Machine Learning Applied to Cholesterol-Lowering Pharmacotherapy: Proof-of-Concept in High-Risk Patients Treated in Primary Care.

Objectives: Machine learning has potential to improve the management of lipid disorders. We explored the utility of machine learning in high-risk patients in primary care receiving cholesterol-lowering medications. Methods: Machine learning algorithms were created based on lipid management guidelines for England [National Institute for Health and Care Excellence (NICE) CG181] to reproduce the guidance with >95% accuracy. Natural language processing and therapy identification algorithms were applied to anonymized electronic records from six South London primary care general practices to extract medication information from free text fields. Results: Among a total of 48,226 adult patients, a subset of 5630 (mean ± standard deviation, age = 67 ± 13 years; male:female = 55:45) with a history of lipid-lowering therapy were identified. Additional major cardiometabolic comorbidities included type 2 diabetes in 13% (n = 724) and hypertension in 32% (n = 1791); all three risk factors were present in a further 28% (n = 1552). Of the 5630 patients, 4290 (76%) and 1349 (24%) were in primary and secondary cardiovascular disease prevention cohorts, respectively. Statin monotherapy was the most common current medication (82%, n = 4632). For patients receiving statin monotherapy, 71% (n = 3269) were on high-intensity therapy aligned with NICE guidance with rates being similar for the primary and secondary prevention cohorts. In the combined cohort, only 46% of patients who had been prescribed lipid-lowering therapy in the previous 12 months achieved the NICE treatment goal of >40% reduction in non-high-density lipoprotein cholesterol from baseline pretreatment levels. Based on the most recent data entry for patients not at goal the neural network recommended either increasing the dose of statin, adding complementary cholesterol-lowering medication, or obtaining an expert lipid opinion. Conclusions: Machine learning can be of value in (a) quantifying suboptimal lipid-lowering prescribing patterns, (b) identifying high-risk patients who could benefit from more intensive therapy, and (c) suggesting evidence-based therapeutic options.

Functional dilator capacity is independently associated with insulin sensitivity and age in central obesity and is not improved by high dose statin treatment.

OBJECTIVE: To test the hypothesis that: (i) functional microvascular dilator capacity is independently associated with insulin sensitivity and age in individuals with central adiposity at risk of cardiovascular disease (CVD); and (ii) functional microvascular dilator capacity is improved by high dose statin treatment. METHODS: Functional dilator capacity (measured as change in laser Doppler blood flux from baseline during post occlusive reactive hyperemia [peak flux%resting flux; PF%RF] and flowmotion (power spectral density [PSD] analysis)) were assessed in 40 people with central adiposity and one or more other CVD risk factors. Measurements were made at rest and during acute hyperinsulinaemia before and six months after high dose atorvastatin (40 mg daily) or placebo. RESULTS: Insulin-induced change in PF%RF was independently associated with insulin sensitivity (M/I) (r = 0.46 p = 0.02) and age (r = -0.46 p = 0.02), which together explained almost half of the variance in PF%RF (adjusted r² = 0.37, p = 0.008). Whilst atorvastatin decreased LDL cholesterol by 51% (p < 0.001), PF%RF and flowmotion remained unchanged. CONCLUSIONS: Insulin sensitivity and age are independently associated with an insulin-induced change in functional microvascular dilator capacity in individuals with central adiposity at risk of CVD. Dilator capacity is not improved by six months high dose statin treatment.

Evolution of Type 2 Diabetes Management from a Glucocentric Approach to Cardio-Renal Risk Reduction: The New Paradigm of Care.

For many years, clinical studies could not show that lowering glucose in patients with type 2 diabetes leads to better macrovascular outcomes. In the past few years, new data have shown that treatment with two classes of dugs developed as "glucose-lowering agents," SGLT2 inhibitors and GLP-1 receptor agonists, can reduce macrovascular and renal complications. These studies have prompted debate about the main aim of type 2 diabetes management. In this review, three eras of diabetes management are described according to the treatment recommendations, such as the ADA/EASD consensus, moving from a pure glucocentric view into the present cardio-renal outcome-oriented approach, this has been endorsed by major diabetes and cardiology societies. While in the first era normalizing HbA1c was the only focus (e.g., UK Prospective Diabetes Study), failing to show a reduction in cardiovascular morbidity and mortality, further studies analyzing the pros and cons of intensified control such as ACCORD, VADT, ADVANCE recognized that treatment intensification was associated with weight gain and hypoglycemia, thereby potentially reducing the benefits of glycemic control. Therefore, the focus in the second area was on controlling HbA1c without these unwanted effects. The consistent beneficial results of several cardiovascular outcome trials with SGLT2 inhibitors and GLP-1 receptor agonists showing significantly improved cardio-renal outcomes, induced a paradigm shift: a change from (only) control of HbA1c to an organ-protective approach with the main focus now on cardio-renal risk; this is now considered as the third era. Recent data indicating beneficial effects of glucose-lowering agents in particular SGLT2 inhibitors even in subjects without diabetes, improving hospitalization for heart failure and renal outcomes might reveal another new era, which could then be considered a fourth era. While current international guidelines call for this paradigm shift, registry data show that we are still far from translating this objective into real-world practice.

