kardiovaskulär säkerhet vid behandling av typ 2-diabetes ... · kardiovaskulär säkerhet vid...
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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!