Non-Insulin Management of T2DM Day 1 Student Copy (2025) PDF

PHAR 2403 SPRING 2025 MANAGEMENT OF DIABETES MELLITUS: NON-INSULIN MEDICATIONS 1 Brian Terrell, Pharm.D., BCACP Assistant Professor – Ambulatory Care Division Department of Pharmacy Practice School of Pharmacy T...

PHAR 2403 SPRING 2025 MANAGEMENT OF DIABETES MELLITUS: NON-INSULIN MEDICATIONS 1 Brian Terrell, Pharm.D., BCACP Assistant Professor – Ambulatory Care Division Department of Pharmacy Practice School of Pharmacy Texas Tech University Health Sciences Center Abilene, Texas OBJECTIVES  Compare and contrast the oral diabetes medications (drug class, mechanism of action, dosing, ADME, contraindications, precautions, and side effects).  Compare and contrast the non-insulin injectable diabetes medications (drug class, mechanism of action, dosing, ADME, contraindications, precautions, and side effects)  Interpret patient specific parameters to develop/modify a patient’s diabetic regimen. 2 HOW TO FOLLOW PRESENTATION  This is not all you need to know but does clarify common questions  If it is a different color or bold, it is important and emphasized  No specific mg dosing of medications will be assessed on exam, but WHEN to adjust dosing is important  Please know brand and generic names  Please know/be able to choose the type of medication for specific patient characteristics 3  THERAPEUTIC GLYCEMIC GOALS IN DIABETES American Diabetes Association Fasting (Preprandial) Glucose 80-130 mg/dL (plasma) Postprandial Glucose < 180 mg/dL (“Maximum Peak”, 1-2 hrs) A1c < 7.0% (global)* * Goals must be individualized. A1C < 7% is the goal if possible without significant hypoglycemia. Less stringent treatment goals may be appropriate for patients with a history of severe hypoglycemia, patients with limited life expectancies, very young children and individuals with comorbid conditions. 4 Diabetes Care 2025;48(Suppl. 1):S128-S145 TREATMENT OF DM WITH NON - INSULIN AGENTS 5 BIG PICTURE  Main problem  Resistance, reduced function, lifestyle  Multiple strategies  Target variety of mechanisms, change lifestyle  How can we do it? 6 TREATMENT OF T2DM  ADA Treatment algorithm  Texas Diabetes Council algorithm  Glycemic Control Algorithm for Type 2 Diabetes Mellitus in Children and Adults Corner Stone of Therapy for DMT2: Diet and Exercise 7  From: 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes —2025 Date of Download: 1/15/2025 Copyright © 2025 American Diabetes Association. All rights reserved. Use of glucose-lowering medications in the management of type 2 diabetes. The left side of the algorithm prioritizes mitigation of diabetes-related complications and end-organ effects, while the right side addresses weight and glucose management goals. ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-to- Diabetes Care. 2024;48(Supplement_1):S181 Figure Legend: creatinine ratio; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; DSMES, diabetes self- management education and support; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; MACE, major adverse -S206. doi:10.2337/dc25- cardiovascular events; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; MI, myocardial infarction; SDOH, social determinants of health; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T2D, type 2 diabetes. Adapted from Davies et al. (89). S009  9 Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes - 2025 Diabetes Care 2025;48(Suppl. 1):S181-S206 PHARMACOLOGIC TREATMENT OF DMT2 USING NON-INSULIN AGENTS  Usually first line therapy  If initial presentation is hyperglycemia PLUS weight loss, use insulin as the initial intervention  Oral agents may be introduced after glycemic control is achieved.  Which non-insulin agent do I use??  