Renal protection: What have we learnt from ADVANCE about kidney disease in type 2 diabetes?

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two-by-two factorial design. In the blood pressure-lowering arm, patients were treated using a fixed combination of the ACE-inhibitor, perindopril, and the thiazide-like diuretic, indapamide, or placebo, whereas in the glucose-lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose-lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end-points were major macro- and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow-up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment.

A European, multicentre, retrospective, non-interventional study (EU-TREAT) of the effectiveness of insulin degludec after switching basal insulin in a population with type 1 or type 2 diabetes.

AIMS: To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care. MATERIALS AND METHODS: This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI]. RESULTS: T1DM (n = 1717): HbA1c decreased by -2.2 [-2.6; -2.0] mmol/mol (-0.20 [-0.24; -0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by -4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by -5.6 [-6.3; -4.7] mmol/mol (-0.51 [-0.58; -0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non-severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period. Total daily insulin dose decreased by -2.48 [-4.24; -0.71] U (-3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months. CONCLUSIONS: This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice.

The Danish cancer pathway for patients with serious non-specific symptoms and signs of cancer-a cross-sectional study of patient characteristics and cancer probability.

BACKGROUND: A Danish cancer pathway has been implemented for patients with serious non-specific symptoms and signs of cancer (NSSC-CPP). The initiative is one of several to improve the long diagnostic interval and the poor survival of Danish cancer patients. However, little is known about the patients investigated under this pathway. We aim to describe the characteristics of patients referred from general practice to the NSSC-CPP and to estimate the cancer probability and distribution in this population. METHODS: A cross-sectional study was performed, including all patients referred to the NSSC-CPP at the hospitals in Aarhus or Silkeborg in the Central Denmark Region between March 2012 and March 2013. Data were based on a questionnaire completed by the patient's general practitioner (GP) combined with nationwide registers. Cancer probability was the percentage of new cancers per investigated patient. Associations between patient characteristics and cancer diagnosis were estimated with prevalence rate ratios (PRRs) from a generalised linear model. RESULTS: The mean age of all 1278 included patients was 65.9 years, and 47.5 % were men. In total, 16.2 % of all patients had a cancer diagnosis after six months; the most common types were lung cancer (17.9 %), colorectal cancer (12.6 %), hematopoietic tissue cancer (10.1 %) and pancreatic cancer (9.2 %). All patients in combination had more than 80 different symptoms and 51 different clinical findings at referral. Most symptoms were non-specific and vague; weight loss and fatigue were present in more than half of all cases. The three most common clinical findings were 'affected general condition' (35.8 %), 'GP's gut feeling' (22.5 %) and 'findings from the abdomen' (13.0 %). A strong association was found between GP-estimated cancer risk at referral and probability of cancer. CONCLUSIONS: In total, 16.2 % of the patients referred through the NSSC-CPP had cancer. They constituted a heterogeneous group with many different symptoms and clinical findings. The GP's gut feeling was a common reason for referral which proved to be a strong predictor of cancer. The GP's overall estimation of the patient's risk of cancer at referral was associated with the probability of finding cancer.

Morning blood pressure surge and target organ damage in newly diagnosed type 2 diabetic patients: a cross sectional study.

BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease. METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE). RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03). CONCLUSION: MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.

Reproducibility of pulse wave analysis and pulse wave velocity in patients with type 2 diabetes.

