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The Growing Challenge of Diabesity: The Role of SGLT2i

李美月內分泌新陳代謝內科小港醫院

Antihyperglycemic Therapy in Adults for T2DM

Diabetes Care 2018;41(Suppl. 1):S73â&#x20AC;&#x201C;S85

Antihyperglycemic Therapy in Adults for T2DM

Diabetes Care 2018;41(Suppl. 1):S73â&#x20AC;&#x201C;S85

Antihyperglycemic Therapy in Adults for T2DM

Diabetes Care 2018;41(Suppl. 1):S73â&#x20AC;&#x201C;S85

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes 5

Metformin

SGLT2 inhibitors

GLP-1 RAs

Efficacy

Hypoglycemia

Weight Change

High

Neutral

Intermediate

High

Loss

CV Effects

Renal Effects

ASCVD

CHF

Potential Benefit

Neutral

Benefit : Canagliflozin Empagliflozin

Neutral : Lixisenatide ; Exenatide ER

Benefit : Canagliflozin Empagliflozin

Cost

Oral/SQ

Progression of CKD

Dosing/Use Considerations

Low

Oral

Neutral

Contraindicated with eGFR<30

GI Side Effect Common (Diarrhea、Nausea) Potential B12 Deficiency

Benefit : Canagliflozin Empagliflozin

Canagliflozin : Not Recommend with eGFR<45 Dapagliflozin : Not Recommend with eGFR<60 ; Contraindicated with eGFR<30 Empagliflozin : Contraindicated with eGFR<30

FDA Black Box : Risk of Amputation(Canagliflozin) Risk of Bone Fractures(Canagliflozin) DKA Risk(all, rare in T2DM) Genitourinary Infection Risk of Volume Depletion, Hypotention Raise LDL

High

Oral

Intermediate

High

Benefit : Liraglutide

Potential Risk : Saxaglipitin Aloglipitin

High

Oral

Neutral

Renal Dose Adjustment Required ; Can be Used in Renal Imparement

Potential Risk of Acute Pancretitis Joint Pain

FDA Black Box : CHF(Pioglitazone、rosiglitazone) Fluid Retention(Edema、CHF) Benefit in NASH Risk of Bone Fractures Bladder Cancer(Pioglitazone) Raise LDL(Rosiglitazone)

FDA Special Warning on Increased Risk of CV Motarlity(Studies from Older SU : Tolbutamide)

Neutral

Increase Risk

Low

Oral

Neutral

No Dose Adjustment Required ; Generally not Recommended in Renal Imparement Due to Fluid Retention

Neutral

Low

Oral

Neutral

Gluburide : not Recommended ; Glipizide & Glimepiride Initiate Conservatively to Avoid Hypoglycemia

Low

SQ Neutral

Injection Site Reactions Lower Insulin Doses Required with a Decrease in eGFR ; Titrate Higher Risk of Hypoglycemia woth Human Insulin (NPH or Premixed Formulations) vs. Analogs per Clinical Respose

TZD

High

Gain

Potential Benefit : Pioglitazone

SU (2nd Generation)

High

YES

Gain

Neutral

Huna n Insulin

Anal ogs

Highest

YES

FDA Black Box : Risk of Thyroid C-cell Exenatide : Not Indicated with Tumors(Liraglutide、Albiglutide、Dulaglutide、Exenatide eGFR<30 ER) Lixisenatide : Caution with GI Side Effect Common(Nausea、Vomiting、Diarrhea) eGFR<30 Injention site reactions Increase Risk of Side Effects in ?Acute Pancretitis Risk Patients with Renal Imparement