Vascular disease in the metabolic syndrome: do we need to target the microcirculation to treat large vessel disease?

The metabolic syndrome of vascular risk is threatening large numbers of ever-younger people. To date, the syndrome has been chiefly viewed as a potential risk marker that confers a heightened probability of developing type 2 diabetes and occlusive atherothrombotic disease of large- and medium-sized arteries. Accumulating evidence suggests that the components of the metabolic syndrome may also adversely affect the microvasculature through several inter-related mechanisms. These include the following observations: classic risk factors for macrovascular disease such as high blood pressure and dyslipidaemia also accelerate microvascular complications of diabetes, lesser disturbances of glucose metabolism (i.e. impaired glucose tolerance) may be associated with some forms of microvascular dysfunction, non-glucose intermediary metabolites may promote renovascular hypertension thereby damaging the microvasculature, and insulin resistance appears to be directly associated with microvascular dysfunction. In turn, microvascular complications such as nephropathy and autonomic neuropathy may promote the development and progression of atherosclerosis. We argue that the vascular implications of the metabolic syndrome should be broadened to include the microvasculature. The hypothesis that vascular events can be prevented, or at least deferred, through earlier therapeutic intervention in pre-diabetic subjects with glucose intolerance is amenable to testing in clinical trials.

New drugs for type 2 diabetes mellitus: what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.

Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease.

OBJECTIVE: To test the hypothesis that polycystic ovary syndrome (PCOS) is associated with an increased risk of atherosclerotic cardiovascular disease (CVD) in older postmenopausal women. DESIGN: Cross-sectional study of community-dwelling non-estrogen-using postmenopausal-white women (N=713; mean+/-SD age, 73.8+/-7.9 years; mean body mass index, 24.0+/-3.5 kg/m) participating in the Rancho Bernardo Study. A putative PCOS phenotype was defined as the presence of three or more of the following features: (1) recalled history of irregular menses, (2) symptomatic premenopausal hyperandrogenism or biochemical evidence of current biochemical hyperandrogenism, (3) history of infertility or miscarriage, (4) central obesity, or (5) insulin resistance. Atherosclerotic CVD was determined from clinical history, electrocardiography, and structured interviews using validated techniques. The analysis was stratified by diabetes status, ascertained from medical history or 75-g oral glucose tolerance tests. RESULTS: The PCOS phenotype was present in 9.3% of the entire cohort and 5.8% of nondiabetic women. The prevalence of CVD was similar between women with the phenotype and unaffected women (27.3% vs 24.4%). Among women with intact ovaries and no diabetes, there was a stepwise graded association between an increasing number of features of the PCOS phenotype (ie, none to three or more) and prevalent CVD (P=0.02). A similar association was also observed for coronary heart disease alone (P=0.03). CONCLUSIONS: Among nondiabetic postmenopausal women with intact ovaries, prevalent atherosclerotic CVD is associated with features of a putative PCOS phenotype. This finding supports the thesis that PCOS increases the risk of atherosclerotic CVD after menopause.

Glucose: archetypal biomarker in diabetes diagnosis, clinical management and research.

The clinical utility of diabetes biomarkers can be considered in terms of diagnosis, management and prediction of long-term vascular complications. Glucose satisfies all of these requirements. Thresholds of hyperglycemia diagnostic of diabetes reflect inflections that confer a risk of developing long-term microvascular complications. Degrees of hyperglycemia (impaired fasting glucose, impaired glucose tolerance) that lie below the diagnostic threshold for diabetes identify individuals at risk of progression to diabetes and/or development of atherothrombotic cardiovascular disease. Self-measured glucose levels usefully complement hemoglobin A1c levels to guide daily management decisions. Continuous glucose monitoring provides detailed real-time data that is of value in clinical decision making, assessing response to new diabetes drugs and the development of closed-loop artificial pancreas technology.

Oral antidiabetic agents: current role in type 2 diabetes mellitus.

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.