AIMS: Patients with type 2 diabetes have increased arterial stiffness and a high incidence of cardiovascular disease compared with non-diabetics. Arterial stiffness and central waveforms can be assessed by carotid-femoral pulse wave velocity (PWV) and pulse wave analysis (PWA) using the SphygmoCor device. These methods can potentially improve cardiovascular risk stratification in the future. However, a prerequisite is acceptable reproducibility. The objective of this study was to assess the intra- and inter-observer reproducibility of PWV and PWA indices in patients with type 2 diabetes using the SphygmoCor device. METHODS: Two trained observers (A and B) each undertook two PWA and two carotid-femoral PWV recordings in random order in 20 patients with type 2 diabetes under standardized conditions on the right side of the patients. Observer A also made double recordings on the left side. The mean of the two recordings was used for inter-observer comparison. Data were analyzed by Bland-Altman plots. RESULTS: The mean intra-observer differences (± 2SD) on the right side for observer A and B, respectively, were 0.0 ± 2.8 mmHg and 0.3 ± 3.2 mmHg (aortic systolic blood pressue (BP)), 0.0 ± 1.2 mmHg and 0.1 ± 1.0 mmHg (aortic diastolic BP), - 1.1 ± 3.2% and 1.1 ± 9.6% (central augmentation index (Aix)), - 1.6 ± 6.6% and 0.1 ± 9.0% (Aix normalized to heart rate 75 beats/min (Aix@HR75)) and 0.1 ± 1.8 m/s and 0.0 ± 1.6 m/s (PWV). The mean inter-observer differences (± 2SD) were - 2.6 ± 13.0 mmHg (aortic systolic BP), - 2.1 ± 7.4 mmHg (aortic diastolic BP), - 0.8 ± 8.4% (Aix), - 1.5 ± 7.4% (Aix@HR75) and - 0.3 ± 1.6 m/s (PWV). Left-vs-right comparison showed comparable results (observer A). CONCLUSIONS: PWA and PWV assessed with the SphygmoCor device are characterized by good reproducibility in patients with type 2 diabetes.

Invasive aortic pulse pressure is not superior to cuff pulse pressure in cardiovascular risk prediction.

OBJECTIVE: Aortic pulse pressure (PP) represents the hemodynamic cardiac and cerebral burden more directly than cuff PP. The objective of this study was to investigate whether invasively measured aortic PP confers additional prognostic value beyond cuff PP for cardiovascular events and death. With increasing age, cuff PP progressively underestimates aortic PP. Whether the prognostic association between cuff PP and outcomes is age-dependent remains to be elucidated. METHODS: Cuff PP and invasively measured aortic PP were recorded in 21 908 patients (mean age 63 years, 58% men, 14% with diabetes) with stable angina pectoris undergoing elective coronary angiography during January 2001--December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination was assessed using Harrell's C-index. RESULTS: During a median follow-up period of 3.7 years (range 0.1-10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both cuff and aortic PP were associated with stroke, myocardial infarction, and death in crude analyses. However, only cuff PP remained associated with stroke (hazard ratio per 10 mmHg, 1.06 (95% confidence interval (CI) 1.01--1.12)] and myocardial infarction [hazard ratio per 10 mmHg 1.05 (95% CI 1.01--1.11)] in multivariate Cox models. Both cuff and aortic PP lost significance as predictors of death in multivariate models. Age did not modify the prognostic association between cuff PP and stroke, myocardial infarction, and death. CONCLUSION: Invasively measured aortic PP did not add prognostic information about cardiovascular outcomes and death beyond cuff PP in patients with stable angina pectoris.

Statin Therapy and Risk of Polyneuropathy in Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: Statins may reduce the risk of diabetic polyneuropathy (DPN) as a result of lipid-lowering and anti-inflammatory effects, but statins have also been associated with neurotoxicity. We examined whether statin therapy affects the risk of DPN. RESEARCH DESIGN AND METHODS: We identified all Danish patients with incident type 2 diabetes during 2002-2016. New users initiated statins between 180 days before and 180 days after their first diabetes record, while prevalent users had initiated statins before that period. Patients were followed for incident DPN using validated hospital diagnosis codes, starting 180 days after their first diabetes record. Cox proportional hazard analysis was used to compute adjusted hazard ratios (aHRs) for DPN. RESULTS: The study cohort comprised 59,255 (23%) new users, 75,528 (29%) prevalent users, and 124,842 (48%) nonusers; median follow-up time was 6.2 years (interquartile range 3.4-9.6). The incidence rate of DPN events per 1,000 person-years was similar in new users (4.0 [95% CI 3.8-4.2]), prevalent users (3.8 [3.6-3.9]), and nonusers (3.8 [3.7-4.0]). The aHR for DPN was 1.05 (0.98-1.11) in new users and 0.97 (0.91-1.04) in prevalent users compared with statin nonusers. New users had a slightly increased DPN risk during the first year (1.31 [1.12-1.53]), which vanished after >2 years of follow-up. Findings were similar in on-treatment and propensity score-matched analyses and with additional adjustment for pretreatment blood lipid levels. CONCLUSIONS: Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.

Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.

OBJECTIVE: To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). RESULTS: Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS: Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.

Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies.

Introduction: Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes and is the most common cause of proteinuric and non-proteinuric forms of end-stage renal disease (ESRD). Control of risk factors such as blood glucose and blood pressure is not always achievable or effective. Significant research efforts have attempted to understand the pathophysiology of DKD and develop new therapies. Areas covered: We review DKD pathophysiology in the context of existing and emerging therapies that affect hemodynamic and metabolic pathways. Renin-angiotensin system (RAS) inhibition has become standard care. Recent evidence for renoprotective activity of SGLT2 inhibitors and GLP-1 agonists is an exciting step forward while endothelin receptor blockade shows promise. Multiple metabolic pathways of DKD have been evaluated with varying success; including mitochondrial function, reactive oxygen species, NADPH oxidase (NOX), transcription factors (NF-B and Nrf2), advanced glycation, protein kinase C (PKC), aldose reductase, JAK-STAT, autophagy, apoptosis-signaling kinase 1 (ASK1), fibrosis and epigenetics. Expert opinion: There have been major advances in the understanding and treatment of DKD. SGLT2i and GLP-1 agonists have demonstrated renoprotection, with novel therapies under evaluation. Addressing the interaction between hemodynamic and metabolic pathways may help achieve prevention, attenuation or even reversal of DKD.

Switching "Real-World" Diabetes Patients to Degludec from Other Basal Insulins Provides Different Clinical Benefits According to Their Baseline Glycemic Control.

INTRODUCTION: The stable, ultra-long duration of action of insulin degludec (degludec) minimizes fluctuations in glucose-lowering activity over the daily (24-h) dosing period, and comparative studies with other basal insulins suggest that these properties translate into a lower risk of hypoglycemia at equivalent levels of glycemic control. Results from the real-world European multicenter, retrospective chart review study of 2550 patients with type 1 and type 2 diabetes (T1D and T2D) in routine clinical care EU-TREAT (NCT02662114) showed that patients benefited from improved glycemic control and significantly reduced rates of hypoglycemia following a switch to degludec. METHODS: In this post hoc analysis, EU-TREAT patients were stratified into good (≤ 7.5% HbA1c), intermediate (> 7.5 to ≤ 8.5% HbA1c), and poor (> 8.5% HbA1c) glycemic control at baseline to investigate the possibility of differential benefits, either improved control or reduced risk of hypoglycemia, whichever the need. Changes in HbA1c, overall hypoglycemia, and total insulin dose from baseline to 6 and 12 months follow-up were assessed for each group. RESULTS: For both T1D and T2D patients, those in good initial control experienced significant reductions in rates of hypoglycemia and total insulin dose following the switch, without compromising control. Those in poor initial control achieved significant improvements in HbA1c with no change in rates of hypoglycemia or total insulin dose. CONCLUSION: This analysis expands the findings of EU-TREAT by showing differential changes in the clinical endpoints depending on particular need. It introduces the possibility that the differential benefits of degludec could address two of the renowned clinical challenges faced when treating diabetes: improving glycemic control for optimal management of T1D and titrating insulin dose in T2D, both without fear of increased hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02662114. FUNDING: Novo Nordisk A/S.

Retinal vessel reactivity is not attenuated in patients with type 2 diabetes compared with matched controls and is associated with peripheral endothelial function in controls.

