ANTI-HYPERGLYCEMIC DIABETES AGENTS in T2DM: Outcomes Comparison Summary Table L Regier BSP BA, M LeBras PharmD, T Trischuk PharmD, J Bareham BSP, L Lu BSP © www.RxFiles.ca Aug 2021 Drug Class Sulfonylureas TZDs Meglitinides DPP4 Inhibitors GLP1 Agonists *** SGLT2 Inhibitors *** Insulin in T2DM Generic Metformin Gliclazide Glyburide Pioglitazone Rosiglitazone Acarbose Repaglinide Saxagliptin ONGLYZA Liraglutide VICTOZA Empagliflozin JARDIANCE Intensity: Intensity: BRAND (MF) DIAMICRON DIABETA ACTOS, g AVANDIA GLUCOBAY GLUCONORM Sitagliptin JANUVIA Exenatide BYETTA, BYDUREON Canagliflozin INVOKANA Less More GLUCOPHAGE Dulaglutide TRULICITY Dapagliflozin FORXIGA, FARXIGA Alogliptin NESINA (e.g. NPH (Multiple daily GLUCOTROL D/C STEGLATRO Glipizide Nateglinide Semaglutide OZEMPIC, RYBELSUS (PO) Ertugliflozin Linagliptin TRAJENTA HS + MF) doses) STARLIX D/C SPREAD-DIMCAD] Lixisenatide ADLYXINE; ALBIGLUTIDE D/C SAVOR-TIMI 53, EMPA-REG, CANVAS, CREDENCE, T2DM: UKPDS-33,80; ADVANCE, Major trials to UKPDS- ProACTIVE ACE 33,34,80 UKPDS- Meta-analysis. TECOS, EXAMINE LEADER, EXSCEL, FREEDOM CVO, DECLARE, VERTIS-CV (2020), ACCORD, VADT, ORIGIN, DEVOTE support ADVANCE (Prevention (ADOPT; 33,80 Ferwana M. Meta- RECORD interim, PROLOGUE, REWIND, SUSTAIN-6, PIONEER-6, DAPA-HF, DAPA-CKD (2020), T1DM: DCCT/EDIC findings/ analysis 2013. trial: Stop- - some use in (ADOPT) ADOPT, DREAM CARMELINA, EMPEROR-Reduced & -Preserved (Also Boussageon et al. Meta- Outcomes* ADVANCE) SR-Liao 2017; IRIS NIDDM) ELIXA, HARMONY CAROLINA (2020), EMPA-Kidney (2022) analysis. BMJ 2011;343:d4169) 3,4,5 4,5 7 9 12 10,11 liraglutide ↓ MACE NNT=53/3.8yr 15 18,19,20 saxagliptin, LEADER empagliflozin in IFG, & ↓ mortality NNT=72/3.8yr , 2 5,6 ↓ MACE alogliptin, sitagliptin, ↓ MACE NNT=63/3.1yr, X? glipizide MACE ↓ MACE semaglutide subcut wkly ↓MACE X?21 > insulin NNT=50/ linagliptin non- NNT=44/2.1yr SUSTAIN-6 ↓ mortality NNT=38/3.1yr in obese, vs MF NNH=10/5yr use with intensive 2.9yr , NNT=40/ ) ↓ Risk of mortality (SPREAD-DIMCAD) inferior to placebo dulaglutide ↓ MACE NNT=72/5.4yr (EMPA-REG 8 3.3yr; REWIND target vs standard NNT=14/10yr but 1 X? for MACE, canagliflozin ↓ MACE 17,18 Death / ? albiglutide ↓MACE NNT=50/1.6yr (HARMONY) therapy, all- MI composite NS But see ?HF below. NNT≈220/yr (CANVAS) but 1 13,14 cause death Major CV NNT=14/10yr (ProACTIVE) in 11 lixisenatide, exenatide extended mortality NS linagliptin vs (UKPDS-34, established release, semaglutide po non-inferior NNH=95/3.5yr, ↓ MACE (IRIS) glimepiride (CAROLINA) dapagliflozin (DECLARE), UKPDS-80) (pts with insulin CVD to placebo for MACE (ELIXA, EXSCEL, & CV death non-inferior for ertugliflozin (VERTIS) resistance & (Chinese) PIONEER-6); semaglutide po NNH=125/3.5yr MACE PIONEER-6 MACE recent CVA/TIA) NS ?