Dirk Müller-Wieland

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies

Aims Statins have modest adverse effects on glycaemic control. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers low-density lipoprotein cholesterol. This study assessed the effects of alirocumab on new-onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline. Methods and results Pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) of 24–104 weeks duration. Six trials (n = 4211) were ≥52 weeks in length. Most patients received background maximally tolerated statin. Alirocumab effect on the rate of diabetes-related treatment-emergent adverse events (TEAEs), and/or fasting plasma glucose (FPG) and glycated haemoglobin A1C (HbA1C) was measured at baseline and every 12–24 weeks. Transition to diabetes analysis combined TEAE and FPG/HbA1C laboratory data. At baseline, 30.7% of individuals had diabetes and were excluded from the current analysis. The remaining 3448 individuals without diabetes had pre-diabetes (39.6%) or were normoglycaemic (29.7%). The hazard ratio (HR; 95% confidence interval) for diabetes-related TEAEs in alirocumab was 0.64 (0.36–1.14) vs. placebo and 0.55 (0.22–1.41) vs. ezetimibe. The HR associated for transition from pre-diabetes to new-onset diabetes for alirocumab was 0.90 (0.63–1.29) vs. placebo and 1.10 (0.57–2.12) vs. ezetimibe. Mean change in FPG/HbA1C over time showed no difference between treatment groups in patients without diabetes. Conclusions There was no evidence of an effect of alirocumab on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6–18 months, compared to either placebo or ezetimibe. Longer follow-up with larger number of individuals is needed to conclusively rule out an effect.

Efficacy and safety of alirocumab in insulin‐treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM‐INSULIN randomized trial

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Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk

AbstractBackgroundType 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator.MethodsDM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-Cxa0≥100xa0mg/dl [≥2.59xa0mmol/l], and triglyceridesxa0≥150 andxa0<500xa0mg/dl [≥1.70 andxa0<5.65xa0mmol/l]) with documented atherosclerotic cardiovascular disease orxa0≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75xa0mg every 2xa0weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient’s current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-Cxa0≥100xa0mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis.ResultsRecruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017.ConclusionsODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint.n Trial registration NCT02642159 (registered December 24, 2015)

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials

To assess the lipid‐lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials.

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

AIMSnThe coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk.nnnMETHODSnODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety.nnnRESULTSnThis is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017.nnnCONCLUSIONnThe ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials

This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials.

Survey to estimate the prevalence of type 2 diabetes mellitus in hospital patients in Germany by systematic HbA1c measurement upon admission

The objective of this survey was to estimate the prevalence of type 2 diabetes mellitus (T2DM) in hospitalised patients ≥55 years based on routine HbA1c measurement upon admission, using the diagnosis algorithm according to the German National Diabetes Care Guideline.

Impact of Autoimmune Thyroiditis on Reproductive and Metabolic Parameters in Patients with Polycystic Ovary Syndrome

BACKGROUNDnAutoimmune thyroiditis (AIT) has been found to be associated with polycystic ovary syndrome (PCOS). The aim of this retrospective cohort study using data from a fertility clinic, with patients recruited from 2009 to 2010, was to confirm the higher prevalence of AIT in PCOS and to evaluate the impact of AIT on reproductive and metabolic parameters of PCOS patients.nnnMETHODSnPatients comprised 827 PCOS subjects seen for reproductive or metabolic complaints. Patients presenting primarily for thyroid problems were excluded. All patients were tested for the presence of AIT by laboratory testing and thyroid ultrasound. The impact of AIT on PCOS was evaluated by determination of reproductive and metabolic parameters.nnnRESULTSnPatients with PCOS and AIT as compared to those only with PCOS, had a lower prevalence of elevated testosterone (45 vs. 61%; p=0,0001), free androgen index (5,96±5,41 vs. 7,02±7,6; p<0,001) and hyperandrogenemia (66 vs. 78%; p<0,001). Also testosterone levels were lower in PCOS patients with AIT (0,50±0,30 vs. 0,63±0,71; p=0,0006). Consequently, in these patients, hirsutism was less frequent (51 vs. 66%; p=0,0021). There was no difference in the prevalence of acne, alopecia, a-/ or oligomenorrhea or PCO-morphology in the two patient groups. Patients with PCOS and AIT were more obese by 2u2009kg/m² BMI on average. A higher BMI correlated with a higher TSH value, although all patients were euthyroid.nnnCONCLUSIONSnAIT is more prevalent in PCOS than in controls. PCOS patients with AIT have less severe hyperandrogenemia and hyperandrogenism but are likely to suffer from an elevated metabolic risk.