BACKGROUND AND AIMS: Attenuated retinal vasoreactivity in patients with type 2 diabetes preceding diabetic retinopathy development has been proposed to reflect local endothelial dysfunction. Whether retinal vessel reactivity is associated with peripheral endothelial dysfunction and large artery stiffness in patients with type 2 diabetes remains to be elucidated. METHODS: Twenty patients with type 2 diabetes without retinopathy and 20 sex- and age matched controls (diabetes duration: 9.9 years (range 6.0;12.4), 40% male, age: 66.5 ±â€¯7.3 (diabetes) and 65.2 ±â€¯7.6 years (controls)) were included. Endothelial function was assessed using EndoPAT. Arterial stiffness was assessed by carotid-femoral pulse wave velocity using the SphygmoCor. Retinal blood supply regulation was examined by retinal arteriolar diameter change during 1) isometric exercise (hand-weight lifting), 2) exposure to flickering lights, and 3) a combined stimulus of 1) + 2) using the Dynamic Vessel Analyzer. RESULTS: No significant differences were observed in retinal vessel reactivity in T2DM patients compared to controls. Endothelial function was associated with mean arteriolar diameter change during only the combination intervention, (Beta = 0.033 [0.0013;0.064], p = 0.042) in the overall population of patients and controls. When groups were analyzed separately, the associations was statistically significant only in controls. However, formal test for interaction was not statistically significant, p = 0.40. No association was observed between pulse wave velocity and retinal arteriolar %-diameter change in patients or controls. CONCLUSION: Peripheral endothelial function was associated with retinal arteriolar diameter change in the combined sample. The association seemed to be driven primarily by the controls. Our findings indicate that peripheral endothelial function is reflective of endothelial function in the retina mainly in subjects without T2DM, whereas an association in T2DM without retinopathy was not observed. Further studies are needed in T2DM patients with more advanced retinopathy.

Pulse pressure lowering effect of dual blockade with candesartan and lisinopril vs. high-dose ACE inhibition in hypertensive type 2 diabetic subjects: a CALM II study post-hoc analysis.

BACKGROUND: Elevated pulse pressure (PP) is strongly associated with micro- and macrovascular complications in type 2 diabetic patients. We examined the effect of 12 months of dual blockade with candesartan and lisinopril vs. high-dose lisinopril monotherapy on ambulatory PP in hypertensive type 2 diabetic patients from the CALM (Candesartan and Lisinopril Microalbuminuria Trial) II study. METHODS: The CALM II study was a 12-month prospective, randomized, parallel-group, double-masked study that included 75 type 1 and type 2 diabetic subjects with hypertension. Participants were randomized for treatment with either high-dose lisinopril (40 mg once daily (o.d.)) or for dual blockade treatment with candesartan (16 mg o.d.) and lisinopril (20 mg o.d.). In this article, we present data from the post-hoc subgroup of 51 type 2 diabetic subjects who completed the full 12-month study period with successful ambulatory blood pressure (BP) measurements at both baseline and follow-up visits. RESULTS: Baseline 24-h BP values were similar in the two groups (24-h systolic BP (SBP) 130 +/- 12 vs. 127 +/- 9, 24-h diastolic BP (DBP) 77 +/- 8 vs. 74 +/- 7, and 24-h PP 53 +/- 8 vs. 53 +/- 7 mm Hg, for the lisinopril and dual blockade groups, respectively, P > 0.2 for all). Compared with lisinopril monotherapy, dual blockade treatment caused a highly significant reduction in 24-h PP levels (-5 +/- 5 mm Hg, P = 0.003), albeit the difference in the BP lowering effect between the treatment groups did not differ significantly for 24-h systolic (P = 0.21) or diastolic (P = 0.49) BP. Dual blockade treatment significantly lowered 24-h SBP (-5 +/- 11 mm Hg, P = 0.03), but not 24-h DBP (-2 +/- 7 mm Hg, P = 0.29), whereas in the lisinopril group, the opposite effect was observed (24-h SBP -1 +/- 9 mm Hg, P = 0.45, 24-h SBP -3 +/- 7 mm Hg, P = 0.03). CONCLUSIONS: Twelve months of dual blockade with candesartan and lisinopril significantly reduced PP when compared with high-dose monotherapy with lisinopril. Larger studies are needed to confirm this observation, and to evaluate whether this effect translates into a greater degree of end-organ protection from dual blockade treatment than from conventional angiotensin-converting enzyme (ACE) inhibition.

The IGF system in patients with type 2 diabetes: associations with markers of cardiovascular target organ damage.

