Triglyceride-rich lipoproteins, remnant-cholesterol, and atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: Despite indisputable role of LDL-C lowering, a considerable residual risk for atherosclerotic cardiovascular disease (ASCVD) persists. The precise mechanism(s) underlying this phenomenon remain unclear. Triglyceride-rich lipoproteins (TRL) appear to be one of the main mediators, based on the genetic and epidemiologic data. However, whether this is caused by direct effects of Triglycerides or other components of TRL remains uncertain. The cholesterol component of TRL remnants (Rem-C) has been proposed as a more pertinent mediator of the increased risk associated with high triglycerides. RECENT FINDINGS: Several long-term observational studies have shown a significant relationship between Rem-C and ASCVD events, compared with other triglyceride-related parameters. Recent trials have shown that lowering of triglyceride levels by various agents, including fibrates and omega-3 fatty acids, in statin-treated subjects, did not explain the reduction in ASCVD events. In a large clinical trial with pemafibrate, a highly selective PPAR-α agonist, in type 2 diabetes and elevated triglycerides, the reduction in triglycerides was accompanied by a significant increase in LDL-C and Apo-B levels, despite a reduction in Rem-C, and no effect on ASCVD events. SUMMARY: Elevated Rem-C as a risk determinant, with LDL-C at goal, requires additional studies in clinical trials. Standardization and accuracy of Rem-C assays (calculated versus direct method) is also needed.

Diabetes in ageing: pathways for developing the evidence base for clinical guidance.

Older adults with diabetes are heterogeneous in their medical, functional, and cognitive status, and require careful individualisation of their treatment regimens. However, in the absence of detailed information from clinical trials involving older people with varying characteristics, there is little evidence-based guidance, which is a notable limitation of current approaches to care. It is important to recognise that older people with diabetes might vary in their profiles according to age category, functional health, presence of frailty, and comorbidity profiles. In addition, all older adults with diabetes require an individualised approach to care, ranging from robust individuals to those residing in care homes with a short life expectancy, those requiring palliative care, or those requiring end-of-life management. In this Review, our multidisciplinary team of experts describes the current evidence in several important areas in geriatric diabetes, and outlines key research gaps and research questions in each of these areas with the aim to develop evidence-based recommendations to improve the outcomes of interest in older adults.

When to lower triglycerides?

PURPOSE OF REVIEW: Substantial risk of ASCVD events persists despite intensive statin therapy and other agents to lower LDL-C. The optimal way to address other elements of dyslipidemia, such as triglyceride-rich particles (TRL) and when to treat has remained unclear. RECENT FINDINGS: Several lines of evidence indicate that TRL are associated with atherogenesis, partly because of associated factors, such as cholesterol-enriched remnant particles, high LDL particle number, high apo-B, high apo-CIII, and others. High triglyceride is increasingly prevalent because of worsening of lifestyle factors, obesity, and diabetes. Trials with fibrates, and niacin to reduce residual dyslipidemia have not provided evidence of benefits after statin therapy, thus far. A recent trial with an omega 3 fatty acid (OM3FA), icosapent-ethyl (IPE), provided evidence for a 25% reduction in ASCVD events in statin-treated high-risk population. These results were unexplained by triglyceride reduction alone, and are likely related to unique biologic effects of IPE on atherosclerosis. Finally, in patients with very high triglycerides, lifestyle measures and several triglyceride-lowering agents are indicated, often in combination, to prevent episodes of pancreatitis. A novel Apo C-III inhibitor may provide additional benefit in such patients. SUMMARY: There is evidence for the benefits of IPE in preventing ASCVD events. A novel fibrate is in clinical trials.

Unusual responses to PCSK9 inhibitors in a clinical cohort utilizing a structured follow-up protocol.

