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DM management

DM management. Dr.Duaa Hiasat. ORAL HYPOGLYCEMIC AGENT. New Recommendation: Pharmacologic Therapy For T2DM.

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DM management

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  1. DM management Dr.DuaaHiasat

  2. ORAL HYPOGLYCEMIC AGENT

  3. New Recommendation: Pharmacologic Therapy For T2DM • In patients with long-standing suboptimallycontrolled type 2 diabetes and established atherosclerotic cardiovascular disease, empagliflozinor liraglutideshould be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes. B American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

  4. METFORMIN Preferred initial agent for T2DM • Advantages • One of most potent at reducing A1c 1-2% • Weight neutral or weight loss of 0.6-2.9 kg • Little risk of hypoglycemia with monotherapy • Decreases CV events and mortality • Meta-analysis showed no CV harm with possible benefit vs. placebo • Diabetes, Obesity Metabolism May be useful for pre-DM

  5. Advantages (cont.) • – 1-2xd dosing • – May have a positive effect on osteoblast • – Generic – Low cost ~$4/month • • Disadvantages • – GI side effects, start low with low dose • – Lactic acidosis risk? • • Multiple cautions & contraindications • • Assess renal & liver function

  6. SULFONYLUREAS • • Stimulate insulin secretion – requires residual ß-cell function • 2nd generation greater potency & efficacy • 66-70% initially respond 5-10%/y failure rate • Islet cell “burnout” • Noncompliance • Disease progression • Often need additional agents

  7. Advantages • One of most potent at lowering A1c 1-2% • Many years of use • Low GI • 1xd dosing • Low cost ~$4/month • CKD –Glipizide (Glucotrol) no dosage change, • • Glimepiride (Amaryl) lower dose • • Disadvantages • – May induce ß-cell failure – “tolerance” develops • – Increases insulin release

  8. Disadvantages (cont.) • Hypoglycemia > with elderly & renal/hepatic dysfunction, missed meals > with Glyburide Weight gain of 1.5-2 kg in 1st year is common Due to hyperinsulinemiaContributes to insulin resistance & drug failure • Avoid Glyburide (Micronase) in renal dysfunction • FDA warning about increased risk of CV death? • Hypersensitivity – sulfa

  9. MEGLITINIDES • • Repaglinide (Prandin), Nateglinide (Starlix) • • Reduce A1c 0.5-1.5 • • Advantages • – Rapid onset and duration of insulin release – ¯ PPG • • Dose with meals – no meal then no dose • – Safer than some SUs with CKD • • eGFR < 30 start Repaglinide 0.5 mg or Nateglinide 60 mg • • Disadvantages • – Hypoglycemia, weight gain • – Frequent dosing with meals • – Higher cost than SUs, > $100/month

  10. Thiazolidinediones • (TZDs, Glitazones) Pioglitazone (Actos), Rosiglitazone (Avandia) • Reduce A1c 0.5-2% • • Advantages • – Improve insulin sensitivity & preserve ß-cell • • No tolerance? • – No hypoglycemia • – Pioglitazone reduces lipids and CV? • – Pioglitazone CKD – no dose change • – Used in preDM • – 1xd dosing

  11. TZDs/Glitazones Disadvantages • • ­ weight (~5kg) by activation of adipose tissue • • Fluid retention • – Edema • – CHF – contraindicated in NYHA III or IV • Possible increased MI risk with rosiglitazone?? • Bladder cancer with pioglitazone Negative effect on bone with 2x risk of fractures • FDA Med Watch March 2007. • Moderate to high cost

  12. α-GLUCOSIDASE INHIBITORS • • Acarbose (Precose),Miglitol(Glyset) • • Reduce A1c 0.5-1% • • Advantages • – No weight gain, No hypoglycemia • – Slows glucose absorption& reduces PPG • – Used for pre-DM • – May reduce CV events • – Moderate cost –generic • • Disadvantages • – GI side effects are common • – 3xd dosing • – Caution with GI diseases • – Caution in CKD • with eGFR <25-30

