Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

ABCD
: Appropriate Blood pressure Control in Diabetes
ABI
: ankle–brachial index
ABPM
: ambulatory blood pressure monitoring
ACCESS
: Acute Candesartan Cilexetil Therapy in Stroke Survival
ACCOMPLISH
: Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension
ACCORD
: Action to Control Cardiovascular Risk in Diabetes
ACE
: angiotensin-converting enzyme
ACTIVE I
: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events
ADVANCE
: Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
AHEAD
: Action for HEAlth in Diabetes
ALLHAT
: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack
ALTITUDE
: ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints
ANTIPAF
: ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation
APOLLO
: A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People
ARB
: angiotensin receptor blocker
ARIC
: Atherosclerosis Risk In Communities
ARR
: aldosterone renin ratio
ASCOT
: Anglo-Scandinavian Cardiac Outcomes Trial
ASCOT-LLA
: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
ASTRAL
: Angioplasty and STenting for Renal Artery Lesions
A-V
: atrioventricular
BB
: beta-blocker
BMI
: body mass index
BP
: blood pressure
BSA
: body surface area
CA
: calcium antagonist
CABG
: coronary artery bypass graft
CAPPP
: CAPtopril Prevention Project
CAPRAF
: CAndesartan in the Prevention of Relapsing Atrial Fibrillation
CHD
: coronary heart disease
CHHIPS
: Controlling Hypertension and Hypertension Immediately Post-Stroke
CKD
: chronic kidney disease
CKD-EPI
: Chronic Kidney Disease—EPIdemiology collaboration
CONVINCE
: Controlled ONset Verapamil INvestigation of CV Endpoints
CT
: computed tomography
CV
: cardiovascular
CVD
: cardiovascular disease
D
: diuretic
DASH
: Dietary Approaches to Stop Hypertension
DBP
: diastolic blood pressure
DCCT
: Diabetes Control and Complications Study
DIRECT
: DIabetic REtinopathy Candesartan Trials
DM
: diabetes mellitus
DPP-4
: dipeptidyl peptidase 4
EAS
: European Atherosclerosis Society
EASD
: European Association for the Study of Diabetes
ECG
: electrocardiogram
EF
: ejection fraction
eGFR
: estimated glomerular filtration rate
ELSA
: European Lacidipine Study on Atherosclerosis
ESC
: European Society of Cardiology
ESH
: European Society of Hypertension
ESRD
: end-stage renal disease
EXPLOR
: Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination
FDA
: U.S. Food and Drug Administration
FEVER
: Felodipine EVent Reduction study
GISSI-AF
: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation
HbA1c
: glycated haemoglobin
HBPM
: home blood pressure monitoring
HOPE
: Heart Outcomes Prevention Evaluation
HOT
: Hypertension Optimal Treatment
HRT
: hormone replacement therapy
HT
: hypertension
HYVET
: HYpertension in the Very Elderly Trial
IMT
: intima-media thickness
I-PRESERVE
: Irbesartan in Heart Failure with Preserved Systolic Function
INTERHEART
: Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries
INVEST
: INternational VErapamil SR/T Trandolapril
ISH
: Isolated systolic hypertension
JNC
: Joint National Committee
JUPITER
: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
LAVi
: left atrial volume index
LIFE
: Losartan Intervention For Endpoint Reduction in Hypertensives
LV
: left ventricle/left ventricular
LVH
: left ventricular hypertrophy
LVM
: left ventricular mass
MDRD
: Modification of Diet in Renal Disease
MRFIT
: Multiple Risk Factor Intervention Trial
MRI
: magnetic resonance imaging
NORDIL
: The Nordic Diltiazem Intervention study
OC
: oral contraceptive
OD
: organ damage
ONTARGET
: ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial
PAD
: peripheral artery disease
PATHS
: Prevention And Treatment of Hypertension Study
PCI
: percutaneous coronary intervention
PPAR
: peroxisome proliferator-activated receptor
PREVEND
: Prevention of REnal and Vascular ENdstage Disease
PROFESS
: Prevention Regimen for Effectively Avoiding Secondary Strokes
PROGRESS
: Perindopril Protection Against Recurrent Stroke Study
PWV
: pulse wave velocity
QALY
: Quality adjusted life years
RAA
: renin-angiotensin-aldosterone
RAS
: renin-angiotensin system
RCT
: randomized controlled trials
RF
: risk factor
ROADMAP
: Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention
SBP
: systolic blood pressure
SCAST
: Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke
SCOPE
: Study on COgnition and Prognosis in the Elderly
SCORE
: Systematic COronary Risk Evaluation
SHEP
: Systolic Hypertension in the Elderly Program
STOP
: Swedish Trials in Old Patients with Hypertension
STOP-2
: The second Swedish Trial in Old Patients with Hypertension
SYSTCHINA
: SYSTolic Hypertension in the Elderly: Chinese trial
SYSTEUR
: SYSTolic Hypertension in Europe
TIA
: transient ischaemic attack
TOHP
: Trials Of Hypertension Prevention
TRANSCEND
: Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease
UKPDS
: United Kingdom Prospective Diabetes Study
VADT
: Veterans' Affairs Diabetes Trial
VALUE
: Valsartan Antihypertensive Long-term Use Evaluation
WHO
: World Health Organization