↓ mortality NNT=72/1.3yr (ACCORD) Effect on A1c** . Weight (loss vs A1 A2 A2 A3 A4 A5 A6 A7 A8 A9 A10 A10 X X XX XX X XX neutral vs gain) X ? Risk of ? XX ? less risk Severe, Low risk with Severe, occurs at with MR occurs at Increased risk when given with sulfonylurea or insulin Hypoglycemia monotherapy 1.8%/yr formulation 1.4%/yr 30 32 22,23 26 25,27 X? HF saxagliptin ↓ CV Death or XX XX 31 NNH=143/2.1yr (SAVOR), worsening HF/hospitalization 33,34 34 1st line in HF HF HF NNH=69 ↓ Risk of HF 23,24 23,25 28 29 alogliptin (EXAMINE posthoc) Entire class of GLP1 agonists dapagliflozin NNT=21/1.5yr with eGFR NNH=50/2.9yr, /5.5yr (RECORD), /Edema neutral for HF hospitalizations. (DAPA-HF), >30 mL/min edema HF NNH=250 Sitagliptin & linagliptin = empagliflozin NNT=19/1.3yr (? HF risk) ( HF risk) (DC’18) NNH=8/2.9yr /3yr (DREAM) HF neutral (Emperor-Reduced) Effect on GI X X Nausea, vomiting, diarrhea XX Start low & rate of flatulence 74% Titrate as tolerated (as per product tolerability titrate 1.8%/yr diarrhea 31% monograph); often improves with time Cost X X X XX X XX 35 PPBG 46 canagliflozin ↓ESRD, X FDA +/- HC warnings: PPBG doubled SCr & renal/CV death May have to ? HF (see above), ? FDA +/- HC warning: 38 injection site irritation CREDENCE; DAPA-CKD hold or dose HF (saxa- & NNT=23/2.6yr fractures (NNH≈30/~3.5yr) PPBG, ?↑ pancreatitis,39 in acute alogliptin); arthralgia, X outcome & safety data limited Caution: ? macular edema (conflicting Possible PPBG, 40 illness/HF/ Used in hypersensitivity rx, pancreatic cancer, FDA +/- HC warning: DKA; AKI accumulates data) benefit flexibility 41 (caution: intravascular volume & PPBG renal dysfx ?↑ pancreatitis ?↑ thyroid cancer (liraglutide) combination renal function), BP; (? lactic if ↓ renal Pio:? bladder ca >12 mos of with meals (ARI 0.13%),39 (once weekly agents may have Other with (HR ~2) limb amputations Cana;43 acidosis); function (27.5 excess /100,000 person yrs), laxative pancreatic cancer40 42 metformin GI adverse events) ?↑UTI/urosepsis/pyelonephritis; Fear/ may B12. (& in older avoid co-admin with effect in Linagliptin: no renal 46 perception (ADVANCE) gallbladder disease (liraglutide) genital tract skin infection 36 dose adjustment 1st line for adults) dapaglifozin some (OR 3.5 vs placebo);44 of insulin Cana fracture (HR 1.3)/BMD ; injections T2DM Rosi: Restricted access in CDN X new agents – Fear/ X new agents – outcome & dapagliflozin ?↑bladder/ breast (UKPDS-34) (SK-EDS; not covered on NIHB) perception of TID outcome & safety cancer (avoid with pioglitazone);45 37 TID dosing safety data still limited insulin injections ( CV risk concerns) dosing data still limited Fournier’s gangrene47 ? liraglutide (CV + mortality ? empagliflozin . Overall ? ? X? benefit), semaglutide SC (CV (CV + mortality benefit, benefit, SKH , NIHB coverage ) SKH & NIHB coverage ) . X? *Drugs that lower blood glucose come with various levels of evidence regarding their balance of benefits & harms. This chart relies on current evidence, especially from randomized controlled trials that have evaluated patient oriented outcomes. Direct Individualize approach comparisons between agents have not been done so one is left to evaluate each drug for its relative advantages & disadvantages. **A1c will vary depending on dose, combinations & initial A1c. considering balance of See full version of this ANTI-HYPERGLYCEMIC DIABETES AGENTS: Outcomes Comparison Summary Table online for additional notes: http://www.rxfiles.ca/rxfiles/uploads/documents/Diabetes-Agents-Outcomes-Comparison-Summary-Table.pdf potential benefits & harms. AKI=acute kidney injury DKA=diabetic ketoacidosis IFG=impaired fasting glucose MACE=major adverse cardiovascular events PPBG=postprandial blood glucose