Neutral

Benefit : Liraglutide

DPP-4 inhibitors

Additional Considerations

Gain

Neutral

Neutral High

Diabetes Care 2018;41(Suppl. 1):S73–S85

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes 6 Efficacy

Metformin SGLT2 inhibitors

GLP-1 RAs

High

Intermediate

High

Hypoglycemia Weight Change NO

CV Effects ASCVD CHF

Neutral

Potential Benefit

Neutral

Loss

Benefit : Canagliflozin Empagliflozin

Loss

Neutral : Lixisenatide ; Exenatide ER

Neutral

Benefit : Liraglutide

DPP-4 inhibitors TZD

Intermediate

High

Neutral

Potential Risk : Saxaglipitin Aloglipitin

Gain

Potential Benefit : Pioglitazone

Increase Risk

Diabetes Care 2018;41(Suppl. 1):S73â&#x20AC;&#x201C;S85

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes 7 Cost

Metformin

Low

Oral/SQ Progression of CKD Oral

Neutral

Renal Effects Dosing/Use Considerations Contraindicated with eGFR<30

Additional Considerations GI Side Effect Common (Diarrhea、Nausea) Potential B12 Deficiency

Canagliflozin : Not Recommend with eGFR<45 FDA Black Box : Risk of Amputation(Canagliflozin)

SGLT2 inhibitors

High

Oral

Benefit : Canagliflozin Empagliflozin

Dapagliflozin : Not Recommend with eGFR<60 ; Contraindicated with eGFR<30 Empagliflozin : Contraindicated with eGFR<30

Risk of Bone Fractures(Canagliflozin) DKA Risk(all, rare in T2DM) Genitourinary Infection Risk of Volume Depletion, Hypotention Raise LDL

Exenatide : Not Indicated with FDA Black Box : Risk of Thyroid C-cell Tumors(Liraglutide、 eGFR<30 Albiglutide、Dulaglutide、Exenatide ER) Lixisenatide : Caution with GI Side Effect Common(Nausea、Vomiting、Diarrhea) eGFR<30 Injention site reactions Increase Risk of Side Effects in ?Acute Pancretitis Risk Patients with Renal Imparement

GLP-1 RAs

High

Benefit : Liraglutide

DPP-4 inhibitors

High

Oral

Neutral

Renal Dose Adjustment Required ; Can be Used in Renal Imparement

Potential Risk of Acute Pancretitis Joint Pain

Neutral

No Dose Adjustment Required ; Generally not Recommended in Renal Imparement Due to Fluid Retention

FDA Black Box : CHF(Pioglitazone、rosiglitazone) Fluid Retention(Edema、CHF) Benefit in NASH Risk of Bone Fractures Bladder Cancer(Pioglitazone) Raise LDL(Rosiglitazone)

TZD

Low

Oral

Diabetes Care 2018;41(Suppl. 1):S73–S85

2018 AACE/ACE Comprehensive T2DM Management Algorithm

J Chin Med Assoc. 2018 Feb 13. pii: S1726-4901(18)30018-2. TW-4292_XIG_28/03/2018

Choices of second-line therapy Glycemic efficacy consideration:

SGLT-2 inhibitors

DPP-4 inhibitors

14 TW-4292_XIG_28/03/2018

Systematic review and meta-analysis demonstrated: Combination of metformin plus SGLT2i reduced HbA1c more than DPP4i and SU

179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations are included

15 Ann Intern Med 164(11):740-51 (2016)

Systematic review and meta-analysis demonstrated: Combination of metformin plus SGLT2i reduced weight more than DPP4i 16

Ann Intern Med 164(11):740-51 (2016)

Natural history of diabetic nephropathy

Glomerular filtration rate (GFR) (mL/min)

Pre 1

Incipient diabetic nephropathy

Overt diabetic nephropathy

End-stage renal disease

5000

150

1000

100

200

20 0 5

Years Functional

Urinary protein excretion (mg/d)

Urinary protein excretion

GFR

Hyperfiltration

Microalbuminuria, hypertension

Albuminuira, declining GFR

Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000.

A DPP4i would be a logical next step as add-on to metformin, but what if we change the order (SGLT2i ahead of DPP4i)?

