Disclosures Speakers Bureau none Research Funding Novo Nordisk, [PDF]

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ILDIKO LINGVAY, MD, MPH, MSCS

UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX

Disclosures

Speakers Bureau none Research Funding Novo Nordisk, Merck, Pfizer, Mylan, Gan & Lee, Novartis, GI Dynamics Consulting/Advising/ Steering Committee Novo Nordisk, Sanofi, Eli Lilly, Boeringer-Ingelheim, Astra Zeneca, Intarcia, Valeritas, TARGETPharma, Mannkind, Janssen

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Timeline of Glucose Lowering Medications in USA

1920 1930 1940 1950 1980 1990 1995 2000 2005 2010 2015 2020 Number of medications & classes

19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

Iletin insulin PZI insulin NPH insulin 1st gen. SU Ultralente, Lente & Semilente insulin Human insulin: Regular, NPH & U500 glipizide, glyburide glimepiride metformin acarbose lispro miglitol troglitazone repaglinide rosiglitazone pioglitazone glargine nateglinide aspart glulisine detemir exexatide pramlintide sitagliptin colesevelam saxagliptin bromocriptine liraglutide linagliptin exenatide weekly empagliflozin inhaled insulin albiglutide dapagliflozin dulaglutide glargine U300 degludec FiAsp basaglar ertugliflozin semaglutide

12 Distinct Classes 45 Agents >70 Products

Goals of Treatment

I. Metformin II. Co-existing comorbidities/complications (ASCVD/ HF/ CKD) III. Glycemic control

 Weight control  Hypoglycemia  Cost Davies et al, Diabetes Care 2019

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Goals of Treatment

Maintain/improve Quality of Life Prevent/Manage Prevent/Manage Macrovascular Disease Prevent/Manage Prevent/Manage Microvascular Disease

 Asymptomatic  Prevent acute complications  Manageable side effects  Practical  Route  Frequency of administration  Cost  Co-manage weight  Tight glycemic (and BP) control  Targeted interventions  Anti-VEGF therapy (retinopathy, DME)  SGLT2 inhibitors (nephropathy) Other SOC (Statins/β-blockers/ACEI…) Targeted interventions GLP-1 RAs SGLT2 inh Davies et al, Diabetes Care 2019

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GLP-1 Receptor Agonists (GLP-1 RA)

Nauck MA. J Clin Endocrinol Metab. 1986;63:492-498

The Incretin Effect

Oral Glucose Intravenous Glucose C-peptide (nmol/L) Time (min) 0.0 0.5 1.0 1.5 2.0 Incretin Effect * * * * * * * 60 120 180 N = 6; Mean (SE); *P0.05

GLP-1
GIP
PYY
Cholecystokinine
Oxyntomodulin
VIP
Secretin
Ghrelin
…

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GLP-1 RAs: Metabolic Actions

Saraiva FK. Cardiovascular

Diabetology. 2014;13:142

GLP-1 RA Class

Agent Brand Name Half Life Route Frequency Exenatide Byetta 2.4 hrs SQ Twice Daily Lixisenatide Adlyxin* 3 hrs SQ Daily Liraglutide Victoza 13 hrs SQ Daily Albiglutide Tanzeum* 5 Days SQ Weekly Dulaglutide Trulicity 5 Days SQ Weekly Exenatide Bydureon/ Bcise 7-14 Days SQ Weekly Semaglutide Ozempic 7 Days SQ Weekly Semaglutide Rybelsus 7 Days PO Daily

*no longer marketed Duration of Action

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GLP-1 RAs in T2D: HbA1c

*Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; †liraglutide 1.2 mg. 1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9; 4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439.