Most APPROPRIATE agent(s)  A1c lowering capabilities; compelling need, side effects  Drug characteristics  Patient characteristics  Cost 10  CLASSES OF AGENTS  Biguanides (Metf)  Thiazolidinediones (TZD)  Sulfonylureas (SU) – 2nd Generations  Meglitinides (Meglit)  Alpha-glucosidase inhibitors (AGI)  Glucagon-like peptide agonists (GLP-1)  Glucose-dependent Insulinotropic Polypetide (GIP)/GLP- 1 dual agonists  Dipeptidyl peptidase-4 inhibitors (DPP4)  Sodium glucose co-transporter 2 inhibitors (SGLT-2)  Miscellaneous (bile acid sequestrants, dopamine agonists, amlynomimetic)  New agents????? 11  ACTION OF THE DIFFERENT CLASSES SU Meglit Metf TZDs AGI GLP-1 GIP/GLP-1 DPP-4 SGLT-2 Increases insulin XXX XXX XX XX X output Increases X insulin X XXX X X (min) (weight ↓ ?) (weight ↓ ?) sensitivity Decreases hepatic X X X X XXX X gluco- (min) (Indirect) (Indirect) (Indirect) neogenesis Decreases GI glucose X XXX X X absorption Increases XXX glucosuria 12 NON-INSULIN AGENTS – GENERAL FOR ALL  Contraindications/Precautions  Type 1 Diabetes  Diabetic ketoacidosis  Pregnancy??? (not approved in US)  Monitoring  Home blood sugar monitoring (BGM/CGM)  A1c  SCr, eGFR or LFTs (depends on drug)  Side effects  Drug interactions  Beta blockers (really anything that blunts adrenergic signals)  Decrease hypoglycemia awareness (esp SU/Meglit)  Non-selective > selective agents  Others – depends on drug (hypo or hyperglycemia) 13 “INSULIN SENSITIZERS” Liver and peripheral 14  BIGUANIDE Class Drug Name Onset of Effect Duration Metf metformin (Glucophage) Days-weeks (up to 6 weeks) Weeks metformin XR (Glucophage XR, Days-weeks Fortamet, Glumetza) (up to 6 weeks) Weeks Metformin (Main effect) Decreases gluconeogenesis ultimately decreasing basal endogenous glucose production Historically 1st Line Therapy unless CI or Pt X Glucose characteristics favor other 15  METFORMIN Hepatic Drug Name Excretion Renal Insufficiency Insufficiency Metformin Renal Precaution in (90%) Contraindicated if: eGFR 45 no adjust monitor frequently Class Additional Contraindications / Precautions Metformin Black Box- metformin levels increased in Renal impairment, Use of iodinated contrast, Acute heart failure episode. [Metformin does not cause the above, drug level increases in these situations] Dehydration, Metabolic acidosis (including DKA), Excessive EtOH, elderly with poor kidney fx, hypoxemia/hypoperfusion Ovulation may resume, surgery Class Side Effects Metformin Weight loss (Weight neutral) GI (N/V/D), B12 Deficiency Lactic acidosis – Black box 16  METFORMIN  Efficacy (High)  Reduces fasting glucose levels  Longstanding evidence for efficacy and safety Metformin (Main effect) Decreases gluconeogenesis ultimately decreasing basal endogenous glucose production  Characteristics of a Best Response  Central obesity (weight loss/weight neutral)  Mild-moderate hyperglycemia  Insulin resistance strongly suspected  Can be considered 1st line therapy, unless patient characteristic prevents use/ signals other might be preferred 17  METFORMIN Counseling/Practice Tips: Ghost Tablet May take several weeks to see effect Take with food to help with GI intolerance Try alternate dosing strategies to titrate up dose successfully Drug Name Standard Starting Dose Max Clinical Dose metformin (Glucophage) 500 mg 1-2 times daily 2000 mg per day metformin XR (Glucophage XR, Fortamet, Glumetza) 500 -1000 mg once daily 2000 mg per day  High efficacy, Low risk of hypoglycemia; weight neutral/loss; potential benefit in ASCVD; HF neutral; low cost; neutral on progression of CKD  Actual maximum dose of immediate release is 850 mg TID (more GI intolerance with minimal benefit past 2000 mg/day)  XR product in clinical practice has less GI issues, usually still dosed twice daily  MULTIPLE combination products to help decrease pill burden  Check drug interactions  Guideline