacy; low inherent risk of hypoglycaemia; weight loss (high); cardiorenal effects unknown (trials in progress) 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.
  • 46. Copyright ADA/EASD 2022 Clinical Inertia Clinical inertia: failure of healthcare providers to initiate or intensify therapy when indicated, due to: •overestimation of care provided •use of “soft” reasons to avoid intensification of therapy •lack of education, training, and practice organisation aimed at achieving therapeutic goals 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. .
  • 47. Treat to Failure Traditional stepwise approach versus early intervention approach to diabetes management, adapted from Del Prato S, et al. A stepwise approach often leads to unacceptable delays in achieving and maintaining glycemic goals. An early intervention approach can be considered a ‘proactive’ approach versus the ‘reactive’ stepwise approach and is suggested to provide better and more rapid glycemic control. OAD, oral antidiabetic drug. 1. Khunti K, et al. Prim Care Diabetes 2017;11:3–12; 2. Khunti K, et al. Diabetes Care 2013;36:3411‒7; 3. Del Prato S, et al. Int J Clin Pract. 2005;59:1345–55. Early intervention approach (conceptual data) 10 HbA 1c % 9 8 7 6 2.9 years 7.2 years 6.7 years Time 8.5% OAD monotherapy 9.7% Insulin 8.7% OAD dual combination 9.1% OAD triple combination Traditional stepwise treatment approach (actual data) Dr. Usama Ragab Youssif 50
  • 48. Dr. Usama Ragab Youssif The 2022 ADA–EASD consensus report recommends that combination therapy should be tailored to the individual 51 Combination therapy has several potential advantages including: 1) Increased durability of the glycaemic effect, addressing therapeutic inertia 2) Simultaneous targeting of the multiple pathophysiological processes characterised by T2D 3) Impact on medication burden, medication-taking behaviour, adherence and treatment persistence 4) Complementary clinical benefits (e.g. on glycaemic control, weight and CV risk profiles and additional cardio-renal risk reduction*) Glycaemic management: choose approaches that provide the efficacy to achieve goals: Metformin OR agent(s) including COMBINATION therapy that provide adequate EFFICACY to achieve and maintain treatment goals Consider avoidance of hypoglycaemia a priority in high-risk individuals
  • 50. Treatment recommendations for elderly = Simplify Simplify Simplify Simplify Avoid strict glycemic target to avoid hypo Metformin is first line if tolerated not CI DPP4i is safe tolerable Assess adherence avoid polypharmacy Dr. Usama Ragab Youssif 53
  • 51.  High risk of hypoglycemia: sulfonylureas; meal-time insulin 1. ADA. Diabetes Care. 2021;44:S168. 2. pro.aace.com/disease-state-resources/diabetes/guidelines. Medications With Low Risk of Hypoglycemia Oral Metformin Pioglitazone DPP-4 inhibitors SGLT2 inhibitors Injection GLP-1 RA Basal insulin Slide credit: clinicaloptions.com
  • 52. Patients with CKD Dr. Usama Ragab Youssif 55
  • 54. eGFR values are ml/min per 1.73 m2. *For agent-specific recommendations, please refer to the manufacturers’ prescribing information. KDIGO, Kidney Disease: Improving Global Outcomes; TZD, thiazolidinedione. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int 2022;102:S1 KDIGO 2022 treatment algorithm for selecting glucose-lowering drugs for people with T2D and CKD Lifestyle therapy in addition to first-line therapy is the cornerstone of glycaemic management for people with T2D and CKD (2/4) 57 GLP-1 RA (preferred) DPP-4 inhibitor Insulin Sulphonylurea TZD Alpha-glucosidase inhibitor • Guided by individual preferences, comorbidities, eGFR and cost • Includes people with eGFR <30 ml/min/1.73 m2 or those treated with dialysis Metformin eGFR <45 eGFR <30 Dialysis Discontinue Reduce dose Discontinue SGLT2 inhibitor eGFR <20* Dialysis Do not initiate Discontinue Lifestyle therapy First-line therapy Additional drug therapy as needed for glycaemic control Physical activity, nutrition and weight loss
  • 55. Patient factors influencing the selection of glucose-lowering drugs other than SGLT2i and metformin in T2D and CKD Dr. Usama Ragab Youssif 58 Kidney International. 2022 Nov 1;102(5):S1-27.
  • 57. Final bottom-line Dr. Usama Ragab Youssif 60
  • 58. Profiles of Antihyperglycemic Medications MET GLP-1 RA SGLT2i DPP4i AGi TZD (moderate dose) COLSVL BCR-QR INSULIN PRAML HYPO Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral Moderate to severe Neutral WEIGHT Slight loss Loss Loss Neutral Neutral Gain Gain Neutral Neutral Gain Loss RENAL/GU Contra- indicated if eGFR <30 mL/min/1.73 m2 Exenatide not indicated CrCl <30 Not indicated for eGFR <45 mL/min/1.73 m2 Dose adjustment necessary (except linagliptin) effective in reducing albuminuria Neutral Neutral More hypo risk Neutral Neutral More hypo risk Neutral See #1 Genital mycotic infections Potential benefit of LA GLP-1 RA Potential CKD Benefit; See #1 GI Sx Moderate Moderate Neutral Neutral Moderate Neutral Neutral Mild Moderate Neutral Moderate CHF CARDIAC ASCVD Neutral Neutral Prevent Hf hospitalization manage HFrEF; see #2 See #4 HHF with saxagliptin Neutral Moderate Neutral Neutral Neutral CHF risk Neutral Possible ASCVD risk Lowers LDL-C Safe Neutral Potential benefit of LA GLP-1 RA May reduce stroke risk See #3 BONE Neutral Neutral Neutral Neutral Neutral Moderate fracture risk Neutral Neutral Neutral Neutral Neutral KETOACIDOSIS Neutral Neutral DKA can occur in various stress settings Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral SU GLN Severe Mild Few AEs or possible benefits Use with caution Likelihood of AEs 1. Canagliflozin indicated for eGFR ≥30 mL/min/1.73 m2 in patients with CKD 3 + albuminuria. 2. Dapagliflozin–potential primary prevention of HF hospitalization and demonstrated efficacy in HFrEF. 3. Empagliflozin–FDA approved to reduce CV mortality. Canagliflozin– FDA approved to reduce MACE events. 4. Possible increased hospitalizations for heart failure with alogliptin and saxagliptin. Slide credit: clinicaloptions.com American Association of Clinical Endocrinology. Endo Pract. 2020;26:139.
  • 59. Thank You Dr. Usama Ragab Youssif 62