Characteristics associated with polypharmacy in people with type 2 diabetes: the Dutch Diabetes Pearl cohort.

AIM: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes. METHODS: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications). RESULTS: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease. CONCLUSIONS: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 diabetes.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Body mass index and the efficacy of needle-free jet injection for the administration of rapid-acting insulin analogs, a post hoc analysis.

We recently showed in a euglycaemic glucose clamp study among 18 healthy volunteers that using jet injectors rather than conventional pens significantly improved the time-action profiles of rapid-acting insulin analogs. Here, we investigated whether such profiles were modified by body mass index (BMI) and related weight parameters by comparing insulin administration by jet injection to that by conventional pen in subgroups defined by BMI, waist-to-hip ratio, waist circumference and insulin dose. After conventional administration, times to peak insulin levels (T-INS(max)) occurred 31.1 [95% confidence interval (CI) 13.7-48.5] min later and time to maximum glucose requirement (T-GIR(max)) 56.9 (95%CI 26.6-87.3) min later in more obese (BMI > 23.6 kg/m(2)) than in lean subjects (BMI < 23.6 kg/m(2)). In contrast, T-INS(max) and T-GIR(max) were similar in subjects with high and low BMI, when insulin was administered by jet injection. We conclude that using jet injection for insulin administration may especially benefit subjects with higher body weight.

Effect of dipyridamole on myocardial reperfusion injury: A double-blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery.

Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I -3% [95% confidence interval -23% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release.

Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands.

BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands. METHODS: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. RESULTS: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c >or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. CONCLUSION: Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels.

Effects of pioglitazone in familial combined hyperlipidaemia.

OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.

BACKGROUND: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. METHODS: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. RESULTS: Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). CONCLUSION: Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Vascular effects of metabolic inhibition by 2-deoxy-D-glucose in humans.

2-Deoxy-D-glucose (2DG) is a structural analogue of glucose that inhibits the glycolytic pathway. In vitro 2DG induced vasodilation, which was inhibited by glibenclamide (blocker of ATP-dependent potassium channels). The vasodilation induced by 2DG may be an interesting model for metabolic vasodilation. In this study, we investigated whether 2DG induces vasodilation in the human skeletal muscle vascular bed and whether this vasodilation was inhibited by glibenclamide. We measured forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial 2DG (0.4 and 0.8 mg/min x dl of forearm volume, each dose for 30 min), either alone or with co-infusion of insulin to increase the cellular 2DG uptake, and compared the results with insulin infusion alone. Glibenclamide infusion (1.0 microg/min x dl) was added in a subgroup. 2DG alone did not change FBF ratio (experimental/control arm, 11 +/- 9%, p = 0.34), but 2DG with insulin significantly increased FBF ratio (32 +/- 17%, p = 0.04). The increase in FBF by 2DG and insulin was significantly more pronounced than the vasodilation induced by insulin alone (p = 0.03). Co-infusion of glibenclamide had no effect on the vasodilation induced by 2DG and insulin (percentage increase in FBF ratio 11 +/- 18% without and 17 +/- 12% with glibenclamide, p = 0.85). In conclusion, 2DG induces manifest vasodilation in humans when infused in combination with insulin. This vasodilation is not mediated by ATP-dependent potassium channels.

Reproducibility of skin microcirculatory measurements in humans, with special emphasis on capillaroscopy.

The reproducibility of capillaroscopic measurements of capillary blood cell velocity (CBV) in human nailfolds was investigated by use of the computerized system CapiFlow. Therefore, CBV measurements of two capillaries of each of three fingers together with laser Doppler fluxmetry (LDF) and skin temperature measurements were performed three times in five healthy volunteers. Short-term (1.5 h) intra-individual coefficient of variation (CV) of CBV was 18.4%. Long-term (7 days) CV amounted to 55.8%. Inter-individual CV was 55.9%. Short- and long-term intra-individual CVs of LDF were 25.4% and 37.3%. Inter-individual variation was 36.0%. Skin temperature showed short- and long-term CVs of 3.7% and 5.5% and inter-individual CV of 5.8%. In conclusion, measurement of CBV using CapiFlow is a suitable method to assess acute effects, but has limited value in investigating long-term effects. Because of the wide interindividual variability in both CBV and LDF, power calculations will reveal large numbers to investigate. Skin temperature has a relatively small intra- and inter-individual variation and is more suitable for long-term studies.

Microcirculatory effects of KATP channel blockade by sulphonylurea derivatives in humans.

BACKGROUND: Recent investigations have shown that glibenclamide inhibits the opening of vascular ATP-sensitive potassium channels during ischemia. This observation may implicate cardiovascular effects of sulphonylurea derivatives when used under conditions of ischemia in patients with Type 2 diabetes mellitus. In addition to resistance arteries, the (pre) capillary vessels also contain ATP-dependent potassium channels. Closure of these channels by sulphonylurea derivatives might affect the development of microvascular disease in Type 2 diabetes mellitus. Therefore, we investigated the microcirculatory effects of sulphonylurea derivatives in Type 2 diabetic patients as compared with healthy volunteers. MATERIALS AND METHODS: Arteriovenous blood flow (skin temperature and laser Doppler flux) and capillary blood cell velocity were measured before and during infusion of four doses of glibenclamide (0.1, 0.3, 1.0 and 3.0 microg min-1 dL-1) into the brachial artery of 14 Type 2 diabetic patients and 13 healthy controls. The experiments included appropriate time control studies. RESULTS: Both skin temperature and laser Doppler flux decreased in response to glibenclamide in healthy volunteers (-7 +/- 2%, P < 0.0005 and -31 +/- 11%, P = 0.001, respectively), but did not change in Type 2 diabetic patients (1 +/- 3%, P = 0.29 and 4 +/- 14%, P = 0.97). However, capillary blood cell velocity decreased in Type 2 diabetic patients (-38 +/- 18%, P = 0.04), but did not change in healthy volunteers (-1 +/- 11%, P = 0.28). CONCLUSIONS: The results of the present study indicate that glibenclamide indeed affects microvascular blood flow. Glibenclamide may induce redistribution of the microvascular skin flow from nutritive flow to arteriovenous shunt flow in Type 2 diabetic patients. Therefore, closure of ATP-dependent potassium channels by glibenclamide possibly plays a role in the development of microangiopathy in Type 2 diabetic patients.

Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes.

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation.

Vascular effects of glibenclamide vs. glimepiride and metformin in Type 2 diabetic patients.

AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.