Robert M. Stoekenbroek

High daily insulin exposure in patients with type 2 diabetes is associated with increased risk of cardiovascular events.

AIMSnIntensive glucose control, often involving insulin treatment, failed to improve cardiovascular outcomes in several clinical trials. Observational studies reported an association between insulin use and cardiovascular disease (CVD) risk. It has therefore been suggested that insulin adversely affects CVD risk. To investigate the feasibility of this hypothesis, we studied the association between insulin dose and CVD risk in type 2 diabetes.nnnMETHODSnA case-control study was conducted of new users of oral antidiabetics who were prescribed insulin, using the Dutch Pharmo database. Cases were hospitalized for a cardiovascular event (CVE) and matched 1:2 to patients who were not hospitalized for a CVE, by sex, age, duration of diabetes and type of oral antidiabetic. Patients were divided into tertiles according to mean daily insulin dose. Conditional logistic regression analyses were used to explore the association between insulin exposure and CVE risk.nnnRESULTSnWe included 836 patients (517 (62%) male, mean age 66 years). After adjusting for available potential confounders, including HbA1c and triglycerides, insulin exposure was positively related to CVE risk (odds ratios for high (≥53.0 U/day) and intermediate (24.3-52.9 U/day) vs. low exposure (≤24.2 U/day): 3.00 [95% confidence interval (CI) 1.70 to 5.28] and 2.03 [95% CI 1.17 to 3.52].nnnCONCLUSIONnOur findings are in line with the suggestion that high-dose insulin therapy adversely affects CVD risk, but need to be interpreted with caution due to the observational nature of the study. The role of particularly high-dose insulin in the progression of CVD warrants further investigation.

PCSK9 inhibition: the way forward in the treatment of dyslipidemia

Barely a decade after the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its recognition as a key player in cholesterol metabolism, PCSK9 inhibition is now considered an exciting approach in the reduction of residual risk of cardiovascular disease. The progress from PCSK9 discovery to the development of targeted treatment has been unprecedented in terms of scale and speed. The first suggestion of a link between PCSK9 and hypercholesterolemia was published in 2003; a decade later, two meta-analyses of clinical trials comparing anti-PCSK9 treatment to placebo or ezetimibe, including >10,000 hypercholesterolemic individuals, were published. Currently, three PCSK9 inhibitors are being evaluated in clinical outcome trials and the results will determine the future of these lipid-lowering therapies by establishing their clinical efficacy in terms of cardiovascular event reduction, safety, and the consequences of prolonged exposure to very low levels of LDL-cholesterol. Irrespective of their outcomes, the exceptionally rapid development of these drugs exemplifies how novel technologies, genetic validation, and rapid clinical progression provide the tools to expedite the development of new drugs.

Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Pre-Specified Secondary End Points in ORION 1

Background: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described. Methods: ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment. Results: The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non–HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non–HDL-C was lowered dose-dependently: by 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL (P<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non–HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non–HDL-C <100 and <130 mg/dL. Conclusions: Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02597127.

How common are foot problems among individuals with diabetes? Diabetic foot ulcers in the Dutch population

Aims/hypothesisContemporary data on diabetic foot ulcer prevalence are scarce. Most studies were conducted in the 1990s, reporting incidence rates of 1.9–2.6%. Since then the prevalence of diabetes has doubled and the organisation of diabetes care has undergone major changes. Up-to-date data that quantify the occurrence of diabetic foot ulcers are required and could serve as baseline measures for future studies.MethodsIndividuals with diabetes (nxa0=xa081,793) were identified from the NIVEL (Netherlands institute for health services research) Primary Care Database, which contains data for standardised routine care and is representative of the Dutch population. The annual incidence rates of ulcers and other foot abnormalities were calculated using data collected between 2010 and 2013. To account for inaccuracies, incidence rates were calculated using: (1) only individuals with a documented foot examination; (2) all individuals; and (3) individuals with explicit documentation of present/absent foot ulceration.ResultsThere were 412 individuals with documented ulceration during the registration period (0.50%). The annual incidence rate of foot ulcers was 0.34% (range 0.22–1.08%). Of those individuals with a documented foot examination, 14.6% had absent pedal pulsations, 17.3% had neuropathy and 10.1% had callus/pressure marks.Conclusions/interpretationThe annual incidence rate of foot ulcers in the current study was lower than previously reported. This observation could reflect the efficacy of screening practices and an increased awareness among professionals and patients. Nevertheless, approximately one in every five diabetic individuals had at least one identifiable risk factor on foot examination. This signifies the importance of preventive screening.

