CV RISK MANAGEMENT IN TYPE 2 DIABETIC PATIENTS

Asst. Prof. Praew Kotruchin

Cardiologist and Emergency Physician

Department of Emergency Medicine

Faculty of Medicine, Khon Kaen University

Backgrounds

■ Type 2 diabetes (T2D) imposes a substantial disease burden, predominantly

from cardiovascular disease (CVD),

– >50% of deaths in this population

■ 12-year reduction in the life expectancy in patient with T2D and CVD

compared with the general population

International Diabetes Federation. IDF Diabetes Atlas, 7th ed. 2015:1–140.

The results from mandatory cardiovascular outcome trials (CVOTs)

are of great interest

3x risk

1.3x risk

Current available hypoglycemic agents: simplified

Oral

• Insulin sensitizer (metformin)

• Thiazolidinediones (glitazones)

• Secretagogues:

• Sulphonylureas

• Repaglinide and nateglinide

• Incretin mimetics

• DPP4 inhibitors (gliptins)

• Glycosurics (SGLT2 inhibitors)

• Dapa-Cana-and Empa-gliflozin

Injectable

• Insulin

• Incretin mimetics

• GLP-1 Mimetics

• GLP analogues

Helena C. Circulation Research, 2019

Mitochondria

Oxidative stress

Lipotoxicity

Inflammation

Currently available hypoglycemic agents (simplified)

Oral

• Insulin sensitizer

• Metformin

• TZD

• Secretagogues

• Sulfonylureas

• Repaglinide and nateglinide

• DPP4 inhibitor (gliptins)

• Glycosurics

• SGLT2 inhibitors

(dapa-,cana-,empa-glifozin)

Injectable

• Insulin

• Incretin mimetics

• GLP-1 mimetics

• GLP analogues

E Ferrannini et al. European Heart Journal 2015

Metformin

TZD

Metformin

TZD

SGLT2

inhibitor

Alpha-glucosidase

Inhibitor,

GLP-1 RA

Insulin,

Sulfonylurea,

GLP-1 RA,

DPP-4 i

Diabetes pathophysiology and anti-diabetic drugs that inhibit the pathway

Hyperglycemia

Root of the CVOTs

2000s—muraglitazar vs standard therapy

- rosiglitazone vs comparators,

meta-analysis

**The FDA issued its CV safety guidance**

>2x CHF and death

43% increased risk of MI*

64% increased risk of CV death

TZDs are not recommended in

DM and HF patients

2016 ESC guidelines

Metformin is 1st line in

DM and HF patients

Diabetes Care Jan 2018, 41 (1) 14-31; DOI: 10.2337/dci17-0057

Do not lost track

Until now…

No RCT that

compare any

hypoglycemic drugs

in certain

HF patients

What we have is “cardiovascular outcome” in DM patients

With different cardiovascular profiles

ADA 2019 Guideline

2nd-line drug

consideration

• established ASCVD or

CKD

• glycaemic efficacy

• safety

• need for weight loss

• cost

However, a need remains for additional glucose-lowering agents with proven glycaemic efficacy and long-term CV and kidney safety profile

Diabetes care, J Clin Appl Res Ed, 2019: 42(1)

First line therapy is metformin

Contraindications Cautions

• History of serious hypersensitivity

reaction to drug

• Severe renal impairment; ESRD or

dialysis

• Increased incidence of bone

fractures (Canagliflozin)

• Increase risk of genital infection;

Fournier gangrene

• Euglycemic ketoacidosis in

vulnerable patients

Contraindications and cautions for SGLT2 inhibitors

DPP-4 inhibitor

CARMELINA and CAROLINA

1. Rosenstock J et al. JAMA 2019;321:69;

2. Marx N et al. Diab Vasc Dis Res 2015;12:16415

N=6979

CARMELINA1

Patients with established

CV disease and/or CKD

HbA1c 6.5–10%

N=6041

CAROLINA2

Early T2D patients with

increased CV risk

HbA1c 6.5–8.5%

Long-term safety profile of Linagliptin

Published Jan 2019

CARMELINA : Study participants

14.8-yr mean duration of diabetes mellitus

63% reduced kidney function (eGFR <60 ml/min/1.73 m2) at baseline

57% Established CVD; 27% heart failure

• High CV risk = history of CAD, stroke or PAD, and

microalbuminuria or macroalbuminuria

• High renal risk was defined as

(1) eGFR 45 to 75 mL/min/1.73 m2 and UACR

higher than 200 mg/g or

(2) eGFR 15 to 45 mL/min/1.73 m2 regardless of

UACR

• ESRD (eGFR < 15 mL/min/1.73 m2 or requiring

maintenance dialysis) were excluded

Adults with T2DM, HbA1c 6.5% - 10.0% and high CV and renal risk were eligible for inclusion

placebo + standard of care

N=6979

Randomised

1:1

Linagliptin 5 mg/day + standard of care

After ≥611 CV events

Primary endpoint: 3P-MACE

Time to first occurrence of any of the following:

• CV death (including fatal stroke and fatal MI)• Non-fatal MI (excluding silent MI)• Non-fatal stroke

Time to first occurrence of any of the following:

• Death due to kidney disease

• Progression to sustained end-stage kidney disease

• Sustained eGFR decrease by ≥40%

Secondary endpoint

Rosenstock J et al. JAMA 2019;321:69

CARMELINA : Study flow

RESULTS

0

5

10

15

20

25

30

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

*Two-sided; HR and 95% CI based on Cox regression model with terms for treatment group (p=0.7398) and region (p=0.7878)Rosenstock J et al. JAMA 2019;321:69

20

Time to first occurrence of 3P-MACE

HR 1.02(95% CI 0.89, 1.17)

p=0.0002 for non-inferiorityp=0.7398* for superiority

Time (years)

Pat

ien

ts w

ith

eve

nt

(%)

No. at risk

Placebo 3485 3353 3243 2625 1931 1285 758 251

Linagliptin 3494 3373 3254 2634 1972 1306 778 269

Placebo Linagliptin

The long-term CV safety profile

0

5

10

15

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

*Two-sided; HR and 95% CI based on Cox regression model with terms for treatment group (p=0.2635), region (p=0.0012), history of heart failure (p≤0.0001) HF, heartfailure

Rosenstock J et al. JAMA 2019;321:69

21

Time to first occurrence of hospitalisation for HF

HR 0.90(95% CI 0.74, 1.08)

p=0.2635*

Time (years)

Placebo 3485 3336 3222 2621 1923 1285 767 258

Linagliptin 3494 3361 3243 2647 1979 1317 787 280

No. at risk

Placebo LinagliptinPat

ien

ts w

ith

eve

nt

(%)

Risk of hospitalisation for HF

*Defined as the composite of time to first occurrence of death due to kidney disease, progression to sustained ESKD or sustained eGFR decrease by ≥40%; †Two-sided; hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.6164) and region (p<0.0001)

eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney diseaseRosenstock J et al. JAMA 2019;321:6922

0

5

10

15

20

25

30

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

HR 1.04(95% CI 0.89, 1.22)

p=0.6164†

Time (years)

Placebo 3485 3213 2995 2298 1608 1005 496 103

Linagliptin 3494 3227 3018 2345 1675 1040 518 109

No. at risk

Placebo LinagliptinPat

ien

ts w

ith

eve

nt

(%)

Time to first occurrence of any of the following:

• Death due to kidney disease

• Progression to sustained end-stage kidney disease

• Sustained eGFR decrease by ≥40%

The long-term kidney safety profile

Trajenta® is not indicated for the treatment of albuminuriaTreated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.0034) and region (p<0.0001)

Rosenstock J et al. JAMA 2019;321:69

23

Time to first occurrence of albuminuria progression

Years

HR 0.86(95% CI 0.78, 0.95)

p=0.0034†

Placebo Linagliptin

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50

20

80

60

40

Placebo (n) 2129 1972 1434 1139 667 430 200 35

Linagliptin (n) 2162 2004 1554 1263 756 487 213 39

No. at risk

Pat

ien

ts w

ith

eve

nt

(%)

Change from normo- to micro- or macroalbuminuria,

or from micro- to macroalbuminuria

The progression to albuminuria

The adverse

event

Not significant

1. Rosenstock J et al. Cardiovasc Diabetol 2018;17:39; 2.

Rosenstock J et al. JAMA 2019;321:69

25

Proven the long-term CV and kidney clinical safety profile in adults with

T2D and were high risk of heart and kidney disease

Linagliptin is effective and safe

Summary of CARMELINA

CVOTs with DPP- 4 inhibitors

SAVOR-TIMI 531 EXAMINE2 TECOS3 CAROLINA®4,5 CARMELINA®6

Intervention Saxagliptin/ placeboAlogliptin/placebo

Sitagliptin/ placeboLinagliptin/ glimepiride

Linagliptin/ placebo

Main inclusion criteriaHistory of or multiple risk factors for CVD

ACS within 15–90 days before

randomisationCVD

Pre-existing CVD or CV risk factors

High CV risk (previous CVD and

albuminuria, and/or renal dysfunction)