1.9
1.6
1.4
0.8
1.5
1.4
1.1
1.5
1.8
0.5
1
1.5
1.8
1.7
1.5
0.9
1.1
1
1
1.4
0.8
1.3
1.2
0.3
0.8
0.9
1.4
1
2.5
2
1.5
1
0.5

DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10

8.3 8.3 Baseline HbA1c

Change from baseline in HbA1c (%)

8.5 8.4 8.7 8.7 8.0 8.0 8.1 8.1 8.1 8.1 8.2 8.1 8.4 8.5 8.4 8.4 7.4 7.2 8.2 8.2 8.4 8.3 8.2 8.2 8.2 8.3

Exenatide 10 µg BID Exenatide 2 mg QW Liraglutide 1.8 mg OD Lixisenatide 20 µg OD Albiglutide 50 mg QW Dulaglutide 1.5 mg QW Semaglutide 1.0 mg QW

DURATION-11 DURATION-51 Ji et al.1 GetGoal-X1 AWARD-12 AWARD-61 LEAD-61 DURATION-61 Nauck et al.3 Kapitza et al.1* HARMONY-71 SUSTAIN-34 SUSTAIN-75 SUSTAIN-106†

Long acting agents more effective than short acting
GLP-1 RA class has the greatest glucose lowering efficacy

(similar to insulin)

“Equivalent” Doses Amongst GLP-1 RA Glycemic effect

Almandoz et al. Clinical Diabetes, in press

†Equivalency based on clinical trials and expert opinion.

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Oral semaglutide (GLP-1 RA) vs sitagliptin (DPP IV inh): Hypoglycemia by SU background

11.8 14.2 15.5 11.3 Semaglutide 3 mg 33.2 Semaglutide 7 mg 33.6 Semaglutide 14 mg 42.3 Sitagliptin 100 mg 38.5 10 20 30 40 50 Metformin

nly

Metformin + SU Proportion of participants experiencing a hypoglycemic event (%) over 78 weeks

PIONEER 3, JAMA. 2019:2942

* * * 0.0

0.4
0.8
1.2
1.6
0.6
1.0
1.3
0.8
0.6
0.8
1.1
0.7

† Week 26 Week 78 HbA1c change from baseline (%) HbA1c change from baseline

GLP-1 RAs have low risk of hypoglycemia
glucose-dependent mechanism of action
Hypoglycemia risk increased when co-administered with SU or INS

GLP-1 RAs in T2D: weight

BID, twice daily; BW, body weight; GLP-1 RA, glucagon-like peptide-1 receptor agonist; OD, once daily; QW, once a week; T2D, type 2 diabetes. *Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; †liraglutide 1.2 mg.

1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9;
4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439.
3.7
2.3
1.6
3
1.3
3.6
3.2
3.6
4.3
2.4
2.2
5.6
6.5
5.8
3.6
1.4
2.5
4
1.1
2.9
2.9
2.7
3.7
1.6
0.6
1.9
3
1.9
7
6
5
4
3
2
1

DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10

102 102 Baseline BW

Change from baseline in BW (kg)

97 94 70 70 94 96 96 97 94 94 93 93 91 91 102 101 93 91 93 92 96 95 96 93 97 97

Exenatide 10 µg BID Exenatide 2 mg QW Liraglutide 1.8 mg OD Lixisenatide 20 µg OD Albiglutide 50 mg QW Dulaglutide 1.5 mg QW Semaglutide 1.0 mg QW

DURATION-11 DURATION-51 Ji et al.1 GetGoal-X1 AWARD-12 AWARD-61 LEAD-61 DURATION-61 Nauck et al.3 Kapitza et al.1* HARMONY-71 SUSTAIN-34 SUSTAIN-75 SUSTAIN-106†

GLP-1 RA class has by far the greatest weight lowering effect Sema>lira>dula>exenatide>lixisenatide

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Davies et al, Diabetes Care 2019 Davies et al, Diabetes Care 2019

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CV Composite in Prespecified Subgroups

Gerstein et al, REWIND, Lancet 2019: 121

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GLP-1 RA: Potential Mechanisms for CVD Benefit

Drucker DJ. Cell Metab. 2016;24:15-30. Rakipovski et al. JACC Basic Transl Sci 2018; 3: 844-857

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Davies et al, Diabetes Care 2019