### 1.1 Principles

The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

/pdf/2013-esh-esc-guidelines-for-the-management-of-arterial-4ydvs5ifsx.pdf

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Role of Insulin Resistance in Human Disease

Aims/hypothesis. Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with Type II (non-insulin-dependent) diabetes is limited and controversial. Therefore, we carried out a prospective study to examine the predictive value of fasting plasma insulin and “hyperinsulinaemia cluster” with regard to the risk of CHD mortality.¶Methods. At baseline risk factors for CHD were determined in 902 patients aged 45 to 64 years with Type II diabetes not treated by insulin (499 men and 403 women). These patients were followed up to 7 years for CHD mortality.¶Results. Coronary heart disease mortality (16.2 % in men, 9.2 % in women) increased significantly in men with increasing plasma insulin tertiles (p = 0.006) and in both sexes combined (p = 0.010) but not in women (p = 0.090). The predictive value of hyperinsulinaemia with regard to death from CHD was independent of conventional cardiovascular risk factors but not of risk factors clustering with hyperinsulinaemia. By applying factor analysis and principal component analysis we showed that “hyperinsulinaemia cluster” (a factor having high positive loadings for body mass index, triglycerides and insulin; and a high negative loading for high-density lipoprotein cholesterol) was predictive of death from CHD in patients with Type II diabetes (hazard ratio with 95 % confidence intervals 1.43 (1.18, 1.73), p < 0.001).¶Conclusion/interpretation. Our results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in patients with Type II diabetes not treated with insulin. [Diabetologia (2000) 43: 148–155]

/pdf/cardiovascular-risk-factors-clustering-with-endogenous-1zp3mrto6u.pdf

Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with Type II diabetes.

BACKGROUND. Inflammatory process has been found to play an important role in the pathogenesis of coronary heart disease (CHD) and in the prognosis of CHD patients. AIM. The aim of this study was to investigate the prognostic value of C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and tumour necrosis factor-α (TNF-α) in patients with unstable angina pectoris (UAP), including factor analysis to assess their joint effects.METHODS. The study comprised 263 consecutive patients (159 men, 104 women; median age 68 years) with UAP. Blood samples for the acute-phase protein and cytokine determinations were drawn on admission.RESULTS. Coronary mortality during the median follow-up time of 17 months was 6-fold higher in the highest tertile for CRP and IL-6 and 3.5-fold higher in the highest tertile for fibrinogen and TNF-α than in the respective combined lower tertiles. Factor analysis produced two underlying factors, ie the ‘inflammation’ factor, including CRP, fibrinogen and IL-6, and the ‘injury’ factor,...

https://www.tandfonline.com/doi/pdf/10.3109/07853890109002058

C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-α in the prognostic classification of unstable angina pectoris

OBJECTIVE To examine the predictors of lower extremity amputation in patients with NIDDM.

RESEARCH DESIGN AND METHODS At baseline, risk factors for amputation were determined in 1,044 NIDDM patients (571 men, 473 women) aged 45 to 64 years. These patients were followed up to 7 years with respect to amputation.