Diabetes patientsâ&#x20AC;&#x2122; renal function declines over time

Metformin

+ DPP-4 INHIBITOR

Metformin

+ SGLT-2 INHIBITOR

+ DPP-4 INHIBITOR

Efficacy is dependent on renal function

Efficacy is not dependent on renal function

Rule out the SGLT2i class

Efficacy is not dependent on renal function

Singapore, ACE Appropriate Care Guides: Oral glucose-lowering agents in type 2 diabetes mellitus (3 July 2017)

https://www.moh.gov.sg/content /dam/moh_web/ACE-HTA/ourguidance.html TW-4292_XIG_28/03/2018

Review article: favor SGLT2i as second-line therapy

• We favor the use of SGLT2 inhibitors over DPP4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. • We particularly favor SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. cardiovascular disease. • Care should be taken to warn patients about genital fungal infections, and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. • We favor DPP-4 inhibitors in those where side-effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use. 20

Diabetes Metab Res Rev. 2018 Jan 10. doi: 10.1002/dmrr.2981. TW-4292_XIG_28/03/2018

The use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors

• This network meta-analysis of 236 trials randomizing 176 310 participants • SGLT-2 inhibitors (HR, 0.78 [95%CrI, 0.68 to 0.90]) and GLP-1 agonists (HR, 0.86 [95%CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. • SGLT-2 inhibitors (HR, 0.79 [95%CrI, 0.69 to 0.91]) and GLP-1 agonists (HR, 0.85 [95%CrI, 0.77 to 0.94]) were significantly associated with lower CV mortality than were the control groups. • SGLT-2 inhibitors were significantly associated with lower rates of HF events (HR, 0.62 [95%CrI, 0.54 to 0.72]) and MI (HR, 0.86 [95%CrI, 0.77 to 0.97]) than were the control groups. • GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (HR, 1.80 [95%CrI, 1.44 to 2.25]) and DPP-4 inhibitors (3.1%; HR, 1.93 [95%CrI, 1.59 to 2.35]). 21

Efficacy of Canagliflozin Metformin + Canagliflozin Dose-Ranging Study Mean Baseline A1C (%)

7.71

8.01 7.81 7.57 7.70 7.71 7.62

* * Diabetes Care 35:1232â&#x20AC;&#x201C;1238, 2012

* *PË&#x201A;.001 vs. placebo calculated using LS means

SGLT2 inhibitor improves risk factor in T2DM with 23 Metabolic syndrome

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2017:10 47â&#x20AC;&#x201C;55

SGLT2 inhibitor improves risk factor in T2DM with 24 Metabolic syndrome

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2017:10 47â&#x20AC;&#x201C;55

Weight Loss Effect of Canagliflozin N=127 ; 52 weeks LOCF ; Baseline=68.54 kg

Weight Loss(kg) Baseline (kg)

Weight Loss

Monotherapy : A1c Reductions

100 ; 300mg

5 ; 10mg

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014. 2. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014. 3. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014. 4. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58. 5. Zang M, Zhang L, Wu B, et al. Diabetes Metab Res Rev. 2014;30:204-21. 6. Liakos A, Karagiannis T, Athanasiadou E, et al. Diabetes Obes Metab. 2014; 16: 984-93.

10 ; 25mg

FPG Reductions

100 ; 300mg

5 ; 10mg

10 ; 25mg

Canagliflozin, dapagliflozin and empagliflozin for treating type 2 diabetes: Network Meta-analysis HbA1c

Health Technology Assessment, No. 21.2

Canagliflozin, dapagliflozin and empagliflozin for treating type 2 diabetes: Network Meta-analysis SBP

Health Technology Assessment, No. 21.2

Dapagliflozin: A novel insulin-independent approach to remove excess glucose1–3 Reduced glucose reabsorption

Proximal tubule

SGLT2 inhibitor

SGLT2 Glucose

Glucose filtration

Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*)

SGLT2 inhibitor selectively inhibits SGLT2 in the renal proximal tubule *Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.4 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

SGLT2 I

Empagliflozin 25mg: A novel insulin-independent approach to remove excess glucose1–3 Reduced glucose reabsorption

Proximal tubule

SGLT2 inhibitor

SGLT2 Glucose

Glucose filtration

Increased urinary excretion of excess glucose (~76g/day, corresponding to 280 kcal/day*)

Glycosuria Effect of Canagliflozin

服用Canaglu®100mg 每天可以多排出100g 的葡萄糖

相當 +

750 ml

250 ml

Energy Balance after SGLT2 inhibition

Effect of SGLT1 / SGLT2 Intestine SGLT1 • Main uptake mechanism for glucose and galactose in the intestine • S2 and S3 segments of the proximal renal tubule are responsible for ~10% of the renal glucose re-absorption • High-affinity (Km=~0.5 mM), low-capacity transporter which transfers glucose and sodium with a Na+:glucose coupling ratio of 2

1. Chao EC and Henry RR. Nat Rev Drug Discov. 2010;9:551–559; 2. Mather A and Pollock C. Kidney Int Suppl. 2011;(120):S1–6; 3. Wright EM, et al. J Intern Med. 2007;261:32–43.