GLP-1 RA & Heart Failure

0.5 1 1.5

HR (CI) Study

ELIXA LEADER SUSTAIN-6 EXSCEL PIONEER 6 0.96 (0.75, 1.23) 0.87 (0.73, 1.05) 1.11 (0.71, 1.61) 0.94 (0.78, 1.13) 0.83 (0.77, 1.12) Favors placebo Favors GLP-1 RA REWIND 0.86 (0.48, 1.55)

HR approx. 0.81 HARMONY Hospitalization for Heart Failure

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Renal Composite Outcome

New Macroalbuminuria, 30% fall in eGFR, or Renal Replacement Rx

Gerstein et al, REWIND, Lancet 2019: 121

Sustained eGFR Decline ≥ 30, 40 & 50%

Sustained eGFR decline ≥ 40% HR 0.70 (0.57, 0.85) 0.0004 Sustained eGFR decline ≥ 50% HR 0.56 (0.41, 0.76) 0.0002

≥ 30% Decline ≥ 40% Decline ≥ 50% Decline

Sustained eGFR decline ≥ 30% HR 0.89 (0.78, 1.01) 0.066 Sensitivity Analyses

Gerstein et al, REWIND, Lancet 2019: 121

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GLP-1 RA Side Effects

GI issues (up to 40%):
Nausea
Vomiting
Heartburn
Diarrhea
Constipation
Cramping
Mitigating actions:
Decrease intake
Only eat if hungry
Eat slowly
Increase fiber content
Reassurance (resolves over time)
OTC remedies (ginger, preggy pops, etc)
Slow (back down) titration
Good to know:
Medullary Thyroid Carcinoma
Retinopathy
Pancreatitis
Cholelithiasis

Oral Semaglutide: first oral GLP-1 RA

SNAC: Sodium N-(8-(2-hydroxybenzoyl) amino) caprylate

a small fatty acid derivative
SNAC causes a local increase of pH leading to

higher solubility and protection from proteolytic degradation

The effect is fully reversible
Approximately 1% of semaglutide is

absorbed, the rest is degraded in the GI tract

Buckley ST et al. Sci Transl Med 2018

Maximum concentration after po intake: 1 hr
Half-life: 1 weeks
Steady state: 4-5 weeks
≈5 wks to be eliminated after last dose
Dosing conditions:
Fasting for 6 hrs
Small amount of water only
No intake for MINIMUM 30 minutes

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Sodium GLucose Co-transporter 2 Inhibitors (SGLT2 inh)

Majority of glucose is reabsorbed by SGLT2 (90%)1,2

Proximal tubule

Remaining glucose is reabsorbed by SGLT1 (10%)1,2 Glucose filtration ≈ 180 g/day1,2 Minimal to no glucose excretion3

SGLT 2 inh: Mechanism of Action

1. Wright EM. Am J Physiol Renal Physiol. 2001;280:F10. 2. Lee YJ, et al. Kidney Int Suppl. 2007;106:S27.
3. Hummel CS, et al. Am J Physiol Cell Physiol. 2011;300:C14-C21.

X X

↑glucosuria ↑natriuresis SGLT 2 inhibitor

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SGLT 2 Inhibitors

Agent Brand Name Dose Route Frequency Empagliflozin Jardiance 10 mg & 25 mg Oral Daily Canagliflozin Invokana 100 mg & 300 mg Oral Daily Dapagliflozin Farxiga 5 mg & 10 mg Oral Daily Ertugliflozin Steglatro 5 mg & 15 mg Oral Daily

1.2
1
0.8
0.6
0.4
0.2

0.2 9 7

SGLT 2 inh: HbA1c

1. List JF, et al. Diabetes Care 2009;32(4):650–7; 2. Bailey CJ, et al. Lancet 2010;375(9733):2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13(10):928–38; 4. Wilding

JP, et al. Diabetes Obes Metab 2013;15(8):750–9; 5. Stenlof K, et al. Diabetes Obes Metab 2013;15(4):372–82; 6. Rosenstock J, et al. Diabetes Care 2012;35(6):1232–8; 7. Wilding JP, et al. Int J Clin Pract 2013;67(12):1267–82; 8. Dumas R, et al. Can J Diabetes 2013;37(S4):S28;9. Ferrannini E, et al. Diabetes Obes Metab 2013;15:721–8; 10. Rosenstock J, et al. Diabetes Obes Metab 2013;15(12):1154–60; 11. Häring HU, et al. Diabetes Care 2013;36(11):3396–404; 12. Rosenstock J, et al. Can J Diabetes 2013;37(S4):S32. The results of 12 studies are displayed. None of these were head-to-head studies and direct comparisons should not be made.

