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Non insulin glucose-lowering therapy in type 2 DM

A practical approach to the use of non-insulin agents in the management of DM 2

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Non insulin glucose-lowering therapy in type 2 DM

  1. 1. Non-insulin glucose-loweringNon-insulin glucose-lowering therapy in type 2 diabetestherapy in type 2 diabetes Mohsen Eledrisi, MD, FACE, FACP Department of Medicine Hamad Medical Corporation Doha, Qatar eledrisi@yahoo.com
  2. 2. CASE 1CASE 1 • A 41-year-old man with no past medical history • Presents for routine check up • Fasting plasma glucose 10 mmol (180 mg) • Kidney and liver function tests: normal • HbA1c 8.3 • How to approach?
  3. 3. CASE assessmentCASE assessment • The diagnosis of diabetes can be made • As fasting plasma glucose is ≥ 7 mmol (126 mg) • This was confirmed with A1c ≥ 6.5
  4. 4. • Lifestyle patterns: • Weight: prior attempts for weight loss • Physical activity • Smoking, alcohol • Comorbidities (HTN, dyslipidemia,…) • Medications • Family history (DM, CVD) Approach to newly- diagnosed DM: history
  5. 5. • Blood pressure • Weight, height, BMI • Thyroid • Skin • Foot Approach to DM: physical exam American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S34
  6. 6. • A1c • Lipids • Serum creatinine, eGFR • K+ (if on ACEI, ARB, or diuretic) • ALT, AST • Urine albumin:creatinine ratio (UACR) • TSH for type 1 DM Approach to DM: lab. tests American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S34
  7. 7. Glucose targetsGlucose targets depend on:depend on: AgeAge Comorbid conditionsComorbid conditions Vascular diseaseVascular disease Disease durationDisease duration Life expectancyLife expectancy Risks of treatmentRisks of treatment American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S34
  8. 8. Individualized A1cIndividualized A1c targets in DMtargets in DM American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S61 Canadian Diabetes Association. Can J Diabetes 2018;42:S42 < 7 General (most adults) - Short duration of DM or - No medication or only metformin or - No CVD < 6.5 7 to 8.5 - Advanced complications or - Extensive comorbid conditions or - Functionally dependent or - Severe hypoglycemia or - Limited life expectancy
  9. 9. Home glucose targets Before meals: 80-130 mg (4.4-7.2 mmol) 2 hours after meals: < 180 mg (10 mmol) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S61
  10. 10. Components of lifestyle changes 1) Self-management education – Refer to educator 2) Medical nutrition therapy – Refer to dietitian 3) Physical activity – Advise 150 minutes/week – Over 3-5 days/week American Diabetes Association. Diabetes Care 2019;42 (suppl 1):S46
  11. 11. • ADA/EASD guidelines: (American Diabetes Association/European Society for the study of diabetes - Start at the time of diagnosis ADA/EASD statement. Diabetes Care 2018;Oct pii: dci180033 When to start medications in DM 2?
  12. 12. 11stst choicechoice medicationmedicationMetforminMetformin American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  13. 13. Benefits of Metformin American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 • High efficacy: ↓ A1c by 1 to 1.5 % • Rare hypoglycemia • Weight loss or weight neutral • Low cost • Potential ↓ cardiovascular events & CV mortality
  14. 14. Starting Metformin American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 • Before starting: kidney function (cr, eGFR), ALT, AST • Start 500 mg twice/day then increase to 1000 mg bid • Take with meals • If GI upset, go back to 500 mg bid • XR form is more tolerated • Some are intolerant even to small dose: have to stop • Maximum effective dose: 1000 mg bid • Adherence is less with 3 times/day (avoid TID)
  15. 15. Metformin & the kidneys ♦ Obtain eGFR before starting metformin: • Don’t start if eGFR < 45 • eGFR 30-44 on Metformin: - Assess the benefits and risks - Consider reducing the dose • Stop if eGFR < 30 • Yearly eGFR; more frequent if high risk (low eGFR, elderly) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 Inzuchhi S et al. JAMA 2014;312:2668; www.fda.org
  16. 16. Metformin: Side effects • GI side effects (nausea, vomiting, diarrhea) • Vitamin B12 deficiency: - Periodic monitoring is recommended (consider yearly) (especially if there is anemia or peripheral neuropathy) • Avoid in unstable or hospitalized patient with heart failure. Can be used in stable HF • Hold if contrast procedure when eGFR 30-60. Resume after 48 hours if serum creatinine is stable • Lactic acidosis (rare) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  17. 17. CASE 2CASE 2 • A 42-year-old man with DM 2 for 2 years • Metformin 1000 mg bid • Had education on diet and exercise • Exam: BMI 27 • HbA1c 8.2, kidney & liver function tests are normal • How to approach?