Kidney SGLT2 • Almost completely expressed in the brush-border membrane of proximal renal tubular cells in the S1 + S2 segment • Responsible for ~90% of the total renal glucose re-absorption • Low-affinity (Km=~2 mM), high-capacity transporter which transfers glucose and sodium with a Na+:glucose coupling ratio of 1

Canagliflozin能同時抑制SGLT2及SGLT1受體

Liakos A et al. Diabetes Obes Metab 2014;16:984-93

x14

Structure and selectivity profiles for SGLT2 over SGLT1 Selectivity SGLT-1 : SGLT-2

Dapagliflozin

1:1200

Empagliflozin

1:2500

Canagliflozin

1:414

Singh AK et al. Indian J Endocrinol Metab. 2015 Nov-Dec;19(6):722-30.

Canagliflozin increase aGLP-1 through SGLT1 inhibition

SGLT2 Inhibition

Canagliflozin

SGLT1 Inhibition

Glucose

Glucose Retention

Reduce Reabsorbtion

Intestine

Blood Glucose

L-cell

GLP-1

Canagliflozin Lowers Postprandial Glucose and Insulin by DelayingIntestinal Glucose Absorption in Addition to Increasing UrinaryGlucose Excretion

Endocrine Journal 2017, 64 (9), 923-931

Effects of treatment with a combination of canagliflozin and teneligliptin during OGTT in ZDF rats 40

Journal of Pharmacological Sciences 127 (2015) 456e461

EMPA-REG vs CANVAS : Body Weight

Canagliflozin Reduce Adipose Tissue visceral adipose tissue

subcutaneous adipose tissue

Percentage Change Baseline : 89.6kg ; BMI 31.0kg/m2 , n=70, 52wks LOCF Lancet 2013; 382: 941â&#x20AC;&#x201C;50

SGLT2 inhibitor improves risk factor in T2DM with 43 Metabolic syndrome

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2017:10 47â&#x20AC;&#x201C;55

Canagliflozin Improve Beta Cell Function Baseline of HOMA-Beta

Before

24wks

Percentage Change

Diabetes is associated with significant loss of life years

58% of the survival difference can be attributed to vascular death

At 40, 50, and 60 years of age, men with diabetes would incur about 6.3, 5.8, and 4.5 years of life lost. At 40, 50, and 60 years of age, women with diabetes would incur about 6.8, 6.4, and 5.4 years Seshasai etof al. Nlife Engllost J Med 2011;364:829-41

16.2%

Heart failure and 14.1% peripheral arterial disease are the most 11.9% common initial manifestations of 11.5% cardiovascular disease in type 2 diabetes. 10.3%

Shah AD, et al. Lancet Diabetes Endocrinol 2015;3:105â&#x20AC;&#x201C;113

Lower MACE incidence of SGLT2i in RCT and RWE EMPA-REG1 (RCT, 100% CVD) MACE

CVD-REAL Nordic3 (real-world evidence,

24% CVD)

14% 4.3 : 3.7 (per 100 patientyears)

CANVAS2 (RCT, 66% CVD)

22% MACE

14%

2.12 : 1.64 (per 100 patient-years)

3.2 : 2.7 (per 100 patientyears) 47

1. N Engl J Med 373:2117-28 (2015); 2. N Engl J Med Jun 12 (2017). doi: 10.1056/NEJMoa1611925. 3. Lancet Diabetes Endocrinol. 2017 Sep;5(9):709-717.