1.2
1
0.8
0.6
0.4
0.2

0.2

Mean change from BL HbA1c (%)

9 7 SGLT-2 inhibitor Placebo

1.2
1
0.8
0.6
0.4
0.2

0.2 9 7

Dapagliflozin Canagliflozin Empagliflozin

Mono1 Met2 SU3 Insulin4 Mono5 Met6 Met7 Insulin8 Mono9 Met10 SU+Met11 Insulin12

BL 7.8 7.9 7.9 8.1 8.1 8.2 8.6 8.5 BL 8.0 8.0 7.7 7.7 8.1 8.1 8.2 8.3 BL 7.8 7.8 7.9 8.0 8.1 8.2 8.3 8.1

0.9
0.2
0.8
0.3
0.8
0.1
1.0
0.5
1.0

0.1

1.0
0.2
1.0

0.0

0.8

0.1

0.6

0.1

0.6

0.2

0.8
0.2
0.5
0.0
SGLT2 inh glycemic efficacy dependent on:
Baseline HbA1c
Baseline renal function

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Empagliflozin (SGLT 2 Inh) vs Glimepiride (SU) – 4 yr F/u

Second Line Therapy after Metformin

Ridderstrale M. Diabetes Obes Metab. 2018;20(12):2768

3% vs 38% = 12.6 times higher!

4
3.5
3
2.5
2
1.5
1
0.5

0.5 1 9 7

SGLT 2 inh: Weight

1. List JF, et al. Diabetes Care 2009;32(4):650–7; 2. Bailey CJ, et al. Lancet 2010;375(9733):2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13(10):928–38; 4. Wilding

JP, et al. Diabetes Obes Metab 2013;15(8):750–9; 5. Stenlof K, et al. Diabetes Obes Metab 2013;15(4):372–82; 6. Rosenstock J, et al. Diabetes Care 2012;35(6):1232–8; 7. Wilding JP, et al. Int J Clin Pract 2013;67(12):1267–82; 8. Dumas R, et al. Can J Diabetes 2013;37(S4):S28;9. Ferrannini E, et al. Diabetes Obes Metab 2013;15:721–8; 10. Rosenstock J, et al. Diabetes Obes Metab 2013;15(12):1154–60; 11. Häring HU, et al. Diabetes Care 2013;36(11):3396–404; 12. Rosenstock J, et al. Can J Diabetes 2013;37(S4):S32. SGLT-2 inhibitors are not indicated for weight management. The results of 12 studies are displayed. None of these were head-to-head studies and direct comparisons should not be made.

4
3.5
3
2.5
2
1.5
1
0.5

0.5 1

Change from BL body weight (kg)

9 7 SGLT-2 inhibitor Placebo

4
3.5
3
2.5
2
1.5
1
0.5

0.5 1 9 7

Dapagliflozin Canagliflozin Empagliflozin

Mono1 Met2 SU3 Insulin4 Mono5 Met6 Met7 Insulin8 Mono9 Met10 SU+Met11 Insulin12

BL 92 89 86 88 81 81 95 95 BL 87 88 86 86 94 91 99 102 BL 81 82 88 88 77 76 92 91

3.1
1.1
2.9
0.9
2.3
0.7
1.6
0.8
3.4
0.5
2.9
0.8
3.1
1.0
2.7

0.0

2.0
0.8
2.7
1.2
2.2
0.4
2.2

0.7

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Davies et al, Diabetes Care 2019

SGLT 2 inhibitors: Proposed CV protection mechanisms

J Clin Med Res. 2018, 615-625.