  18. 18. • Duration of diabetes • Medications and any side effects • Presence of complications • Screening for complications • Comorbidities (HTN, dyslipidemia,…) • Social: smoking, work, alcohol, …. • Prior visits to educator/dietitian • Family history (DM, HTN, CVD) Approach to DM: history
  19. 19. • Blood pressure • Weight, height, BMI • Thyroid • Skin • Foot Approach to DM: physical exam
  20. 20. • A1c • Lipids (LDL, HDL, TG) • Serum creatinine, eGFR • Serum potassium (if on ACEI, ARB, or diuretic) • ALT, AST • Urine albumin creatinine ratio (UACR) Approach to DM: Labs
  21. 21. CASE 2:CASE 2: Patient assessmentPatient assessment • Uncontrolled DM (A1c 8.2) • A1c target: ♦ < 7 (or even < 6.5 given young age, short duration of DM & being on metformin only) • Patient is already following lifestyle changes • Metformin alone is not enough • We need to add another agent • Which medication?
  22. 22. What’s best afterWhat’s best after Metformin?Metformin? American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 • No clear advantage of any medication • Decision is based on: - Comorbidities (ASCVD, HF, CKD) - Risk of hypoglycemia - Effect on weight - Side effects - Cost - Patient preference
  23. 23. 22ndnd line agentsline agents • Sulfonylureas • DPP-4 inhibitors • Glitazones (TZD) • GLP-1 receptor agonists • SGLT-2 inhibitors • Basal insulin (Meglitinides & Alpha-glucosidase inhibitors are less commonly used) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  24. 24. SulfonylureasSulfonylureas • Stimulate insulin release • Gliclazide MR (Dimicron MR® ): - Starting dose: 60 mg daily - Maximum: 120 mg daily • Glimepiride (Amaryl® ): - Starting dose: 1 or 2 mg daily - Maximum: 8 mg daily (usually 4 mg qd) • Glibenclamide (Glyburide), Glipizide: - Starting dose: 2.5 or 5 mg qd - Maximum: 10 mg bid Vijan S. In the clinic. Ann Intern Med 2015
  25. 25. Sulfonylureas dosingSulfonylureas dosing • Glibenclamide, Glyburide, Glipizide, Gliclazide – 15 to 20 minutes before main meal (breakfast or lunch) • Gliclazide MR, Glimepiride - With main meal (breakfast or lunch) Vijan S. In the clinic. Ann Intern Med 2015
  26. 26. Sulfonylureas:Sulfonylureas: which one?which one? • All have same efficacy • Gilbenclamide is associated with ↑ hypoglycemia • Most of the benefit is seen with half-maximum dose • Observational studies: ? adverse cardiac effect • UKPDS: no increased cardiovascular events American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 Vijan S. In the clinic. Ann Intern Med 2015
  27. 27. Sulfonylureas: pros & consSulfonylureas: pros & cons • Advantages: – Highly effective: lower A1c by 1 to 1.5 % – Low cost • Disadvantages: – Hypoglycemia – Weight gain – High rate of secondary failure American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  28. 28. ↑↑ Insulin secretionInsulin secretion ↓↓ Glucagon secretionGlucagon secretion ↓↓ Gastric emptyingGastric emptying ↓↓ AppetiteAppetite GLP-1GLP-1 (Glucagon-like peptide 1)(Glucagon-like peptide 1) The incretin systemThe incretin system