  13. INCRETIN-BASED THERAPY • • GLP-1 receptor agonists – Incretinmimetics“tides” • – Exenatide (Byetta), Exenatide ER (Bydureon) • – Liraglutide (Victoza), Albiglutide (Tanzeum) • • Dipeptidyl peptidase-4 inhibitors (DPP-4Is) • – “gliptins” • – Linagliptin (Tradjenta) • – Sitagliptin (Januvia) • – Saxagliptin (Onglyza) • – Alogliptin (Nesina)

  14. INCRETIN-BASED THERAPY • • Incretins normally released after meals by intestine Rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) • • Incretinmimetics – GLP1 agonists: • – Increases insulin when PG is high (glucose-dependent) • – Decreases glucagon secretion (glucose-dependent) • – Slows gastric emptying • – Promotes satiety with decreased food intake • • DPP-4 inhibitors • – Inhibits break down of incretins • – Prolongs incretin survival

  15. Dipeptidyl peptidase-4 inhibitors (DPP-4 Inhibitors Prolongs duration of endogensousincretinaction • Decrease A1c 0.5-1% • “apparently are similar with regard to efficacy and tolerability”

  16. Possible pancreatitis and pre-cancerous findings from incretinmimetics • Postmarketing reports of acute pancreatitis associated with incretinmimetics – previously reported Unpublished findings – Increased risk of pancreatitis and pre-cancerous cellular changes (pancreatic duct metaplasia) • FDA not reached any conclusions Will obtain and evaluate new information • “patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals … follow the prescribing recommendations in the drug labels.”

  17. AMYLIN MIMETICS • Pramlintide (Symlin) • Reduce A1c by 0.5-1 • Advantages – Weight loss – No hypoglycemia with monotherapy – Decrease PPG • Disadvantages – SC injection – GI SIDE EFFECT – 3xd dosing – Hypoglycemia with insulin FDA warning – Not recommended GFR < 30 – High cost

  18. SGLT2 INHIBITORS • Canagliflozin (Invokana), Dapagliflozin (Farxiga) • Novel mechanism of action - inhibits SGLT2 – Inhibit ~30-50% of filtered glucose – Increases urinary glucose excretion to ~ 80 g/d • Increasing dose after 50% inhibition does not increase – Dose-dependent decrease in FPG and PPG – Reduces A1c 0.5-1.5% Agents dependent on ß-cell and/or peripheral insulin resistance – May see decreased activity over time as DM progression occurs • Action not dependent on ß-cell or peripheral insulin sensitivity – May continue to be effective over time

  19. SGLT2 INHIBITORS • Advantages – Weight loss of ~2-4.7 kg – No hypoglycemia in monotherapy. – Reduces FPG and PPG • Decreases total glucose vs. time area under the curve – May be as effective as metformin in monotherapy – Decreases SBP ~2-10 mmHg & DBP ~1.3-1.9 – Canagliflozin 1xd before bkfst; Dapagliflozin 1xd anytime

  20. SGLT2 INHIBITORS • Disadvantages – Polyuria, frequency – caution orthostasis in elderly – Genital yeast infections ~3-8% (OR 3.5-5 vs. comparators) – UTIs – ~0.3-2% (OR ~1.3 vs. comparators) – Don’t use: Canagliflozin GFR < 45, Dapagliflozin GFR < 60 – Bladder cancer with dapagliflozin? – Hyperkalemia – ACEIs/ARBs, K-sparing diuretics – Hypermagnesemia, hyperphosphatemia – High cost ~$290/month

  21. BILE ACID SEQUESTRANTS • Colesevalam (Welchol) • Reduce A1c by ~0.5-1% • Advantages – Weight neutral – No hypoglycemia – Decrease LDL – May be safe CKD • Disadvantages – GI – Increase TG – DDI with adsorption – High cost ~$330/month

  22. References ADA 2018 www.guidelines.diabetes.ca Care.DiabetesJournals.org

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