OBJECTIVE: Perturbations in the insulin-like growth factor (IGF) system may contribute to the accelerated cardiovascular disease (CVD) that occurs in patients with type 2 diabetes (T2D). However, it remains unknown whether the IGF system is also involved in the development of early, subclinical CVD. We characterised the IGF system in T2D patients and matched controls and examined the associations with markers of subclinical target organ damage. METHODS: The study included 99 patients with recently diagnosed T2D and 99 age- and sex-matched controls. IGF-1 and IGFBP-1 to -4 were measured by immunoassays, as were pregnancy-associated plasma protein-A (PAPP-A) and the PAPP-A-generated N-terminal (NT) and C-terminal (CT) IGFBP-4 fragments, which are novel CVD risk markers. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV). Cerebral white matter lesions (WMLs) and carotid artery remodelling were determined by MRI. RESULTS: After multivariate adjustments, patients with T2D had lower concentrations of IGFBP-2, IGFBP-4, NT- and CT-IGFBP-4, when compared with controls. IGFBP-2 was inversely correlated to PWV in all subjects in multivariate analysis (P < 0.05), and IGFBP-3 was inversely associated with severity of WMLs (P < 0.05). The NT-IGFBP-4 fragment was associated with the degree of carotid artery remodelling among all subjects (regression coefficient (95% CI): 2.95 (0.70, 5.16), P = 0.011). Levels of NT- and CT-IGFBP-4 were reduced in T2D patients receiving metformin compared to those in controls and patients not receiving metformin. CONCLUSIONS: Even in recently diagnosed and well-controlled T2D patients, IGF protein levels are altered and associated with CVD risk factors.

Long-term dual blockade with candesartan and lisinopril in hypertensive patients with diabetes: the CALM II study.

OBJECTIVE: To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35-74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure. RESULTS: Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups. CONCLUSIONS: There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes.

Reduced Subendocardial Viability Ratio Is Associated With Unfavorable Cardiovascular Risk Profile in Women With Short Duration of Type 2 Diabetes.

BACKGROUND: The pathophysiological perturbations underlying the unfavorable cardiovascular prognosis in women with type 2 diabetes (T2DM) remain elusive. Low subendocardial viability ratio (SEVR), an index of myocardial oxygen supply and demand, has been associated with intermediate cardiovascular risk markers and cardiovascular mortality in various populations. However, whether SEVR is associated with sex and cardiovascular risk markers in patients with T2DM remains to be clarified. METHODS: We examined 86 T2DM patients (mean age 59±10 years, 47% women, median diabetes duration 1.9 (range 0.2-5.0) years) and 86 sex- and age-matched control subjects in a cross-sectional study. SEVR was noninvasively assessed by tonometry and markers of cardiovascular risk by carotid-femoral pulse wave velocity (PWV), homeostasis model assessment of insulin resistance (HOMA2-IR), C-reactive protein, urinary albumin/creatinine ratio, and heart rate variability. RESULTS: Women with diabetes had significantly lower SEVR compared to both men with diabetes (161% ± 26% vs. 178% ± 32%, P < 0.01), women without diabetes (185% ± 24%, P < 0.001), and men without diabetes (188% ± 28%, P < 0.001). The differences remained significant after adjustment for age, systolic blood pressure, heart rate, diabetes, and smoking. SEVR was associated with PWV, HOMA2-IR, C-reactive protein, and reduced heart rate variability in patients and control subjects, but the associations became nonsignificant after adjustment for heart rate. CONCLUSIONS: SEVR is reduced in women with short duration of T2DM and associated with cardiovascular risk markers. The latter association seems to be at least partly mediated via heart rate. We hypothesize that reduced SEVR may contribute to the unfavorable cardiovascular prognosis in women with diabetes.

Invasively Measured Aortic Systolic Blood Pressure and Office Systolic Blood Pressure in Cardiovascular Risk Assessment: A Prospective Cohort Study.

