Kardiovaskulär säkerhet vid behandling av typ 2

Kardiovaskulär säkerhet vid behandling av typ 2

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?
Baseline Risk of Patient Populations Enrolled
in CV Outcome Trials of DPP-4 Inhibitors
Risk Factors
Stable CAD-CVD-PAD
Post ACS patients
Alogliptin EXAMINE (N=5,380)1
ACS within 15–90 days
Saxagliptin SAVOR-TIMI (N=16,492)2
Pre-existing CVD or multiple risk factors for CVD
Sitagliptin TECOS (N=~14,000)3
Pre-existing CVD
Linagliptin CARMELINA (N=8,300)4
Pre-existing CVD + albuminuria or impaired renal function
Presented
Sept 2013
Presented
Sept 2013
End Dec 2014
End Jan 2018
Vildagliptin does not have an ongoing CV outcomes trial
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.
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EXAMINE, SAVOR-TIMI, and TECOS
HbA1c
Range, %
Duration of Treatment (as part of usual care)
Alogliptin
EXAMINE1
SAVORTIMI2
6.5–11.0
CV death,
Nonfatal MI, or
Nonfatal stroke
R
Placebo
Saxagliptin
6.5–12.0
CV death,
Nonfatal MI, or
Nonfatal stroke
R
Placebo
Sitagliptin
TECOS3
6.5–8.0
CV death,
Nonfatal MI,
Nonfatal stroke, or UA
req. hospitalization
R
Placebo
Randomization
Year 1
Primary
End point
Year 2
Year 3
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.
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SAVOR-TIMI 53, EXAMINE, and TECOS:
Major Adverse Cardiovascular Events
Test for heterogeneity for 3 trials:
p=0.877, I2=0%
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
*Lower Confidence Limit not
given for EXAMINE trial
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)
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•
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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
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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
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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!