RESULTS The incidence of amputation was 5.6% in men and 5.3% in women. High fasting plasma glucose at baseline examination and the duration of diabetes were associated with a twofold risk for amputation. Similarly, glycemic control measured at baseline by HbA1 was an important predictor of amputation. There was a dose-response relationship between plasma glucose or HbA1 and the risk for amputation. The effect of hyperglycemia on the risk of amputation was seen clearly even after the adjustment for other cardiovascular risk factors. Signs of peripheral neuropathy and bilateral absence of Achilles tendon reflexes and vibration sense were important predictors for amputation. Furthermore, absent peripheral artery pulses and femoral artery bruit on auscultation predicted amputation.

CONCLUSIONS Our 7-year follow-up study gives strong evidence that poor glycemic control is an important predictor of amputation in patients with NIDDM in addition to clinically detectable peripheral arterial disease and peripheral neuropathy.

Risk Factors Predicting Lower Extremity Amputations in Patients With NIDDM

Aims To assess the predictive value of fasting and 2-h glucose after a 75g glucose load, with regard to incidence of coronary heart disease and cardiovascular mortality.

Methods and Results 6766 subjects from five Finnish cohorts aged 30–89 years were followed up for 7–10 years. Hazards ratios associated with increasing glucose concentrations were homogeneous over studies. Multivariate Cox regression analyses showed that the hazards ratio for one standard deviation increase in 2-h glucose after logarithmic transformation was 1·17 (95% CI 1·05–1·30) for coronary heart disease incidence and 1·22 (1·09–1·37) for cardiovascular mortality. For fasting glucose, they were 1·05 (0·94–1·17) and 1·13 (1·01–1·25), respectively. Inclusion of 2-h glucose in the model based on fasting glucose significantly improved the prediction ( P 0·10 for both events).

Conclusion In subjects without a prior history of diabetes the association of 2-h glucose with coronary heart disease incidence and cardiovascular morality is graded and independent. The results of our study indicate that 2-h glucose is superior to fasting glucose in assessing the risk of future cardiovascular disease events.

/pdf/two-hour-glucose-is-a-better-risk-predictor-for-incident-3g2fgk1rlq.pdf

Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose.

AIMS/HYPOTHESIS: Risk scores have been developed to predict cardiovascular or coronary risk, and while most have included diabetes as a risk factor, none have included lower glucose concentrations, either at fasting or following a 2-h oral glucose tolerance test. This article develops 5- and 10-year risk scores for cardiovascular mortality that include glucose concentrations as well as known diabetes status. METHODS: Data is from the DECODE cohort: 16,506 men and 8,907 women from 14 European studies. The risk factors studied were as follows: age, fasting and 2-h glucose (including cases of known diabetes), fasting glucose alone (including cases of known diabetes), cholesterol, smoking status, systolic blood pressure and BMI. For an absolute risk score the 1995 country- and sex-specific cardiovascular death rates were used. RESULTS: In men, for both 5- and 10-year cardiovascular mortality, after adjusting for age and study centre, all studied risk factors, except BMI, were significantly associated with cardiovascular mortality (p<0.05). These results were unchanged in multivariate models with all factors included. In women, after adjusting for age and centre, glucose categories, systolic blood pressure and BMI were predictive of 5-year cardiovascular mortality. With all factors in the model, only age and glucose categories were predictive. In terms of 10-year cardiovascular mortality, smoking status and blood pressures were also predictive in the women. For men and women, the same scores were used for the risk factors, except for age and glucose categories where the hazard ratios differed significantly. CONCLUSIONS/INTERPRETATION: Including glucose concentrations as well as diabetic status provides quantitative information on cardiovascular risk prediction.

/pdf/prediction-of-the-risk-of-cardiovascular-mortality-using-a-1t63svbe5j.pdf

Kalevi Pyörälä

Papers

Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with Type II diabetes.

C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-α in the prognostic classification of unstable angina pectoris

Risk Factors Predicting Lower Extremity Amputations in Patients With NIDDM

Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose.

Prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor. The DECODE Study.