Aortic systolic blood pressure (BP) represents the hemodynamic cardiac and cerebral burden more directly than office systolic BP. Whether invasively measured aortic systolic BP confers additional prognostic value beyond office BP remains debated. In this study, office systolic BP and invasively measured aortic systolic BP were recorded in 21 908 patients (mean age: 63 years; 58% men; 14% with diabetes mellitus) with stable angina pectoris undergoing elective coronary angiography during January 2001 to December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination and reclassification were assessed using Harrell's C and the Continuous Net Reclassification Index. Data were analyzed with and without stratification by diabetes mellitus status. During a median follow-up period of 3.7 years (range: 0.1-10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both office and aortic systolic BP were associated with stroke in patients with diabetes mellitus (hazard ratio per 10 mm Hg, 1.18 [95% confidence interval, 1.07-1.30] and 1.14 [95% confidence interval, 1.05-1.24], respectively) and with myocardial infarction in patients without diabetes mellitus (hazard ratio, 1.07 [95% confidence interval, 1.02-1.12] and 1.05 [95% confidence interval, 1.01-1.10], respectively). In models including both BP measurements, aortic BP lost statistical significance and aortic BP did not confer improvement in either C-statistics or net reclassification analysis. In conclusion, invasively measured aortic systolic BP does not add prognostic information about cardiovascular outcomes and all-cause mortality compared with office BP in patients with stable angina pectoris, either with or without diabetes mellitus.

Macular edema reflects generalized vascular hyperpermeability in type 2 diabetic patients with retinopathy.

OBJECTIVE: Diabetic maculopathy (DMa) is the most prevalent sight-threatening type of retinopathy in type 2 diabetes and a leading cause of visual loss in the western world. The disease is characterized by hyperpermeability of retinal blood vessels and subsequent formation of hard exudates and macular edema, the degree of which can be estimated by measurement of retinal thickness. We examined associations between retinal thickness as evaluated by optical coherence tomography scanning (OCT), glomerular leakage as evaluated by urinary albumin excretion rate (UAE), and general vascular leakage as evaluated by the transcapillary escape rate of albumin (TER(alb)) in type 2 diabetic patients with and without DMa. RESEARCH DESIGN AND METHODS: In 20 type 2 diabetic patients with DMa and 20 type 2 diabetic patients without retinopathy matched for age, sex, and duration of diabetes, we performed OCT, fundus photography, fluorescein angiography, and 24-h ambulatory blood pressure measurement. UAE was determined by radioimmunoassay. TER(alb) was determined as the initial disappearance of intravenously injected (125)I-labeled human serum albumin. RESULTS: Patients with diabetic maculopathy had higher HbA(1c) (8.5 +/- 1.5 vs. 7.4 +/- 1.2%, P < 0.05) and higher total cholesterol (5.8 +/- 0.7 vs. 5.2 +/- 0.9 mmol/l, P < 0.05) than patients without retinopathy. UAE was higher in the DMa group than in the group with no retinopathy (9.3 x// 3.1 vs. 3.9 x// 1.9 micro g/min, P < 0.01). There was no difference in TER(alb) between the two groups (6.0 +/- 1.6 vs. 6.6 +/- 1.5%, NS). In the group with DMa, OCT, TER(alb), and UAE correlated significantly (OCT versus TER(alb): r = 0.55, P < 0.05; OCT versus UAE: r = 0.58, P < 0.01; UAE versus TER(alb): r = 0.81, P < 0.01). Conversely, there were no correlations between these three parameters in the group without retinopathy. CONCLUSIONS: Macular edema seems to reflect a generalized vascular leakage in type 2 diabetic patients.

Dual blockade with candesartan cilexetil and lisinopril in hypertensive patients with diabetes mellitus: rationale and design.

BACKGROUND: Blood pressure (BP) reduction is the key to risk reduction of cardiovascular disease or renal failure in hypertensive patients with diabetes mellitus. Inhibition of the renin-angiotensin system by an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) provides efficient BP reduction and renal protection in hypertensive diabetes patients. But, despite this, the recommended BP levels can be difficult to achieve and dual blockade therapy might be a possible way of obtaining efficient BP reduction in hypertensive patients with diabetes. Dual blockade treatment is based on a principle of obtaining the broadest and most efficient blockade of angiotensin II, by using the combination of an ACE-inhibitor and an ARB. METHODS: The Candesartan And Lisinopril Microalbuminuria (CALM II) study is a one centre, one observer, double-blind, randomised, active-controlled, parallel-group study, investigating the efficacy and tolerability of candesartan cilexetil in combination with lisinopril, compared with the maximum recommended dose of lisinopril in hypertensive patients with diabetes mellitus. The study design consists of two treatment arms with either 16 mg candesartan cilexetil or 20 mg lisinopril added to concomitant treatment with 20 mg lisinopril. It comprises 80 patients with a minimum of 35 patients in each group and statistical power of 90% to detect a difference in systolic BP reduction of 6.5 mmHg. CONCLUSION: The CALM II study aims to investigate the effects of dual blockade on systolic BP, albuminuria, left ventricular mass and function, and retinopathy in hypertensive patients with diabetes mellitus.