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Proposed SGLT 2 inh Effects on Na/H Exchangers 1 (heart) & 3 (kidneys)

Packer M, et al. JAMA Cardiol 2017; 2: 1025-1029 Packer M. Circulation 2017; 136: 1548-1559

Empagliflozin (SGLT 2 Inh) Elevates Ketone Bodies Changing Cardiac Metabolism?

Ferrannini et al, Diabetes 2016;65:1190–1195

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SGLT 2 inh & MACE by CV Risk: Preexistent CV Event or Risk Factors

The Lancet 2019 393, 31-39DOI: (10.1016/S0140-6736(18)32590-X)

SGLT 2 inh and HHF/CV Death Outcomes

The Lancet 2019 393, 31-39DOI: (10.1016/S0140-6736(18)32590-X)

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DAPA-HF: SGLT 2 Inh in Heart Failure

Age 66.2 yrs 67.7% NYHA II LVEF 31.2% DM 41.8% HHF 47.8% McMurray et al. NEJM 2019:1995 (DAPA-HF) Dapagliflozin Placebo HHF or CV death

Dedicated Heart Failure Studies

HFrEF HFpEF GLP-1 RA ? (maybe) SGLT2 inh DAPA-HF DELIVER dapagliflozin dapagliflozin EMPEROR-Red EMPEROR-Pres empagliflozin empagliflozin SOLOIST-WHF sotagliflozin

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SGLT 2 Inh: Proposed Renal-protection Mechanisms

Heerspink HJL. Kidney Int. 2018; 94:26

CREDENCE: Renal Outcome Study for Canagliflozin (SGLT 2 Inh)

Perkovik et al. NEJM. 2019; 380(24):2301

ESRD, doubling of creatinine,

r renal or CV death
DM 100%
Age 63 yrs
Diabetes

duration 15.8 yr

CVD 50.4%
eGFR 56.2
ACR 927

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CREDENCE: Renal Outcome Study for Canagliflozin (SGLT 2 Inh)

NEJM. 2019; 380(24):2301

ESRD, doubling of creatinine,

r renal or CV death

SGLT 2 Inhibitors Renal Dosing Label

eGFR Canagliflozin Empagliflozin Dapagliflozin Ertugliflozin >60 45-60 100mg only* avoid use 30-45 ACR>300 avoid use avoid use <30 Do not start, may continue contraindicated contraindicated contraindicated Dialysis contraindicated

CV benefits are independent of eGFR
Glycemic benefits decrease with GFR and become negligible when eGFR <45

*if on UGT enzyme inducers avoid use when eGFR<60

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Dedicated Renal Outcome Studies with Glucose Lowering Drugs

Renal GLP-1 RA FLOW semaglutide sq SGLT2 inh DAPA-CKD dapagliflozin EMPA-Kidney empagliflozin CREDENCE canagliflozin

SGLT 2 Side Effects

Mycotic genital infections
Urinary tract infections
Dehydration & AKI (esp in population with lower eGFR)
Orthostasis
Diabetic Ketoacidosis
Increased LDL
Lower limb amputations
Bone fractures

Assess volume status Manage diuresis Assess current frequency Patient education *hygiene Assess prior occurrence Ensure not type 1! Examine feet Do not start if open wound Patient education re. foot exam

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GLP-1 RA or SGLT2 inh: This IS the Question! (or maybe both…?)

1. Jabbour SA et al. Diabetes Care 2018;41:2136–46

2.Rodbard et al. Diab Care. 2019: 2272

3. Lingvay I et al. Lanced D&E. 2019:834

GLP-1 RA vs SGLT2i: HbA1c

DURATION 81 Intention-to-treat* 52 weeks Baseline: 9.3% PIONEER 22 On-treatment 52 weeks Baseline: 8.1% SUSTAIN 83 On-treatment 52 weeks Baseline: 8.3%

2.0
1.5
1.0
0.5

0.0 Change in HbA1c (%)

–1.4 –1.2 –1.5 –1.0 –1.3 –0.8

Exe 2 mg Dapa 10 mg Oral sema 14 mg Empa 25 mg Sema 1.0 mg Cana 300 mg

*Change from baseline in HbA1c from the ‘on-treatment’ observation period was:

1.8% with Exe 2 mg + Dapa 10 mg, –1.6% with Exe 2 mg, and –1.2% with Dapa 10 mg

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*Change from baseline in body weight in the ‘on-treatment’ observation period was –3.3% with Exe 2 mg + Dapa 10 mg, –1.5% with Exe 2 mg, and –2.3% with Dapa

10 mg. 1. Jabbour SA et al. Diabetes Care 2018;41:2136–46; 2. Novo Nordisk. Data on file.