Hemmung der Proproteinkonvertase Subtilisin/Kexin Typ 9: Identifikation der hiervon profitierenden Diabetespatienten

ZusammenfassungPCSK9 (Proproteinkonvertase Subtilisin/Kexin Typxa09) ist ein endogener Regulator des LDL-Rezeptors (LDL: „low density lipoprotein“) in der Leber, der dessen Anzahl und damit den Abbau atherogener Lipoproteine reduziert. Daher wurden neue Therapiestrategien entwickelt, mit denen die Menge an PCSK9 reduziert werden soll. Hierzu gehören die, auch seit kurzer Zeit auf dem Markt verfügbaren, humanen Antikörper Alirocumab und Evolocumab. Sie werden alle 2 oder 4xa0Wochen subkutan injiziert und senken die LDL-Cholesterin-Spiegel gut verträglich und sicher zusätzlich zu einer bereits bestehenden den Lipidspiegel senkenden Therapie im Mittel um 50–60u202f%. Kürzlich wurde in kardiovaskulären Endpunktstudien für beide Antikörper nachgewiesen, dass durch ihre Verabreichung das Risiko für kardiovaskuläre Komplikationen signifikant gesenkt werden kann. Analysen derjenigen Patienten der Studie mit Diabetes oder auch metabolischem Syndrom oder Prädiabetes ergaben eine vergleichbare Effektivität und Sicherheit für diese Therapie. Es waren keine Beeinflussung verschiedener Parameter der glukosebezogenen Stoffwechsellage und keine erhöhte Inzidenz eines Diabetes während der Studiendauer nachweisbar. In den kardiovaskulären Endpunktstudien war die relative Risikoreduktion kardiovaskulärer Ereignisse bei Patienten mit vs. ohne Diabetes vergleichbar. Da aber das absolute kardiovaskuläre Risiko bei Diabetes per se deutlich erhöht ist, ist diese Therapiestrategie eine neue Perspektive für diejenigen Diabetespatienten mit z.u202fB. bereits vorbestehender kardiovaskulärer Erkrankung, deren LDL-Cholesterin-Spiegel unter einer maximal verträglichen Kombinationstherapie eines Statins mit Ezetimib noch relativ weit vom Zielwert entfernt sind.AbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) is an endogenous regulator of the low-density lipoprotein (LDL) receptor in liver, reducing catabolism of atherogenic lipoprotein particles. Therefore, it has become axa0new drug target aimed at reducing the amount of PCSK9. This therapeutic strategy involves the recently developed and marketed human PCSK9 antibodies alirocumab and evolocumab. These antibodies are usually injected every other week or once every month. They are well tolerated, safe and reduce LDL cholesterol levels by 50%–60% on average alongside existing lipid-lowering treatments. Recent cardiovascular outcome trials for both antibodies have shown that the risk for cardiovascular complications can be reduced by this treatment. Analyses of patients with diabetes, metabolic syndrome, or pre-diabetes included in the studies show comparable efficacy and safety of this therapy. No effect on various parameters of glucose-related metabolism and no increase in the incidence of diabetes was observed during the study periods. In the cardiovascular endpoint trials, the relative risk reduction of major adverse cardiovascular events was similar in patients with or without diabetes at baseline. However, since absolute cardiovascular risk is elevated per se in patients with diabetes, this novel treatment strategy offers axa0new perspective for patients with diabetes already suffering from cardiovascular disease and whose LDL cholesterol levels are elevated despite maximum LDL cholesterol-lowering therapy using anxa0ezetimibe–statin combination.

Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes

To compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add‐on to metformin in patients with type 2 diabetes.