  29. 29. DPP-4 inhibitors (Gliptins)DPP-4 inhibitors (Gliptins) • Inhibit DPP-4 (which breaks down GLP-1): ↑ GLP-1: ↑ insulin, ↓ glucagon • Sitagliptin (Januvia® ) 100 mg qd • Vildagliptin (Galvus® ) 50 mg qd or bid • Saxagliptin (Onglyza® ) 2.5, 5 mg qd • Linagliptin (Tradjenta® ,Trajenta® ) 5 mg qd • Alogliptin (Nesina® ) 25 mg qd • Can be taken at any time of the day
  30. 30. Gliptins: pros & consGliptins: pros & cons • Advantages: – Well tolerated – No weight gain – Rare hypoglycemia • Disadvantages: – Moderate effect (↓ A1c by 0.6 to 1 %) – High cost American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  31. 31. Gliptins: side effectsGliptins: side effects • GI upset, upper respiratory tract symptoms, joint/limb pains, headache, back pain, acute pancreatitis • Reduce dose in chronic kidney disease (except Linagliptin) • Vildagliptin: - Not FDA-approved (approved by European Medicines Agency) - Can affect liver function - Monitor liver enzymes every 3 months in 1st year then periodically. Stop if ALT > 3 times upper limit of normal • Saxagliptin ↑ hospitalization for heart failure especially in patients with cardiovascular or kidney disease American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90;; www.fda.gov; www.ema.europa.eu EXAMINE trial. N Engl J Med 2013;369:1327
  32. 32. GLP-1 receptor agonistsGLP-1 receptor agonists ∀ ↑ GLP-1: leading to ↑ insulin, ↓ glucagon, ↓ appetite • Generally effective (↓ A1c by 0.5-1.5 %) • Associated with weight loss • Rare hypoglycemia • Liraglutide ↓ CV events & mortality in patients with ASCVD American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  33. 33. GLP-1 receptor agonistsGLP-1 receptor agonists • Subcutaneous injection • GI side effects (nausea, vomiting, diarrhea) • ? Acute pancreatitis • Should not be used in patients with medullary thyroid cancer • Very high cost
  34. 34. GLP-1 RA examplesGLP-1 RA examples Exenatide (Byetta® ) • 5 micrograms bid (within 1 hour before main meals) •Maximum dose: 10 micrograms bid •Long-acting (Bydureon® ) [2 mg once/week] Liraglutide (Victoza® ) •Start 0.6 mg daily for 1-2 weeks then if tolerated increase to 1.2 mg qd •Maximum dose: 1.8 mg qd •Take at any time of the day
  35. 35. GLP-1 RA examplesGLP-1 RA examples Dulaglutide (Trulicity® ) • 0.75 mg once-weekly • Maximum 1.5 mg once-weekly • Take at any time of the day Lixisenatide (Lyxumia® , Adlyxin® ) •10 micrograms once-daily •Maximum 20 micrograms once-daily (within 1 hour before meal)
  36. 36. SGLT2 inhibitors (Gliflozins)SGLT2 inhibitors (Gliflozins) • Decrease glucose reabsorption at the kidney by inhibiting sodium-glucose co-transport 2 (SGLT2) causing glucosuria • Canagliflozin (Invokana® ) 100, 300 mg qd • Dapagliflozin (Forxiga® ,Farxiga® ) 5, 10 mg qd • Empagliflozin (Jardiance® ) 10, 25 mg qd • Ertugliflozin (Steglatro® ) 5, 15 mg qd • Take morning, with or without food American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 Vasilakou D, et al . Ann Intern Med 2013;159; www.fda.gov
  37. 37. SGLT2 inhibitors (Gliflozins)SGLT2 inhibitors (Gliflozins) • Modest effect: lower A1c by 0.6-0.8 % ∀ ↓ Weight, ↓ blood pressure • Rare hypoglycemia • Empagliflozin ↓ CV mortality & events in patients with ASCVD • Canagliflozin ↓ CV events in patients with ASCVD American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 Vasilakou D, et al . Ann Intern Med 2013;159; www.fda.gov