GLP-1 RA vs SGLT-2i: weight

DURATION 81 Intention-to-treat* 52 weeks Baseline: 91 kg PIONEER 22 On-treatment 52 weeks Baseline: 92 kg SUSTAIN 82 On-treatment 52 weeks Baseline: 90 kg

6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5

0.0 Change in body weight (kg)

–1.5 –2.3 –5.3 –4.2 –4.7 –3.8

Exe 2 mg Dapa 10 mg Oral sema 14 mg Empa 25 mg Sema 1.0 mg Cana 300 mg

GLP-1 RA OR SGLT 2 INHIBITOR: THIS IS THE QUESTION!

GLP-1 RAs SGLT 2 inhibitors Administration SQ (or PO) PO Frequency Weekly (or daily) daily Glucose lowering +++ + (dependent on baseline HbA1c & eGFR) Weight lowering +++ + MACE +++ + HHF (reduced EF) Neutral ++++ HFpEF ? Pending Renal outcomes Pending Likely, confirmed for CANA (for eGFR>30) eGFR <30 Yes Not indicated Main AE GI Infections

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Pathophysiology of CVD in Diabetes

CV, cardiovascular; CVD, cardiovascular disease; MACE, major adverse cardiovascular events.

Insulin Resistance

Vasculopenia

Oxidative Stress Inflammation Diabetes CV Death Atherosclerotic (MACE) Events Heart Failure Events

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Renal Effects of SGLT 2 inh and GLP1 RAs

Broad kidney endpoint: New macroalbuminuria, doubling of creatinine, 40% decline in eGFR, ESKD, renal death

Zelinker. Circulation 2019:139:2022

Renal Effects of SGLT 2 inh and GLP1 RAs

Kidney endpoint w/o albuminuria: doubling of creatinine, 40% decline in eGFR, ESKD, renal death

Zelinker. Circulation 2019:139:2022

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SGLT2 inh & GLP-1 RA: Ideal Partnership?

2
1.9
1.6
1.6
1.4
1.1
2.5
2
1.5
1
0.5

Combination GLP-1 RA SGLT2 Inh

Frías JP et al. Lancet Diabetes Endocrinol 2016:1004 Abdul-Ghani et al. Diabetes 2018 (Supl 1)

DURATION 8

Exenatide 2mg + Dapagliflozin 10 mg Baseline HbA1c 9.3% 28 wks f/u

UTHSCSA

Liraglutide 1.8mg + Canagliflozin 300 mg Baseline HbA1c 8.2% 16 wks f/u

Change in HbA1c

SGLT2 inh & GLP-1 RA: Ideal Partnership?

3.4
1.5
2.2
4
3.5
3
2.5
2
1.5
1
0.5

Combination GLP-1 RA SGLT2 Inh

Frías JP et al. Lancet Diabetes Endocrinol 2016:1004 Abdul-Ghani et al. Diabetes 2018 (Supl 1)

DURATION 8

Exenatide 2mg + Dapagliflozin 10 mg Baseline weigth 91.1 kg 28 wks f/u

Change in HbA1c

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Ludvik B et al. Lancet Diabetes Endocrinol 2018:370 Zinman B et al. Lancet Diabetes and Endocrinology 2019

Dula 1.5 mg Dula 0.75 mg PBO Sema 1.0 mg PBO

GLP-1 RA added to SGLT-2i : HbA1c

AWARD 10 On-treatment 24 weeks Baseline: 8.0% SUSTAIN 9 On-treatment 30 weeks Baseline: 8.0%

2.5
2.0
1.5
1.0
0.5

0.0

Change in HbA1c (%)