Over-aggressive pursuit of targets can ↑ mortality. ACCORD X XX ? Neutral ***See next page for GLP1 & SGLT2 An Advantage A Disadvantage Unknown/Ongoing color comparison chart 43 GLP1 Agonists & SGLT2 Inhibitors - SUBSET of DIABETES AGENTS in T2DM: Outcomes Comparison Summary Table L Regier BSP BA - www.RxFiles.ca Aug 2021 Drug Class GLP1 Agonists * SGLT2 Inhibitors Generic Dulaglutide Subcut Liraglutide Subcut Semaglutide Subcut Semaglutide PO 14mg Canagliflozin Dapagliflozin Empagliflozin FDA ; new Canada FDA BRAND TRULICITY (SUBCUT WEEKLY) VICTOZA (SUBCUT DAILY) OZEMPIC (SUBCUT WEEKLY) RYBELSUS (PO DAILY) INVOKANA FORXIGA / FARXIGA JARDIANCE n=17160 / 4.2 yr n=7020 / 3.1 yr Major trial(s) to support LEADER n=9340 / 3.8 yr SUSTAIN-6 n=3297 / 2 yr CANVAS n=10142 / 3.6 yr DECLARE-TIMI EMPA-REG n=9901 / 5.4 yr n=3183 / 1.3 yr n=4744 / 1.5 yr n=3730 / 1.3 yr REWIND PIONEER-6 DAPA-HF heart failure Emperor-Reduced in vs placebo (but ↑ insulin use) vs placebo (but ↑ insulin use) CREDENCE n=4401 / 2.6 yr renal dx pts findings/Outcomes* reduced EF pts heart failure reduced EF pts ↓ MACE ↓ MACE ↓ MACE Neutral for MACE: ↓ MACE REWIND LEADER SUSTAIN-6 ↓ MACE ? ↓ Risk of NNT=72/5.4yrs NNT=53/3.8yr NNT=44/2.1yr non-inferior to placebo EMPA-REG PIONEER-6 CANVAS Non-inferior to Placebo NNT=63/3.1yr - - - 3.8% vs 4.8% NNT~220/yr HR 0.93 (0.84-1.03) Major CV - MACE ? N. America - neutral ? N. America - neutral ? N. America – marginal HR: 0.79 (0.57-1.11) (≈NNT of 62/3.6yr) Superiority (NS) over 4.2yr 10mg as good as 25mg HR: 1.14 (0.89-1.47) HR: 1.01 (0.84-1.22) HR: 0.87 (0.57-1.34) Many trial limitations, e.g. short DECLARE HR 0.9 (0.80-1.01) HR 1.05 (0.74-1.50) ? 2 endpoint HR 0.87 (0.74-1.01) CANVAS HR 0.93 (0.82-1.04) 2 endpoint ↓ Risk of All-Death 10.8% vs 12%/5.4 yrs (NS) NNT=72/3.8yrs LEADER 3.8% vs 3.6%/2.1yrs (NS) NNT=72/1.3yrs HR 0.83 (0.68-1.02) CREDENCE NNT=44/1.5yr DAPA-HF NNT=38/3.1yr EMPA-REG HR 0.66 HR 0.76 (0.67-0.87) Less Renal Disease NNT=44/2.1yr (3.8% vs 6.1%) (0.53-0.81) ?class effect NNT=40/5.4yr (17.1 vs 19.6%) NNT=67/3.8yr (5.7% vs 7.2%) FLOW ? (composite/surrogates) ongoing semaglutide NNT=23/2.6 yrs CREDENCE NNT=19/2.4 yrs DAPA-CKD ongoing: EMPA-Kidney ** Effect on A1c ↓ 2.8-4 kg/4-52 wks Weight ↓ 2 kg/12-52 wks ↓ ~1.5-2 kg/3.1 yrs (loss vs neutral vs gain) ↓1.3-3 kg/5-52 wks ↓ 2.3 kg/3.8 yrs ↓ 3-4kg/2.1yrs ↓ 3.4kg/1.3 yrs CANTATA-M Less Risk of ? ? Severe: 2.4% vs 3.3% p=0.02 ? Hypoglycemia (placebo group had more insulin) Severe: 1.4% vs 0.8% Risk when given with sulfonylurea or insulin Less Risk of HF ↓ worsening HF or CV death ↓ HF hospitalization or CV HR: 0.93 (0.77-1.22) HR: 0.87 (0.73-1.05) HR: 1.11 (0.77-1.61) HR: 0.86 (0.48-1.55) 2 endpoint NNT=21/1.5yr DAPA-HF death NNT=19/1.3yr Emperor-Reduced /Edema ↓HF hospitalizations ongoing: HFpEF DELIVER ongoing: HFpEF Emperor-Preserved Effect on GI & D/C X GI X GI X GI X D/C due to GI: 6.8% vs 1.6% D/C due to AE 12% vs 13%; D/C due to AE 8.1% vs 6.9%; D/C due to AE 17.3 vs 19.4%; D/C due to AE 9% vs 6% D/C due to AE 9.5% vs 7.3% D/C due to AE 11.5-14.5% D/C due to AE 11.6% vs 6.5%; ?NNH=100/2.6yr NNH=84/4.2yr DECLARE NNH= 48/3.1yr due to Tolerability NNH=36/5.4yr NNH=46/3.8yr vs 5.7-7.6% NNH≈14/2yr NNH=20/1.3yr AEs: injection site irritations if subcut.