Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients With Diabetes.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia. METHODS: Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones. FINDINGS: Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis. IMPLICATIONS: PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.

Real-World Outcomes of Glucose Sensor Use in Type 1 Diabetes-Findings from a Large UK Centre.

Flash glucose monitoring (FGM) and real-time continuous glucose monitoring (RT-CGM) are increasingly used in clinical practice, with improvements in HbA1c and time in range (TIR) reported in clinical studies. We aimed to evaluate the impact of FGM and RT-CGM use on glycaemic outcomes in adults with type 1 diabetes (T1DM) under routine clinical care. We performed a retrospective data analysis from electronic outpatient records and proprietary web-based glucose monitoring platforms. We measured HbA1c (pre-sensor vs. on-sensor data) and sensor-based outcomes from the previous three months as per the international consensus on RT-CGM reporting guidelines. Amongst the 789 adults with T1DM, HbA1c level decreased from 61.0 (54.0, 71.0) mmol/mol to 57 (49, 65.8) mmol/mol in 561 people using FGM, and from 60.0 (50.0, 70.0) mmol/mol to 58.8 (50.3, 66.8) mmol/mol in 198 using RT-CGM (p < 0.001 for both). We found that 23% of FGM users and 32% of RT-CGM users achieved a time-in-range (TIR) (3.9 to 10 mmol/L) of >70%. For time-below-range (TBR) < 4 mmol/L, 70% of RT-CGM users and 58% of FGM users met international recommendations of <4%. Our data add to the growing body of evidence supporting the use of FGM and RT-CGM in T1DM.

Severe hypercalcaemia secondary to relapsed Graves' disease.

A 21-year-old woman presented to hospital with abdominal pain and nausea. She had a history of Graves' disease which had been effectively treated with carbimazole for 15 months. Investigations revealed a serum adjusted calcium level of 3.69 mmol/L with a suppressed parathyroid hormone, thyroid stimulating hormone <0.01 mu/L (0.2-5.0) and free T4 of 76.1 pmol/L (9-24). She was treated as a relapsed case of Graves' disease and started on propylthiouracil. Calcium levels continued to increase over the next 3 days despite adequate fluid resuscitation. A decision was taken to administer intravenous bisphosphonate (pamidronate) which resulted in a lowering of calcium levels. She became mildly hypocalcaemic following treatment with pamidronate which was presumed secondary to low vitamin D and oral vitamin D replacement was commenced. This case was unique as this is to our knowledge the most significant hypercalcaemia observed in a patient with hyperthyroidism. All other causes of hypercalcaemia were excluded. The learning points were recognising hypercalcaemia as a complication of thyrotoxicosis and the risk of hypocalcaemia following bisphosphonate therapy with low vitamin D stores.

Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.

AIMS: People with type 1 diabetes (T1D) face the daily task of implementing self-management strategies to achieve their glycaemic goals. The UK COVID-19 lockdown has had an impact on day-to-day behaviour, which may affect diabetes self-management and outcomes. We assessed whether sensor-based outcomes pre- and during lockdown periods were different in a cohort of glucose sensor users with T1D. METHODS: Data were collected from Freestyle Libre (FSL) or Dexcom G6 sensor users who remotely shared their data with the diabetes clinic web platform. Sensor metrics according to international consensus were analysed and compared between pre-lockdown period and 2 and 3 weeks into lockdown (periods 1 and 2). RESULTS: Two hundred and sixty-nine T1D patients (baseline HbA1c 57 ± 14 mmol/mol) were identified as FSL (n = 190) or Dexcom G6 (n = 79) users. In patients with sensor use > 70% (N = 223), compared to pre-lockdown period percentage TIR 3.9-10 mM (TIR) significantly increased during period 1 (59.6 ± 18.2 vs. 57.5 ± 17.2%, p = 0.002) and period 2 (59.3 ± 18.3 vs. 57.5 ± 17.2%, p = 0.035). The proportion of patients achieving TIR ≥ 70% increased from 23.3% pre-lockdown to 27.8% in period 1 and 30.5% in period 2. A higher proportion also achieved the recommended time below and above range, and coefficient of variation in periods 1 and 2. Dexcom G6 users had significantly lower % time below range (< 3.9 mM) compared to FSL users during both lockdown periods (period 1: Dexcom G6 vs. FSL: 1.8% vs. 4%; period 2: 1.4% vs. 4%, p < 0.005 for both periods). CONCLUSION: Sensor-based glycaemic outcomes in people with T1D in the current cohort improved during COVID-19 lockdown, which may be associated with positive changes in self-management strategies. Further work is required to evaluate long-term sustainability and support.

Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK.

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

COVID-19: Impact of and on Diabetes.

Diabetes has been identified as a pre-existing health condition linked with worse outcomes following coronavirus disease 2019 infection. Here we explore the association between hyperglycaemia and more severe illness, the impact of the pandemic on diabetes service delivery, and the resultant opportunities for innovation.

Cardiovascular Risk in Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is associated with premature cardiovascular disease (CVD), but the underlying mechanisms remain poorly understood. The American Diabetes Association and the European Association for the Study of Diabetes recently updated their position statement on the management of type 2 diabetes mellitus (T2DM) to include additional focus on cardiovascular risk; improved management of risk factors in T1DM is also needed. There are important differences in the pathophysiology of CVD in T1DM and T2DM. Hyperglycaemia appears to have a more profound effect on cardiovascular risk in T1DM than T2DM, and other risk factors appear to cause a synergistic rather than additive effect, so achievement of treatment targets for all recognized risk factors is crucial to reducing cardiovascular risk. Here we discuss the evidence for addressing established cardiovascular risk factors, candidate biomarkers and surrogate measurements, and possible interventions.

Circulating microRNAs -192 and -194 are associated with the presence and incidence of diabetes mellitus.

We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR-194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes.

Hypercholesterolaemia - practical information for non-specialists.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

A comparison of the effects of low- and high-dose atorvastatin on lipoprotein metabolism and inflammatory cytokines in type 2 diabetes: Results from the Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA) randomized trial.

BACKGROUND: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. OBJECTIVES: Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. METHODS: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol <7 mmol/L, proteinuria <2 g/d, creatinine <200 µmol/L) were randomized to receive atorvastatin 10 mg (n = 59) or 80 mg (n = 60) daily. Baseline and 1-year follow-up data are reported. RESULTS: Patients were at high cardiovascular disease risk (observed combined mortality and nonfatal cardiovascular disease annual event rate 4.8%). The non-high-density lipoprotein cholesterol (HDL-C) goal of <2.6 mmol/L was achieved in 72% of participants receiving high-dose atorvastatin, but only in 40% on low-dose atorvastatin (P < .005). The proportion achieving apolipoprotein B (apoB) <0.8 g/L on high-dose and low-dose atorvastatin was 82% and 70%, respectively (NS). Total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, non-HDL-C, oxidized LDL, apoB, glyc-apoB, apolipoprotein E, and lipoprotein-associated phospholipase A2 decreased significantly, more so in participants on high-dose atorvastatin. Adiponectin increased and serum amyloid A decreased without dose dependency. Neither dose produced significant changes in HDL-C, cholesterol efflux, high-sensitivity C-reactive protein, glycated hemoglobin, serum paraoxonase-1, lecithin:cholesterol acyltransferase, or cholesteryl ester transfer protein. CONCLUSIONS: High-dose atorvastatin is more effective in achieving non-HDL-C therapeutic goals and in modifying LDL-related parameters. Recommended apoB treatment targets may require revision. Despite the increase in adiponectin and the decrease in serum amyloid A, HDL showed no change in functionality.

Effect of Roux-en-Y Bariatric Surgery on Lipoproteins, Insulin Resistance, and Systemic and Vascular Inflammation in Obesity and Diabetes.

PURPOSE: Obesity is a major modifiable risk factor for cardiovascular disease. Bariatric surgery is considered to be the most effective treatment option for weight reduction in obese patients with and without type 2 diabetes (T2DM). OBJECTIVE: To evaluate changes in lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction following Roux-en-Y bariatric surgery in obese patients with and without diabetes. MATERIALS AND METHODS: Lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction were measured in 37 obese patients with (n = 17) and without (n = 20) T2DM, before and 6 and 12 months after Roux-en-Y bariatric surgery. Two way between subject ANOVA was carried out to study the interaction between independent variables (time since surgery and presence of diabetes) and all dependent variables. RESULTS: There was a significant effect of time since surgery on (large effect size) weight, body mass index (BMI), waist circumference, triglycerides (TG), small-dense LDL apolipoprotein B (sdLDL ApoB), HOMA-IR, CRP, MCP-1, ICAM-1, E-selectin, P-selectin, leptin, and adiponectin. BMI and waist circumference had the largest impact of time since surgery. The effect of time since surgery was noticed mostly in the first 6 months. Absence of diabetes led to a significantly greater reduction in total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol although the effect size was small to medium. There was a greater reduction in TG and HOMA-IR in patients with diabetes with a small effect size. No patients were lost to follow up. CONCLUSION: Lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction improve mostly 6 months after bariatric surgery in obese patients with and without diabetes. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT02169518. https://clinicaltrials.gov/ct2/show/NCT02169518?term=paraoxonase&cntry1=EU%3AGB&rank=1.

Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities.

PURPOSE: To assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM). METHODS: IVCCM was performed in 35 participants by a single examiner. For each participant, 4 observers used a standardized protocol to select 6 central corneal nerve images to assess the inter-observer variability. Furthermore, images were selected by a single observer on two occasions to assess intra-observer variability and the effect of sample size was assessed by comparing 6 with 12 images. Corneal nerve fiber density (CNFD), branch density (CNBD) and length (CNFL) were quantified using fully automated software. The data were compared using the intra class correlation coefficient (ICC) and Bland-Altman agreement plots for all experiments. RESULTS: The ICC values for CNFD, CNBD and CNFL were 0.93 (P<0.0001), 0.96 (P<0.0001) and 0.95 (P<0.0001) for inter-observer variability and 0.95 (P<0.0001), 0.97 (P<0.001) and 0.97 (P<0.0001) for intra-observer variability. For sample size variability, ICC values were 0.94 (P<0.0001), 0.95 (P<0.0001), and 0.96 (P<0.0001) for CNFD, CNBD and CNFL. Bland-Altman plots showed excellent agreement for all parameters. CONCLUSIONS: This study shows that implementing a standardized protocol to select IVCCM images results in high intra and inter-observer reproducibility for all corneal nerve parameters and 6 images are adequate for analysis. IVCCM could therefore be deployed in large multicenter clinical trials with confidence.

Knowledge gaps in the management of familial hypercholesterolaemia. A UK based survey.

BACKGROUND AND AIMS: Untreated individuals with familial hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom. METHODS: A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH. RESULTS: 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening. CONCLUSIONS: The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Diabetic dyslipidaemia.

PURPOSE OF REVIEW: The purpose is to discuss recent developments in the understanding of lipoprotein metabolism in diabetes, the cardiovascular risk associated with both type 1 and type 2 diabetes, recently published guidelines on the management of this risk, concerns over the use of statin treatment in diabetes, and other therapeutic options. RECENT FINDINGS: Diabetic dyslipidaemia can be gross with massive hypertriglyceridemia, or subtle with a lipid profile which would be regarded as normal in a nondiabetic patient, but which hides underlying increases in atherogenic subfractions of LDL (e.g., small dense LDL, glycated LDL) and remnant lipoproteins. Statins can decrease these without the clinician being aware from routine biochemistry. In type 2 diabetes, HDL cholesterol levels are often reduced, whereas in type 1, insulin can raise HDL, but its antiatherogenic properties are compromised. Dyslipidaemia and hypertension predate the onset of glycaemia of diabetic proportions (metabolic syndrome). Obese people can thus die of diabetes before they develop it. Obesity should be prevented and treated. Statins decrease the risk of cardiovascular disease in diabetes or metabolic syndrome regardless of whether glycaemia worsens. SUMMARY: One unassailable truth is that statin therapy is beneficial and should rarely, if ever, be withheld.

Diabetes Dyslipidemia.

Diabetes mellitus is associated with a considerably increased risk of premature atherosclerotic cardiovascular disease. Intensive glycemic control has essentially failed to significantly improve cardiovascular outcomes in clinical trials. Dyslipidemia is common in diabetes and there is strong evidence that cholesterol lowering improves cardiovascular outcomes, even in patients with apparently unremarkable lipid profiles. Here, the authors review the pathophysiology and implications of the alterations in lipoproteins observed in both type 1 and type 2 diabetes, the effect of medications commonly used in the management of diabetes on the lipid profile, the evidence for lifestyle and pharmaceutical interventions, and national and international recommendations for the management of dyslipidemia in patients with diabetes.