OBJECTIVE: To characterize unusual responses to PCSK9 inhibitor (PCSK9i) therapy in a real-world setting, given their extremely low prevalence in clinical trials. METHODS: A retrospective study of patients seen in a structured academic PCSK9i clinic who had LDL-C measurements before and after initiation of PCSK9i (up to 12 months). Unusual response was defined as: (1) no response: no changes in LDL-C level at all time points; (2) delayed response: <30% LDL-C reduction by the third dose, but achieving this threshold at a later time; (3) reduced response: <30% LDL-C reduction at all time points; and (4) lost response: ≥30% LDL-C reduction by the third dose, but displaying <30% reduction at a later time. RESULTS: Of the 411 patients meeting inclusion criteria, 54 were initially classified as unusual responders. After excluding those not adherent to prescribed interventions, 31 patients (7.5%) were classified as true unusual responders. These included: 2 with no response, 12 with delayed response, 3 with reduced response, 6 with delayed or reduced response, 4 with lost response, and 4 with delayed and lost response. Response to PCSK9i therapy at all time points revealed higher on-treatment LDL-C values (94-100 vs. 47-51 â€‹mg/dL, p â€‹< â€‹0.001) and lower degree of percent reduction in LDL-C (23.3-34% vs. 61.1-64.5%, p â€‹< â€‹0.001) in the unusual versus usual responders. Lipoprotein (a) (Lp[a]) values were consistently higher in the unusual responders (81-92.5 vs. 28.5-52 â€‹mg/dL, p â€‹< â€‹0.01). Fold change in post-versus pre-treatment PCSK9 plasma results was similar between the two cohorts (p â€‹> â€‹0.05), suggesting that unusual responses were not due to insufficient plasma PCSK9 blockade. Multiple logistic regression analysis identified clinical FH (OR 2.9, 95% CI 1.27-7.24) and no ezetimibe therapy (OR 0.334, 95% CI 0.150-0.728) as factors related to true unusual response. CONCLUSIONS: Unusual responses to PCSK9i in a clinical cohort are more common than reported in clinical trials. Of the suspected unusual responders, nearly half were the result of adherence issues, and thus careful medication reconciliation should be the first step in diagnosing an unusual response.

Beyond Statins: Who and When to Prescribe?

PURPOSE OF REVIEW: Statins are the most evidence-based therapy to target LDL-C to reduce atherosclerotic events. Yet, many people are unable to achieve adequate reduction in this key atherogenic factor. Moreover, residual risk of cardiovascular events may persist even after "optimal" LDL-C due to elevations in triglyceride-rich lipoproteins. Therefore, additional therapies beyond statins are needed, particularly in patients with diabetes. RECENT FINDINGS: Clinical trials with ezetimibe and PCSK9 inhibitors have reported further reductions in cardiovascular events, beyond statins. The latter are particularly effective in lowering LDL-cholesterol and in reducing event rates. However, they are not effective in lowering triglycerides. Currently available fibrates and niacin have not proven effective in combination with statins in clinical trials, while the top line results of the REDUCE-IT trial with EPA, a pure omega-3 fatty acid, reporting 25% relative risk reduction in primary endpoints are of great interest. Recently approved agents have the promise to improve cardiovascular outcomes beyond statins. Many novel drugs in development have the potential to further improve prognosis.

Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management.

Despite the important role of high-intensity statins in reducing atherosclerotic cardiovascular disease events in secondary and primary prevention, substantial residual risk persists, particularly among high-risk patients with type 2 diabetes mellitus, metabolic syndrome, and obesity. Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non-high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies. Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were "optimally controlled" with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials.

AIMS: Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS: Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS: At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with alirocumab 150 (vs -1.0% with placebo), -46.4% with alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with alirocumab. CONCLUSION: Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

Current Consensus and Controversies in Guidelines for Lipid and Hypertension Management in Diabetes.

Despite major advances, many patients with diabetes are currently achieving suboptimal control of lipids and blood pressure. The new cholesterol guidelines by the ACC/AHA have reignited the emphasis on more intensive treatment with statins in the population at high risk of CVD, including those with diabetes. While these guidelines do not include specific lipid goals, several other guidelines have retained previously defined risk-based LDL-C and non-HDL-C goals. More recent data indicate potential benefits in CVD outcomes with non-statin therapy added to statin therapy. On-going long-term trials with PCSK-9 inhibitors may help answer the question of the benefits and safety of very low LDL-C. Regarding the blood pressure guidelines, there remains an inconsistency of evidence for targets to reduce CVD outcomes. The ACCORD trial weighted heavily in the recent meta-analyses, leading to currently recommended goal of <140/90 mmHg. Studies targeting blood pressure goals of <130 mmHg in younger patients with diabetes, including sub-populations of interest, may help solve the controversy. Until we have these data, perhaps it is time to shift our focus from a rigid blood pressure target to risk-based goals.

mHealth Intervention to Improve Diabetes Risk Behaviors in India: A Prospective, Parallel Group Cohort Study.