  38. 38. SGLT-2i: disadvantagesSGLT-2i: disadvantages • UTI, genital infections, AKI, dehydration, ↑ LDL • High cost • Diabetic ketoacidosis (rare) • Canagliflozin ↑ risk of bone fractures • Canagliflozin ↑ risk of leg and foot amputations American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 www.fda.gov
  39. 39. TZD (Gitazones)TZD (Gitazones) ∀ ↑ glucose uptake in muscle and fat tissue • Pioglitazone (Actos® ) 15, 30, 45 mg qd (any time of the day) • Advantages: – Effective (but variable: ↓ A1c 0.5 to 1.5 %) – Rare hypoglycemia – Low cost • Disadvantages: – Edema, weight gain, heart failure – Bone fractures – Urinary bladder cancer (FDA & EMA warnings) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  40. 40. MeglitinidesMeglitinides • Stimulate insulin secretion • Repaglinide (Novonorm® ) 0.5, 1, 2 mg • Nateglinide (Starlix® ) 60, 120 mg • Less effective than Sulfonylurea • Moderate cost • Hypoglycemia & weight gain • Three times/day (skip it if a meal is skipped) • Less commonly used American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  41. 41. Alpha-glucosidase inhibitorsAlpha-glucosidase inhibitors ∀ ↓ digestion/absorption of intestinal carbohydrates • Acarbose, Miglitol • Acarbose: 25 mg tid. Maximum 100 mg tid (with meals) • Rare hypoglycemia, low cost, no weight gain • GI side effects (gases, diarrhea) • Modest effect: lower A1cby 0.5 to 0.7 % • Less commonly used American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  42. 42. Back to CASE 2Back to CASE 2 • A 42-year-old man with DM 2 for 2 years • Metformin 1000 mg bid • BMI 27 • HbA1c 8.2 • Plan: – Add a second agent
  43. 43. CASE 2: OptionsCASE 2: Options • Sulfonylurea: - Effective, low cost - He is not obese with relatively short DM duration - Weight gain, hypoglycemia • DPP-4i: - No weight gain, low risk of hypoglycemia - But high cost
  44. 44. Our patient: optionsOur patient: options • Pioglitazone: - Effective, but weight gain & bladder cancer • GLP-1 RA: - Weight loss, but injections & expensive • SGLT-2i: - Weight loss, but less effective & expensive
  45. 45. CASE 2: finalCASE 2: final decisiondecision- If cost is an issue, go for Sulfonylurea - If cost is not an issue, consider DPP4i or SGLT-2i - DPP-4i is well tolerated, available in combination with metformin & less expensive than SGLT-2i or GLP-1RA - SGLT-2i or GLP-1RA are good options to lose weight, but more expensive
  46. 46. CASE 3CASE 3 • A 55-year-old man with DM 2 for 5 years • Metformin 500 mg bid (could not tolerate 1 gm bid) and Glimepiride 4 mg qd • He tries his best with lifestyle changes • BMI 31 • HbA1c 8.0 • How to approach?
  47. 47. CASE 3:CASE 3: Patient assessmentPatient assessment • Uncontrolled DM (A1c 8) • A1c target: < 7 • Patient is already following lifestyle changes • Drug failure is common in DM 2 • Increasing Glimepiride to 8 mg daily will have a minimal effect • He needs a 3rd agent • Which medication?