Comparison of the effects of canagliflozin (CANVAS) and empagliflozin (EMPA-REG OUTCOME) on the key outcomes48

46 50

Adverse Event Collection in CANVAS Program

絕對風險差距為2.9 pt / 1000pt-year，比起Placebo 一年增加0.29人/100人截肢風險 51

Empagliflozin and Canagliflozin Risk of lower limb amputations EMPA-REG OUTCOMEÂŽ1*

CANVAS2

CANVAS-R2

Placebo (N=2333)

EMPA 10 (N=2345)

EMPA 25 (N=2342)

Placebo (N=1441)

CANA 100 (N=1445)

CANA 300 (N=1441)

Placebo (N=2903)

CANA (N=2904)

Patients with lower limb amputation n (%)

43 (1.8)

42 (1.8)

46 (2.0)

22 (1.5)

50 (3.5)

45 (3.1)

25 (0.9)

45 (1.5)

Lower limb amputation incidence rate (per 1,000 patient-years)

6.5

6.2

6.8

2.8

6.2

5.5

4.2

7.5

Hazard ratio (95% CI)

0.96

1.04

(0.63, 1.47)

(0.69, 1.58)

2.24

2.01

(1.36, 3.69)

(1.20, 3.34)

1.80 (1.10, 2.93)

Direct comparison of trials is not valid due to differences in study design, populations and methodology

*In empagliflozin clinical trials, procedures such as amputations have been classified as therapeutic procedures, and are not routinely captured as adverse events. Post-hoc analyses of amputations in the empagliflozin clinical trial database were performed searching concomitant therapies, comment fields for adverse event listings and case narratives (fields that may contain information regarding amputations). The analysis of the cases of LLA from empagliflozin clinical trials should be interpreted with caution considering the limitations inherited from this strategy of case retrieval. For 19 patients with an event but without an event date the event date was estimated; results are comparable when these patients were excluded from the analyses. Hazard ratio for pooled doses of empagliflozin: HR 1.00 (95% CI 0.70, 1,44) 1. Kohler et al, Adv Ther. 2017;34(7):1-32 and data on file, 2. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm (accessed 6-Jun-2017)

EMA Warning : SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors_Canagliflozin_20/Europe an_Commission_final_decision/WC500227101.pdf

SGLT2i Comparison Empagliflozin

Dapagliflozin

Canagliflozin

ADA/AACE recommendation

Yes

eGFR

Above 45

Above 60

Above 45

CV Outcome

-14%

Primary Prevention

CVD-REAL

CANVAS CVD-REAL

Renal Protection

EMPA-REG

CANVAS

Stroke

+24%

-10%

SGLT1抑制

---

+ 56

SGLT2i Comparison

HbA1c 健保價(每錠)

Empagliflozin

Dapagliflozin

Canagliflozin

0.9%

0.7%

0.91

(25 mg)

(10 mg)

(100 mg)

31.3

29.4

0.024 %/NTD

0.031 %NTD

0.77

(HbA1c↓)/健保價 0.029 %/NTD CP value (v.s. Cana)

0.94

The Role of Early Usage of Canagliflozin After Metformin

Insulin Independent : No Weight Gain，Preserve Beta Cell Function，Low Incidence of Hypoglycemia

CV Protection : Result of CANVAS (3P MACE 14%、 HHF 33%)；Primary/Secondary Prevention

Renal Protection (Reduce Albuminuria 27%)

Stroke Prevention 10%

SGLT1 /SGLT2 Dual Inhibition : High Durability of Weight Loss and HbA1c Reduction

Key Message for Canaglu Canagliflozin可提供T2DM病人心血管與腎臟保護作用

1 2

ADA/AACE guideline建議優先處方Canagliflozin給合併ASCVD的T2DM 患者，因為Canagliflozin具有Primary/Secondary Prevention臨床證據，能降低T2DM病人心血管風險並延緩腎臟惡化

SGLT1及SGLT2受體的雙重抑制效果 SGLT1抑制可延遲小腸吸收葡萄糖，並刺激GLP-1分泌，提供持續有效的血糖和體重控制效果

排糖效果卓越，有效降低HbA1c

每日排出100克葡萄糖，效果卓越。根據HTA資料顯示，Canagliflozin 100mg降低HbA1c效果與Empa 25mg相當，但優於Dapa 10mg。藥價 29.4元與Dapa相同，為同類藥品中價格最低，最具經濟效益

Thanks For Your Attention !!