BACKGROUND: In low/middle income countries like India, diabetes is prevalent and health care access limited. Most adults have a mobile phone, creating potential for mHealth interventions to improve public health. To examine the feasibility and initial evidence of effectiveness of mDiabetes, a text messaging program to improve diabetes risk behaviors, a global nonprofit organization (Arogya World) implemented mDiabetes among one million Indian adults. OBJECTIVE: A prospective, parallel cohort design was applied to examine whether mDiabetes improved fruit, vegetable, and fat intakes and exercise. METHODS: Intervention participants were randomly selected from the one million Nokia subscribers who elected to opt in to mDiabetes. Control group participants were randomly selected from non-Nokia mobile phone subscribers. mDiabetes participants received 56 text messages in their choice of 12 languages over 6 months; control participants received no contact. Messages were designed to motivate improvement in diabetes risk behaviors and increase awareness about the causes and complications of diabetes. Participant health behaviors (exercise and fruit, vegetable, and fat intake) were assessed between 2012 and 2013 via telephone surveys by blinded assessors at baseline and 6 months later. Data were cleaned and analyzed in 2014 and 2015. RESULTS: 982 participants in the intervention group and 943 in the control group consented to take the phone survey at baselne. At the end of the 6-month period, 611 (62.22%) in the intervention and 632 (67.02%) in the control group completed the follow-up telephone survey. Participants receiving texts demonstrated greater improvement in a health behavior composite score over 6 months, compared with those who received no messages F(1, 1238) = 30.181, P<.001, 95% CI, 0.251-0.531. Fewer intervention participants demonstrated health behavior decline compared with controls. Improved fruit, vegetable, and fat consumption (P<.01) but not exercise were observed in those receiving messages, as compared with controls. CONCLUSIONS: A text messaging intervention was feasible and showed initial evidence of effectiveness in improving diabetes-related health behaviors, demonstrating the potential to facilitate population-level behavior change in a low/middle income country. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN): 12615000423516; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367946&isReview=true (Archived by WebCite at http://www.webcitation.org/6j5ptaJgF).

Statin-induced diabetes: incidence, mechanisms, and implications.

Persuasive data from many randomized controlled trials and large, long-term observational studies indicate a modestly increased risk for the emergence of new diabetes after statin initiation. Several meta-analyses of many statin trials as well as longitudinal population-based studies suggest that the risk factors for diabetes in statin-treated persons include underlying risk for diabetes at baseline (specifically features of metabolic syndrome), the intensity of statin therapy, certain genetic traits independent of diabetes risk, and adherence to lifestyle factors. Limited data suggest statins modestly worsen hyperglycemia and A1c levels in those with pre-existing diabetes or glucose intolerance. The precise mechanism(s) of diabetogenesis with statin therapy are unclear, but impaired insulin sensitivity and compromised ß cell function via enhanced intracellular cholesterol uptake due to inhibition of intracellular cholesterol synthesis by statins, as well as other mechanisms, may be involved. Furthermore, while statins are known to have anti-inflammatory effects, it is hypothesized that, under dysmetabolic conditions, they might have pro-inflammatory effects via induction of certain inflammasomes. This concept requires further elucidation in the human. Finally, it is clear that the risk-benefit ratio for cardiovascular disease events is strongly in favor of statin therapy in those at risk, despite the emergence of new diabetes. Adherence to lifestyle regimen is critical in the prevention of new diabetes on statins.

Antihyperglycemic drugs and cardiovascular outcomes in type 2 diabetes.

In patients with diabetes, a complex and controversial relationship exists between intensive glycemic control and cardiovascular (CV) outcomes. Although the value of glucose-lowering agents in preventing microvascular complications associated with diabetes has been established, along with reductions in ischemic coronary events, active treatment in one major glycemic-control trial resulted in an unexplained increase in CV-associated mortality and total deaths compared with controls. Questions of CV safety with specific glucose-lowering agents along with the mechanisms underlying their effects on CV events have not been fully answered, underscoring the need for additional well-designed, long-term randomized controlled trials (RCTs) to prove their CV safety vs an active comparator. The CV benefits of one sodium-glucose cotransporter-2 inhibitor reported in an RCT await confirmation in ongoing trials.