Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin?

AIMS: We investigated in a double-blind study whether metformin reduces blood pressure (BP) in patients with Type 2 diabetes intensively treated with insulin. METHODS: A total of 220 patients with Type 2 diabetes were asked to undergo 24-h ambulatory BP monitoring (24-h ABPM). One hundred and eighty-two gave informed consent. Eighty-nine were randomized to metformin and 93 to placebo. Thirty-five subjects dropped out (13 placebo, 22 metformin users); 147 patients underwent a second 24-h ABPM, 16 weeks after randomization. RESULTS: Systolic BP (SBP), diastolic BP (DBP), pulse BP (PP), mean BP (MP) and heart rate (HR) were measured as office BP measurements and as 24-h ABPM for 24-h, day and night. Office BP measurements did not differ significantly between the placebo- and metformin-treated groups for any BP measure, but showed a non-significant trend for SBP reduction with metformin use (mean baseline-adjusted difference, metformin minus placebo: -4.2 mmHg, 95% CI, -9.9 to +1.5; P = 0.15). The baseline-adjusted differences of the ambulatory measurements were -0.2 mmHg (95% CI, -2.9 to +2.6) for the 24-h SBP, and +1.1 mmHg (95% CI, -0.7 to +2.8) for the 24-h DBP. On the whole, BP differences between metformin- and placebo-treated groups were not statistically significant. The only significant difference was for night-time PP (baseline-adjusted difference: -2.2 mmHg; 95% CI, -4.2 to -0.2). These results were not different after adjustment for age and diabetes duration, or for (changes in) body mass index, glycated haemoglobin, insulin dose or plasma homocysteine. CONCLUSION: Metformin does not significantly affect BP in patients with Type 2 diabetes intensively treated with insulin.

Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial.

OBJECTIVES: The UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation. DESIGN: The Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out. SETTING: The trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands). SUBJECTS: Patients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n = 345) or insulin and metformin (n = 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min(-1), or low plasma cholinesterase (reference value <3.5 units L(-1)), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo). MAIN OUTCOME MEASURES: The HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment. RESULTS: When compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% (-1 to +48; P = 0.06); a decrease in plasma von Willebrand factor of 6% (-10 to -2; P = 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% (-7 to -2; P = 0.0002); a decrease in soluble E-selectin of 6% (-10 to -2; P = 0.008); a decrease in tissue-type plasminogen activator of 16% (-20 to -12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% (-27 to -10; P = 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment. CONCLUSIONS: In patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unrelated to changes in glycaemic control, but not with improvement of chronic, low-grade inflammation.

Autonomic nervous function, arterial stiffness and blood pressure in patients with Type I diabetes mellitus and normal urinary albumin excretion.

Type I diabetic patients (DM-1) with an elevated urinary albumin excretion (UAE>30 mg/24 h) have a high cardiovascular risk. However, DM-1 patients with normal UAE have incipient abnormalities of the cardiovascular and nervous systems, such as elevations of blood pressures, increases in arterial stiffness and deterioration of autonomic nervous function. We studied the interrelationships of these abnormalities in normoalbuminuric DM-1 patients. In 76 patients, we performed two cardiovascular reflex tests (deep in- and expiration test (IE test) and lying-to-standing test (LS test)), and determined aortic pulse wave velocity (PWV), local arterial compliances of the common carotid, femoral and brachial arteries, and 24-h blood pressures. The DeltaRRmax value of the LS test was associated with aortic PWV (negatively) and the compliance coefficients of the carotid, femoral and brachial arteries. Per 100-ms increase in DeltaRRmax, pulse wave velocity decreased by 0.39 m/s, compliance coefficients of the carotid, femoral and brachial arteries increased by 0.06, 0.08 and 0.05 mm2/kPa, respectively. These associations were independent of age, 24-h mean arterial pressure and 24-h heart rate. Increases in arterial stiffness were associated with increases in 24-h systolic and pulse pressure (per 1 m/s increase in PWV, systolic and pulse pressure increased by 2.1 and 1.7 mmHg, respectively). In normoalbuminuric DM-1 patients, deterioration of autonomic nervous function is associated with an increase in arterial stiffness, which, in turn, was associated with, and may cause, increased systolic and pulse pressure. These findings suggest that preventive strategies targeting autonomic dysfunction may reduce cardiovascular morbidity in diabetes.

Effectiveness of clinical rotations as a learning environment for achieving competences.

Competences are becoming more and more prominent in undergraduate medical education. Workplace learning is regarded as crucial in competence learning. Assuming that effective learning depends on adequate supervision, feedback and assessment, the authors studied the occurrence of these three variables in relation to a set of clinical competences. They surveyed students at the end of their rotation in surgery, internal medicine or paediatrics asking them to indicate for each competence how often they had received observed and unobserved supervision, the seniority of the person who provided most of their feedback, and whether the competence was addressed in formal assessments. Supervision was found to be scarce and mostly unobserved. Senior staff did not provide much feedback, and assessment mostly targeted patient-related competences. For all variables, the variation between students exceeded that between disciplines. We conclude that conditions for adequate workplace learning are poorly met and that clerkship experiences show huge inter-student variation.

Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial.

OBJECTIVE: Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin. DESIGN: Placebo-controlled, randomized trial. MEASUREMENTS: at baseline and 16 weeks later. SETTING: This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. SUBJECTS: A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users). INTERVENTION: Addition of metformin or placebo to insulin therapy. PRIMARY OUTCOME PARAMETERS: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. RESULTS: Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. CONCLUSION: In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.

Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial.

OBJECTIVE: Protein restriction delays the progression of non-diabetic and type 1 diabetic renal disorders. This study assessed whether protein restriction delays the onset or early progression of renal disorders in type 2 diabetes. DESIGN: Randomized controlled trial. Outcomes were albuminuria (mg/24 h) and, as an estimate of the glomerular filtration rate, cimetidine-influenced creatinine clearance. SETTING: Primary care. SUBJECTS: Patients with type 2 diabetes and microalbuminuria or at least detectable albuminuria, or a diabetes duration >5 y. INTERVENTIONS: The experimental group received dietary counselling on protein restriction (n=63); a control group (n=68) received the usual dietary advice. The duration of intervention and follow-up was 28+/-7 months. RESULTS: After 6 months, protein intake differed only by 0.08 g/kg/day between the study groups. Subsequently, this difference decreased and eventually disappeared. An initial effect of protein restriction on albuminuria in favor of the experimental group was not sustained, and the glomerular filtration rate decreased in the experimental group at a 1.6+/-2.2 ml/min/1.73 m(2) y lower rate than in the control group (P=0.5). Comparison of patients in the experimental group with a decrease in protein intake of at least 0.20 g/kg/day, with controls with no decrease, indicated a similarly small and insignificant effect on glomerular filtration rate. CONCLUSIONS: It is concluded that, in the longer term prevention or delay of renal damage in patients with type 2 diabetes, protein restriction is neither feasible nor efficacious.

Discontinuation of metformin in type 2 diabetes patients treated with insulin.

BACKGROUND: Metformin added to insulin therapy in type 2 diabetic patients improves glycaemic control and decreases the required daily dose of insulin (DDI). Metformin should be discontinued if cardiac, hepatic or renal failure develops. We examined whether glycaemic control can be maintained after metformin cessation. METHODS: We included 45 type 2 diabetic patients treated with insulin plus metformin, and 45 matched controls treated with insulin only. After discontinuation of metformin in the first group, we aimed for tight fasting and postprandial blood glucose levels, 4-7 and 4-10 mmol/l, respectively, in both groups. During 12 weeks we assessed glycaemic control every two weeks and, if necessary, adjusted the insulin dosage. RESULTS: In the group in which metformin was discontinued, DDI increased from 67.9 +/- 22.9 to 92.2 +/- 29.4 IU (p < 0.001) leaving glycaemic control unchanged. In the controls, glycated haemoglobin (GHb) decreased by 0.93% (p < 0.001), while DDI increased slightly from 62.4 +/- 22.9 to 72.3 +/- 27.3 IU (p < 0.001). The increase in DDI was larger in patients in whom metformin was discontinued than in the controls (p < 0.001). CONCLUSIONS: In type 2 diabetic patients treated with insulin plus metformin, glycaemic control can be maintained after discontinuation of metformin by increasing the DDI substantially (20 to 36%) during application of an intensified treatment protocol.

The effect of profiled hemodialysis on intradialytic hemodynamics when a proper sodium balance is applied.

BACKGROUND: Profiled hemodialysis (HD) has been claimed to ameliorate intradialytic complications such as hypotension. Frequently, these profiles are based on providing the patient with an accumulating sodium load. This increases the risk of interdialytic complications, such as hypertension and increased weight gain. The present study investigated the effect of profiled HD, without an accompanying sodium loading, on intradialytic hemodynamics in stable HD patients. METHODS: In eight stable HD patients a standard hemodialysis (S-HD) was compared to a decreasing Na(+)-profiled hemodialysis (Na-HD), and an ultrafiltration profiled hemodialysis (UF-HD). Care was taken to have the sodium balances similar during these sessions. The patients were monitored non-invasively during dialysis with respect to their cardiac performance by means of electrical impedance cardiography, their variation in blood volume by means of an on-line optical measurement, and their hydration state by means of body impedance analysis. RESULTS: Sodium balance and mean arterial sodium concentrations were similar in the three treatments. Intradialytic hemodynamics during UF-HD were similar to those of S-HD. However, Na-HD improved blood pressure preservation, remarkably without significant blood volume preservation, due to a better stroke volume preservation in the first hour of dialysis. CONCLUSION: Sodium-balanced, Na-profiled HD improves blood pressure preservation in stable HD patients without providing the patients with a sodium load. This effect is due to a better stroke volume preservation early in dialysis, without a significant reduction in blood volume decrease. UF-HD, as mono-therapy, has no beneficial effect on intradialytic hemodynamics in stable patients.