  48. 48. Drug failure in diabetesDrug failure in diabetes Turner RC et al. JAMA 1999;281:2005 20 40 60 80 Patients on sulfonylureaPatients on sulfonylurea 6 years6 years 34 %34 % 24 %24 % 50%50% 3 years3 years 9 years9 years 100 % of patients with HbA1c < 7
  49. 49. β-cell function (% of normal by HOMA) Holman RR. Diab Res Clin Pract 1998;40(suppl):S21 UKPDS. Diabetes. 1995;44:1249 Years 0 20 40 60 80 100 −10 −9 −8 −7 −6 −5 −4 −3 −2 −1 0 1 2 3 4 5 6 Time of diagnosis ? HOMA=homeostasis model assessment Diabetes: a progressive disease Pancreatic function ~ 50% of normal At diagnosis, ~ 50 % of insulin production is lost
  50. 50. 33rdrd line agentsline agents • Sulfonylurea • DPP-4 inhibitor • Glitazones (TZD) • GLP-1 receptor agonist • SGLT-2 inhibitor • Insulin (usually basal)
  51. 51. CASE 3: optionsCASE 3: options • The patient is obese • GLP-1 agonists: best option given weight loss and efficacy But: - Will the patient agree for injections? - Can he afford its high cost? • SGLT-2i: Weight loss, but high cost & moderate effect • DPP-4i: Weight neutral, well-tolerated, high cost (less than GLP-1 agonists)
  52. 52. CASE 3: FinalCASE 3: Final decisiondecision• I would go for a GLP-1 agonist • SGLT-2i is another option if patient refuses injections • DPP-4i is another reasonable choice
  53. 53. CASE 4CASE 4 • A 52-year-old man with type 2 DM for 6 years • Coronary artery disease (acute MI with stent) • Metformin 500 mg bid, Gliclazide MR 60 mg daily • He tries with lifestyle changes • Exam: BP 120/70 and BMI 29.3 • Labs: all normal except A1c 8.1 • How to approach?
  54. 54. CASE 4:CASE 4: Patient assessmentPatient assessment • Uncontrolled DM (A1c 8.1) • A1c target: ♦ < 7 • Patient is already following lifestyle changes • He could not tolerate metformin 1000 mg bid • Increasing SU will have minimal effect • We need to add a 3rd agent • Which medication?
  55. 55.   ASCVD Heart failure American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S103 Metformin Potential benefit Neutral Neutral Neutral Neutral - Neutral (Sita, Lina) - ↑ risk (Saxagliptin) - Benefit (Liraglutide) - Neutral (Exenatide ER, Lixisenatide) Neutral Neutral Neutral Empagliflozin: ↓ mortality & events Canagliflozin: ↓ events Dapagliflozin: neutral Benefit Potential benefit ↑ risk Sulfonylurea DPP-4i GLP-1RA SGLT-2i Pioglitazone Insulin
  56. 56. Diabetes & ASCVD: guidelinesDiabetes & ASCVD: guidelines • Start with Metformin & lifestyle changes • If glucose is not at target: – Add Empagliflozin or Liraglutide ∀↓ CV mortality & events – May consider Canagliflozin ∀↓ CV events * Dapagliflozin did not reduce CV mortality or events American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S103 Canadian Diabetes Association. Can J Diabetes 2018;42:S88
  57. 57. Diabetes & other comorbiditiesDiabetes & other comorbidities • Heart failure: ♦SGLT-2i: - ↓ Hospitalization for HF - This was a secondary outcome & mainly in patients with ASCVD (Level C = weak evidence) • CKD: ♦SGLT-2i or Liraglutide - Decreased progression of CKD - This was a secondary outcome & mainly in patients with ASCVD (Level C) American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90
  58. 58. Use of SGLT-2i & GLP-RAUse of SGLT-2i & GLP-RA in chronic kidney diseasein chronic kidney disease • Empagliflozin: not recommended if GFR < 45 • Canagliflozin : not recommended if GFR < 45 • Dapagliflozin : not recommended if GFR < 60 • Exenatide: not recommended if GFR < 30 • Liraglutide: studied in GFR as low as 15 • Dulaglutide: studied in GFR as low as 15 American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S90 www.fda.gov
  59. 59. CASE 5CASE 5 • A 68-year-old woman with DM 2 for 12 years • She also has hypertension, coronary artery disease • Metformin 1000 mg bid, Glimepiride 4 mg qd • HbA1c 6.2 • How to approach?