No. of patients 16,492 5380 14,671 6033 6979

Primary outcome 3P-MACE 3P-MACE 4P-MACE 3P-MACE 3P-MACE

Key secondary outcome Expanded MACE 4P-MACE 3P-MACE 3P-MACE renal composite

Target no. of events 10407 650 1300 631 6118

Median follow-up 2.1 years 1.5 years 3.0 years 6.3 years 2.2 years

Estimated completion Completed Completed Completed Completed Completed*Ongoing. Refer to slide notes for abbreviations

1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232;

4. clinicaltrials.gov NCT01243424 (accessed 21 February 2016); 5. Marx N et al. Diabetes Vasc Dis Res 2015;12:164; 6. clinicaltrials.gov NCT01897532 (accessed 21 February 2016); 7. Scirica BM et al. Am

Heart J 2011;162:818; 8. Data on file

Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology*Upper bound of the one-sided 95% CI; †4P-MACE4P-MACE, 4-point major adverse cardiovascular events; DPP-4i, dipeptidyl peptidase-4 inhibitor

1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232; 4. Rosenstock J et al. JAMA 2019;321:69

Study drug PlaceboHR (95% CI) HR (95% CI) p-value

n with event/N analysed (%)

SAVOR-TIMI 531

(saxagliptin)613/8280 (7.3) 609/8212 (7.2) 1.00 (0.89, 1.12) 0.99

EXAMINE2

(alogliptin)305/2701 (11.3) 316/2679 (11.8) 0.96 (≤1.16*) 0.32

TECOS3

(sitagliptin)† 695/7257 (9.6) 695/7266 (9.6) 0.98 (0.88, 1.09) 0.65

CARMELINA®4

(linagliptin)434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.74

0.5 1 2

Favours study drug Favours placebo

CV safety results of DPP- 4 inhibitors

Hospitalization due to HF

Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. Zannad F et al. Lancet 2015;385:2067; 3. Green JB et al. N Engl J Med 2015;373:232; 4. Rosenstock J et al. JAMA 2019;321:69

Study drug PlaceboHR (95% CI) HR (95% CI) p-value

n with event/N analysed (%)

SAVOR-TIMI 531

(saxagliptin)289/8280 (3.5) 228/8212 (2.8) 1.27 (1.07, 1.51) 0.007

EXAMINE2

(alogliptin)85/2701 (3.1) 79/2679 (2.9) 1.07 (0.79, 1.46) 0.657

TECOS3

(sitagliptin)228/7332 (3.1) 229/7339 (3.1) 1.00 (0.83, 1.20) 0.98

CARMELINA®4

(linagliptin)209/3494 (6.0) 226/3485 (6.5) 0.90 (0.74, 1.08) 0.26

0.5 1 2

Favours study drug Favours placebo

DPP-4i

CVOT trials

(completed and

ongoing)

Confirmed

CV safety profile

Confirmed kidney safety

profile through

hard outcomes

Hospitalization

for heart failure

The DPP-4i CVOT trials

1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Zannad F et al. Lancet 2015;385:2067;

4. Green JB et al. N Engl J Med 2015;373:232; 5. Rosenstock J et al. JAMA 2019;321:69; 6. Takeda. Nesina® (alogliptin) Prescribing Information. 2016

Vildagliptin None Not investigated No Not investigated

Saxagliptin1 1 Yes No Increased risk

Alogliptin2,3 1 Yes NoNumerically

increased risk*

Sitagliptin4 1 Yes No Safety confirmed

Linagliptin5 2 Yes Yes Safety confirmed

The only DPP-4i CVOT with an active comparator

N=6041Randomized

1:1

Linagliptin 5 mg/day + standard of care

Glimepiride 1–4 mg/day† + standard of care

≥631 CV events

Primary endpoint: 3P-MACE

Time to first occurrence of any of the following:

• CV death (including fatal stroke and fatal MI)

• Non-fatal MI (excluding silent MI)

• Non-fatal stroke

Median T2D duration:6.2 years

37% ≥2 CV risk factors

35% CVD

CAROLINA

“The minimum level of care everyone deserves"

Diabetes UK

• HbA1C

• BP measurement

• Lipid profiles

• Retinopathy screen

• Feet and legs checked

• Kidney function and proteinuria

• Flu vaccination

• Individualized dietary advice

• Emotional support

• Local education course

• High quality of care

• Sexual problem explored

• Stop smoking

• Pregnancy plan

• Specialist consultant when needed

The 15 Healthcare Essentials for diabetes

• Doctors need to update on good diabetes care

• Checking diabetes in heart patients can be done quickly

• Get to know your local diabetologists and make friends

• It is not that complicated

Take home messages

วนัน้ีคณุถามคนไข้หวัใจหรือยงัว่าโรคร่วมอ่ืนๆได้รบัการรกัษาอย่างดีแล้วหรือไม่

Thank you for your attention

ありがとうございます.