Recommendations  CONSIDER AS FIRST LINE THERAPY WITH LIFESTYLE INTERVENTIONS  Unless contraindicated or Pt specific factors warrant 18 other EVIDENCE FOR METFORMIN USE  UKPDS 34 - Metformin  Compared to conventional therapy (diet)  Diabetes related endpoints  Diabetes related death  All cause mortality  MI  Compared to sulfonylurea or insulin  Diabetes related endpoints  All cause mortality  Stroke  When added to sulfonylurea (First Gen)  Increase risk of diabetes death  Increased risk of all cause mortality  Combined epidemiological analysis showed an overall benefit Lancet.1998;352(9131):854-865. 19  THIAZOLIDINEDIONES (TZDS) Class Drug Name Onset of Effect Duration TZDs Pioglitazone (Actos) 4 weeks 4 weeks Rosiglitazone (Avandia) Weeks Weeks TZDs (Main effect) Increases peripheral insulin sensitivity resulting in an increased glucose uptake and lower blood sugar Peripheral Tissues Glucose (Muscle) 20  THIAZOLIDINEDIONES (TZDS) Drug Name Metabolism Hepatic Insuff pioglitazone Hepatic Avoid in active liver disease (Hep C, 3A4, 2C8, 1A1 cirrhosis or EtOH associated) or  AST or rosiglitazone Hepatic ALT > 2.5 times the upper limit of Minor 2C8 (2C9) normal Class Additional Contraindications / Precautions TZDs CHF (NYHA III & IV) – BLACK BOX WARNING CHF (NYHA I & II) Macular Edema Fractures (Females – upper arm, hand, foot) Ovulation may resume Concurrent insulin use - ↑ CV events, edema Bladder carcinoma ? Class Side Effects TZDs Edema / Fluid retention Weight gain Hepatotoxicity (rare) GI Discomfort, anemia 21 THIAZOLIDINEDIONES (TZDS)  Efficacy (High)  Reduces glucose levels by increasing sensitivity to insulin  Other notes  Potential benefit in MASH/MASLD  Characteristics of a Best Response  Mild hyperglycemia  No unstable or significant HF or liver disease  Not concerned with weight gain  Insulin resistance strongly suspected/proven 22  THIAZOLIDINEDIONES (TZDS) Drug Name Standard Starting Dose Max Clinical Dose Pioglitazone (Actos) 15-30 mg once daily 45 mg once daily Rosiglitazone (Avandia) 4 mg in 1-2 doses 8 mg in 1-2 doses  High efficacy, Low risk of hypoglycemia (single agent); weight gain; pioglitazone potential benefit in ASCVD; increased risk in HF; low cost; neutral on CKD progression  Check interactions  No renal dosing adjustments but not generally used 2/2 fluid retention  Not used as often as agents with less issues available  Some controversy with both agents  Pioglitazone- bladder cancer, Rosiglitazone- increased LDL  Guideline Recommendations:  Compelling Need:  Minimize hypoglycemia  Cost is a major issue  Other:  Add on therapy if appropriate for patient 23  PIOGLITAZONE CONTROVERSIES  PROactive trial and Bladder Cancer  Increased incidence but non-significant increase in bladder cancer in patients who used pioglitazone vs controls in patients who used pioglitazone over 1 year  Conflicting results available  France took pioglitazone off the market  FDA recommends not to use in patients:  With active bladder cancer  Prior hx of bladder cancer 24 Lancet. 2005;366(9493):1279-89. http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm REVIEW TIME 25 WHICH INSULIN SENSITIZER IS USUALLY FIRST LINE PHARMACOTHERAPY IN T2DM? a) Rosiglitazone b) Pioglitazone c) Metformin d) Glyburide 26 INSULIN SECRETAGOGUES 27  SULFONYLUREAS Class Drug Name Onset of Effect Duration SU Glyburide (Diabeta, Micronase) 15-60 mins 16-24 hours Glyburide micronized (Glynase) 15-60 mins 12-24 hours Glipizide (Glucotrol) 30 minutes 12-24 hours Glipizide XL (Glucotrol XL) 2-3 hours 24 hours Glimepiride (Amaryl) 2-3 hours Peak effect 16-24 hours a.m. glyb/glip a.m. glipizide XL/glimepiride p.m. glyb/glip 8 12 16 20 00 4 8 8 12 16 20 00 4 8 28  SULFONYLUREAS Hepatic Drug Name Metabolism Renal Insufficiency Insufficiency glyburide Hepatic CrCl