Hyperbaric Oxygen Therapy in the Treatment of Ischemic Lower- Extremity Ulcers in Patients With Diabetes: Results of the DAMO2CLES Multicenter Randomized Clinical Trial

OBJECTIVE Conflicting evidence exists on the effects of hyperbaric oxygen therapy (HBOT) in the treatment of chronic ischemic leg ulcers. The aim of this trial was to investigate whether additional HBOT would benefit patients with diabetes and ischemic leg ulcers. RESEARCH DESIGN AND METHODS Patients with diabetes with an ischemic wound (n = 120) were randomized to standard care (SC) without or with HBOT (SC+HBOT). Primary outcomes were limb salvage and wound healing after 12 months, as well as time to wound healing. Other end points were amputation-free survival (AFS) and mortality. RESULTS Both groups contained 60 patients. Limb salvage was achieved in 47 patients in the SC group vs. 53 patients in the SC+HBOT group (risk difference [RD] 10% [95% CI −4 to 23]). After 12 months, 28 index wounds were healed in the SC group vs. 30 in the SC+HBOT group (RD 3% [95% CI −14 to 21]). AFS was achieved in 41 patients in the SC group and 49 patients in the SC+HBOT group (RD 13% [95% CI −2 to 28]). In the SC+HBOT group, 21 patients (35%) were unable to complete the HBOT protocol as planned. Those who did had significantly fewer major amputations and higher AFS (RD for AFS 26% [95% CI 10–38]). CONCLUSIONS Additional HBOT did not significantly improve complete wound healing or limb salvage in patients with diabetes and lower-limb ischemia.

Is additional hyperbaric oxygen therapy cost-effective for treating ischemic diabetic ulcers? Study protocol for the Dutch DAMOCLES multicenter randomized clinical trial?

The value of hyperbaric oxygen therapy (HBOT) in the treatment of diabetic ulcers is still under debate. Available evidence suggests that HBOT may improve the healing of diabetic ulcers, but it comes from small trials with heterogeneous populations and interventions. The DAMOCLES‐trial will assess the (cost‐)effectiveness of HBOT for ischemic diabetic ulcers in addition to standard of care.

Can we afford not to screen for FH

Almost five decades ago, Wilson and Jungner formulated 10 criteria to guide the selection of conditions for universal screening, which have essentially become the policy standard to date. In particular, conditions should pose an important health problem for which reliable and effective tests and therapies are available, and the overall costs of screening should be acceptable. Judged by these criteria, familial hypercholesterolaemia (FH) is an obvious condition for population screening.

Carotid arterial wall inflammation in peripheral artery disease is augmented by type 2 diabetes: a cross-sectional study

BackgroundPatients with peripheral artery disease (PAD) are at increased risk of secondary events, which is exaggerated in the presence of type 2 diabetes mellitus. Diabetes is associated with a systemic pro-inflammatory state. We therefore investigated the cumulative impact of PAD and type 2 diabetes on carotid arterial wall inflammation. As recent data suggest a detrimental role of exogenous insulin on cardiovascular disease, we also included a group of insulin users.Results18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) imaging showed increased carotid arterial wall inflammation, assessed as target-to-background ratio (TBR), in PAD patients without diabetes (PAD-only: nu2009=u200911, 1.97u2009±u20090.57) compared with matched controls (nu2009=u200912, 1.49u2009±u20090.57; pu2009=u20090.009), with a significant further TBR increase in PAD patients with type 2 diabetes (PAD-DM, nu2009=u200923, 2.90u2009±u20091, pu2009=u20090.033 vs PAD-only). TBR of insulin users (nu2009=u200912, 3.31u2009±u20091.14) was higher compared with patients on oral medication only (nu2009=u200911, 2.44u2009±u20090.76, pu2009=u20090.035), despite comparable PAD severity (Fontaine stages), BMI and CRP. Multivariate regression analysis showed that Hba1c and plasma insulin levels, but not dose of exogenous insulin, correlated with TBR.ConclusionsConcurrent diabetes significantly augments carotid arterial wall inflammation in PAD patients. A further increase in those requiring insulin was observed, which was associated with diabetes severity, rather than with the use of exogenous insulin itself.

Is additional hyperbaric oxygen therapy cost-effective for treating ischemic diabetic ulcers? Study protocol for the Dutch DAMOCLES multicenter randomized clinical trial 对缺血性糖尿病溃疡患者额外进行高压氧治疗的成本效益如何？荷兰DAMOCLES多中心随机临床试验的研究方案

The value of hyperbaric oxygen therapy (HBOT) in the treatment of diabetic ulcers is still under debate. Available evidence suggests that HBOT may improve the healing of diabetic ulcers, but it comes from small trials with heterogeneous populations and interventions. The DAMOCLES‐trial will assess the (cost‐)effectiveness of HBOT for ischemic diabetic ulcers in addition to standard of care.

Response to Comments on Santema et al. Hyperbaric Oxygen Therapy in the Treatment of Ischemic Lower-Extremity Ulcers in Patients With Diabetes: Results of the DAMO2CLES Multicenter Randomized Clinical Trial. Diabetes Care 2018;41:112–119

We thank Drs. Mutluoglu (1) and Huang (2) for their critical comments. They both express concerns regarding our conclusion based on the results of the DAMO2CLES [Does Applying More Oxygen (O2) Cure Lower Extremity Sores?] trial that hyperbaric oxygen therapy (HBOT) does not confer benefit in the treatment of patients with ischemic foot ulcers and diabetes (3).nnDuring the course of the trial, lagging patient inclusion necessitated a downward adjustment of the sample size to meet the time limit imposed by the sponsor of the trial. Nevertheless, this trial still is the largest trial on HBOT in the treatment of ischemic ulcers and allows for future meta-analysis.nnHuang (2) was concerned about the variation in clinical practice. The common treatments for diabetic ischemic foot ulcers, such as wound management, vascular surgery, and total …