Kardiovaskulär säkerhet vid behandling av typ 2-diabetes –

Vad säger senaste data?

Michael Alvarsson Kliniken för Endokrinologi, Metabolism

och Diabetes Karolinska Universitetssjukhuset Solna

Near-normal glucose seems to be good for your heart

…but is it good for you?

Near-normal glucose seems to be good for your heart

Vad har vi för verktyg i verktygslådan?

Hur säkra är de nya verktygen?

10

Vildagliptin does not have an ongoing CV outcomes trial

Linagliptin CARMELINA (N=8,300)4

Pre-existing CVD + albuminuria or impaired renal function End Jan 2018

Risk Factors Stable CAD-CVD-PAD Post ACS patients

Sitagliptin TECOS (N=~14,000)3

Pre-existing CVD End Dec 2014

Alogliptin EXAMINE (N=5,380)1

ACS within 15–90 days

Presented

Sept 2013 Saxagliptin SAVOR-TIMI (N=16,492)2

Pre-existing CVD or multiple risk factors for CVD

Presented

Sept 2013

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS =

acute coronary syndrome; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients

With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With

Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA =

Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk.

1. White W et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Green JB et al. Am Heart J 2013;166:983–989.e7. 4. CARMELINA:

Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/

NCT01703298. Accessed September 12, 2014.

Baseline Risk of Patient Populations Enrolled

in CV Outcome Trials of DPP-4 Inhibitors

12

R

R

R

Median Duration of Follow-upa

aApproximate median duration of follow-up for TECOS, based on the expected event rate at study initiation.

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome;

SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS =

Trial Evaluating Cardiovascular Outcomes With Sitagliptin. CV = cardiovascular; MI = myocardial infarction; UA = unstable angina.

1. White WB et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med 2013;369:1317–1326. 3. Green JB et al. Am Heart J. 2013;166:983–989.e7.

EXAMINE, SAVOR-TIMI, and TECOS

SAVOR-

TIMI2

TECOS3

EXAMINE1

6.5–8.0 CV death,

Nonfatal MI,

Nonfatal stroke, or UA

req. hospitalization

Randomization Year 3 Year 2 Year 1

CV death,

Nonfatal MI, or

Nonfatal stroke

CV death,

Nonfatal MI, or

Nonfatal stroke

Sitagliptin

Saxagliptin

Alogliptin

Placebo

Placebo

Placebo

6.5–12.0

6.5–11.0

HbA1c

Range, %

Primary

End point Duration of Treatment (as part of usual care)

SAVOR-TIMI 53, EXAMINE, and TECOS: Major Adverse Cardiovascular Events

Test for heterogeneity for 3 trials:

p=0.877, I2=0%

*Lower Confidence Limit not

given for EXAMINE trial

1. Scirica BM et al. N Engl J Med 2013; 369: 1317–1326

2. White WB et al. N Engl J Med 2013; 369: 1327–1335

3. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

SAVOR-TIMI 53, EXAMINE, and TECOS: Hospitalization for Heart Failure

Test for heterogeneity for 3 trials:

p=0.178, I2=42%

1. Scirica BM et al. N Engl J Med 2013; 369: 1317–1326

2. White WB et al. N Engl J Med 2013; 369: 1327–1335

3. Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA)

• N=6068

• Randomized, Double-blind, Placebo-controlled

• ACS

• HbA1c 5.5-11.0 %

• Primary outcome: MACE+

• Follow-up 2 years

Ongoing CV safety trials

• GLP-1 receptor agonists – LEADER (liraglutide (Victoza®), Novo Nordisk) – SUSTAIN 6 (semaglutide, Novo Nordisk) – EXSCEL (exenatide weekly (Bydureon®), AstraZeneca) – REWIND (dulaglutide (Trulicity®), Lilly)

• DPP-4 inhibitors – CARMELINA (linagliptin (Trajenta®), Boehringer Ingelheim) – CAROLINA (linagliptin vs glimepiride, Boehringer Ingelheim)

• SGLT2-inhibitors – CANVAS (canagliflozin (Invokana®), Janssen) – DECLARE (dapagliflozin (Forxiga®), AstraZeneca)

EMPA-REG OUTCOME

EMPA-REG OUTCOME

Summering

• Metformin sitter i orubbat bo! (UKPDS)

• SU – ifrågasatt (ADVANCE)

• Insulin - ? (ORIGIN)

• Glitazoner – PROactive + MACE, - HF

• GLP-1 RA – ELIXA neutral effekt

• DPP-4 hämmare – 3 RCT neutral effekt (HF?)

• SGLT2-hämmare – EMPA-REG trendbrott?

Slutsats

• Metformin tryggt att använda vid hög CV risk

• SU känns otryggt

• Basalinsulin bättre än måltidsinsulin (hypo-risk)

• Pioglitazon i nödfall

• GLP-1 RA sannolikt säkert

• DPP-4 hämmare känns säkert

• SGLT2-hämmare lovande (inte bara säkert utan bra?)

• Gäller detta även för pat utan hög CV risk?

Tack för uppmärksamheten!