Assessment of central blood pressure in patients with type 2 diabetes: a comparison between SphygmoCor and invasively measured values.

BACKGROUND: The SphygmoCor is used for noninvasive assessment of ascending aortic blood pressure (BP). However, the validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with substantial imprecision of central BP estimates. We hypothesized that different noninvasive calibration strategies might improve the accuracy of the estimated ascending aortic BPs. METHODS: In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor device and compared these data with invasively recorded data. The validity of the transfer function was assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of noninvasive calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs. DBP+MBP using a form factor (ff) of 0.33 and 0.40, respectively. RESULTS: When calibrating with invasive BP, the difference between estimated and invasively measured ascending aortic SBP and DBP was -2.3±5.6/1.0±0.9 mm Hg. When calibrating with oscillometric brachial BPs, the differences were -9.6±8.1/14.1±6.2 mm Hg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1 mm Hg (DBP and MBP; ff = 0.33), and 1.9±12.2/14.1±6.2 mm Hg (DBP and MBP; ff = 0.40), respectively. Calibration with the average of 3 brachial BPs did not improve accuracy. CONCLUSIONS: The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Noninvasive calibration with DBP and MBP (ff = 0.40) enables accurate estimation of mean ascending aortic SBP at the group level. However, the wide limits of agreement indicate limited accuracy in the individual patient. CLINICAL TRIALS REGISTRATION: Clinical Trials No. NCT01538290.

Carotid-femoral pulse wave velocity is associated with cerebral white matter lesions in type 2 diabetes.

OBJECTIVE: Patients with type 2 diabetes have a high incidence of cardiovascular events including stroke. Increased arterial stiffness (AS) predicts cardiovascular events in the general population. Cerebral white matter lesions (WMLs) are associated with an increased risk of stroke. It is unknown whether AS in patients with type 2 diabetes is associated with WMLs. RESEARCH DESIGN AND METHODS: We examined 89 patients recently diagnosed with type 2 diabetes (<5 years) and 89 sex- and age-matched controls. AS was assessed with carotid-femoral pulse wave velocity (PWV). WMLs were identified using magnetic resonance imaging and graded qualitatively with the Breteler scale (no/slight changes = 0, moderate changes = 1, severe changes = 2) and semiquantitatively. RESULTS: The diabetic population had excellent glycemic control (HbA(1c), 6.5% [6.2-6.8]; median [interquartile range {IQR}]) and had, compared with the controls, lower office blood pressure (BP) (127 ± 12/79 ± 8 vs. 132 ± 14/84 ± 10 mmHg) and total cholesterol (4.3[3.9-4.7] vs. 5.6 [5.1-6.4]; mmol/L; median [IQR]), (P < 0.01 for all). Despite this, PWV was higher in the patients with diabetes compared with controls (9.3 ± 2.0 vs. 8.0 ± 1.6 m/s; P < 0.0001). PWV was associated with Breteler score (OR 1.36 [95% CI 1.17-1.58]; P < 0.001) and WML volume (OR 1.32 [95% CI 1.16-1.51]; P < 0.001) per 1 m/s increase in PWV. These associations remained significant when adjusted for age, sex, diabetes, 24-h mean arterial BP, BMI, heart rate, and use of antihypertensives and statins (Breteler score: OR 1.28 [95% CI 1.03-1.60]; P < 0.05 and WML volume: OR 1.30 [95% CI 1.06-1.58]; P < 0.05). CONCLUSIONS: PWV was higher among patients with well-controlled type 2 diabetes compared with controls and was independently associated with WMLs. PWV may represent a clinically relevant parameter in the evaluation of cerebrovascular disease risk in type 2 diabetes.