  60. 60. ApproachApproach • The A1c is very tight (high possibility of hypoglycemia) • Further history is needed: – Does the patient have a glucometer? – Home glucose monitoring? Documented hypoglycemia? – Patterns of food and timing of medications to food? – Home conditions, level of independence/ambulation?
  61. 61. AssessmentAssessment • The patient is 68-year-old with CVD • Her glucose is tightly controlled • This may be harmful (ACCORD study) – The cause is not known. It was not due to hypoglycemia • ADA recommends looser target for such patients (7 to 8 %) ACCORD study group. N Engl J Med 2008; 358:2545 American Diabetes Association. Diabetes Care 2019;42 (suppl. 1):S61
  62. 62. PlanPlan • I would stop sulfonylurea • Check A1c after 3 months – Expected to rise by 1-1.5 % (so would still be in target of 7 to 8) • If A1c rises above target, may consider other agents: – Empagliflozin or Liraglutide are preferred given ASCVD
  63. 63. CASE 6CASE 6 • A 62-year-old man with DM 2 for 8 years ago • Metformin 1000 mg bID, Gliclazide MR 60 mg QD, Pioglitazone 30 mg QD • About 1 year ago, HbA1c was 10.2. • So, physician ↑ Metformin to 1000/500/1000 and ↑ Gliclazide MR to 120 mg QD • Today, HbA1c is 9.8 • Physician added Sitagliptin • Do you agree with the plan?
  64. 64. Physicians are late in startingPhysicians are late in starting insulininsulin Brown JB et al. Diabetes Care 2004;27:1535 7 8 9 MeanA1c 9.19.1 8.88.8 8.68.6 2.5 years2.5 years 10 2.9 years2.9 years Diet/Exercise 2.2 years2.2 years 2.8 years2.8 years   Metformin         Sulfonylurea 3rd  drug 9.69.6 Diagnosis of DM          Time
  65. 65. Clinical inertiaClinical inertia • Recognition of a problem with patient’s management, but failure to act. Phillips L et al. Ann Intern Med 2001;135:825
  66. 66. Why do physicians delayWhy do physicians delay insulin?insulin? • Lack of time or personnel to teach patients • Inadequate training/experience with using insulin • Sense of inadequacy about being unable to manage without insulin • Fear of patient non-adherence • Concerns about hypoglycemia & weight gain • Belief that insulin will not help or has cardiovascular risk Peyrot M, et al. Diabetes Care 2005;28:2673 Korytkowksi M. Int J Ob Metab Relat Metab Disord 2002;26(supp 3)S18
  67. 67. CASE 6: lessonsCASE 6: lessons • Studies on 4-drug combination are limited • Guidelines do not recommend using 4 drugs • Physicians (not patients) are sometimes reluctant to start insulin • Remember: oral medications or GLP-1 agonists lower A1c by an average of 1 % • Do not delay insulin
  68. 68. Diagnosis of type 2 DMDiagnosis of type 2 DM Lifestyle changes + MetforminLifestyle changes + Metformin If A1c < 8: add 3If A1c < 8: add 3rdrd non-insulin agentnon-insulin agent Start Insulin UncontrolledUncontrolled on 3 agentson 3 agents ASCVDASCVD Empagliflozin orEmpagliflozin or LiraglutideLiraglutide GLP-1RA or GLP-1RA or  SGLT-2iSGLT-2i DPP-4i, SGLT-2i,DPP-4i, SGLT-2i, GLP-1RA, or TZDGLP-1RA, or TZD HypoglycemiaHypoglycemia concernconcern WeightWeight concernconcern CostCost concernconcern SU or SU or  TZDTZD Liraglutide orLiraglutide or EmpagliflozinEmpagliflozin SGLT-2i, DPP-4i,SGLT-2i, DPP-4i, GLP-1RA, or TZDGLP-1RA, or TZD SGLT-2i orSGLT-2i or GLP-1RA  GLP-1RA   TZD or SUTZD or SU A1cA1c ≥≥ 88 on 2 agentson 2 agents or

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