1.34
1.5
0.1
1.2
0.5

GLP-1 RA added to SGLT-2i : weight

3.4
1.5
2.2
5.0
4.0
3.0
2.0
1.0

0.0 Change in body weight (kg)

4.7
0.9
3.1
2.6
2.1

Dula 1.5 mg Dula 0.75 mg PBO Sema 1.0 mg PBO

AWARD 10 On-treatment 24 weeks Baseline: 91.5 kg SUSTAIN 9 On-treatment 30 weeks Baseline: 91.7 kg Ludvik B et al. Lancet Diabetes Endocrinol 2018:370 Zinman B et al. Lancet Diabetes and Endocrinology 2019

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SGLT2 Inhibitors added to GLP 1 RA

CANVAS Study – patients on GLP-1 RA

Fulcher G. DiabObesMetab 2016 18:82

SGLT2 Inhibitors added to GLP 1 RA

CANVAS Study – patients on GLP-1 RA

Fulcher G. DiabObesMetab 2016 18:82

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GLP-1 RA + SGLT2 = Match Made in Heaven?

Martinez R et al. Diabetes 2019:1182

Looking to the Future

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Cardiovascular Outcome Studies (CVOTs)

` TECOS CAROLINA CARMELINA EXAMINE SAVOR-TIMI Sitagliptin Linagliptin* Linagliptin Alogliptin Saxagliptin GLP-1 RA ELIXA SUSTAIN 6 PIONEER 6 EXCSEL LEADER HARMONY REWIND AMPLITUDE O SOUL Lixisenatide Semaglutide SQ Semaglutide PO Exenatide ER Liraglutide Albiglutide Dulaglutide Efpeglenatide Semaglutide PO Dual Agonists SURPASS- CVOT Tirzepatide* SGLT 2 Inh EMPA-REG DECLARE CANVAS VERTIS SCORED Empagliflozin Dapagliflozin Canagliflozin Ertugliflozin Sotagliflozin Insulin DEVOTE Degludec*

*active comparator

Related Outcome Studies with Glucose Lowering Drugs

HFrEF HFpEF Nephropathy Retinopathy Obesity CVOT GLP-1 RA ? FLOW FOCUS SELECT semaglutide sq semaglutide sq semaglutide sq semaglutide sq SGLT 2 inh DAPA-HF DELIVER DAPA-CKD dapagliflozin dapagliflozin dapagliflozin EMPEROR-Red EMPEROR-Pres EMPA-Kidney empagliflozin empagliflozin empagliflozin CREDENCE canagliflozin SOLOIST-WHF sotagliflozin

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Dual and Triple Agonists

Capozzi et al. Endo Reviews 2018; 39:719

GLP-1 GLP-1 GLP-1 GLP-1 GIP GIP GIP GIP Glucagon Glucagon Glucagon Glucagon

Tirzepetide – dual GIP-GLP-1 Agonist - phase 2 study

Frias et al, Lancet, 2018

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Tirzepetide – dual GIP-GLP-1 Agonist - phase 2 study

Frias et al, Lancet, 2018

Therapeutic Areas Investigated for Incretin Therapy

Type 2 Diabetes
Obesity
Cardiovascular event reduction
NASH
Diabetic Kidney Disease
Diabetic Retinopathy
Mental Health (Alzheimer, dementia, addiction)

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Conclusions

CONCLUSIONS

Diabetes treatment guidelines are progressing:
Cardiovascular and renal protection are taking a higher priority
Glycemic control still important, but a secondary goal
SGLT 2 inhibitors have proven efficacy in preventing:
heart failure hospitalizations and CV death – in high risk patients (ASCVD or HFrEF)
progression of kidney disease – in patients with diabetic nephropathy (eGFR 30-90 and

ACR>300)

GLP-1 RAs have proven efficacy in:
preventing major cardiovascular events – in high and medium risk patient
weight management
Are safe and effective in more advanced renal dysfunction (eGFR<45)
Combination therapy is tempting, data supporting it are limited at this time

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Research Volunteers
Research Staff
Collaborators
Colleagues
Fellows and Trainees
Funders