Paul L. Drury

Diabetes and arterial hypertension

SummaryThe epidemiology, pathogenesis, significance and management of hypertension in diabetic subjects are discussed. In Type 1 diabetes the presence of diastolic hypertension is closely related to the presence of diabetic nephropathy, from the stage of persistent proteinuria onwards. There may also be some elevation of systolic pressure. The apparent increased prevalence of hypertension in Type 2 diabetes is largely explicable, directly or indirectly, by obesity but there may be an excess of systolic hypertension among elderly patients. Hypertension in the diabetic population is associated with an increased incidence of both microvascular and macrovascular complications, but whether the high blood pressure is causal is not clear. The possible roles of sodium and insulin, the renin-angiotensin system, catecholamines and physical factors are explored. All current antihypertensive agents have additional limitations and disadvantages when used in diabetic patients: diuretics and beta-blockers are probably the initial drugs of choice. Only in the case of diabetic nephropathy is there yet reasonable evidence of antihypertensive treatment reducing the rate of progression of the disease.

The need for a large-scale trial of fibrate therapy in diabetes : the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

BackgroundFibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting.MethodsSubjects with type 2 diabetes, aged 50–75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0–6.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible.ResultsA total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods.ConclusionsType 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.Background Fibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting. Methods Subjects with type 2 diabetes, aged 50–75 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0–6.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible. Results A total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events (primary endpoint: first nonfatal myocardial infarction or coronary death) over 5 years, to have 80% power to identify as statistically significant at 2P = 0.05 a 22% reduction in such events, using intention-to-treat methods. Conclusions Type 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005.

Glycated haemoglobin and cardiovascular outcomes in people with Type 2 diabetes: a large prospective cohort study

Aims  To investigate the association between long‐term glycaemic control, measured by glycated haemoglobin (HbA1c), and time to first cardiovascular disease (CVD) event for people with Type 2 diabetes in New Zealand.

Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment The FIELD study

OBJECTIVE Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.

Increased vasopressor responsiveness to angiotensin II in Type 1 (insulin-dependent) diabetic patients without complications

SummaryThe blood pressure response to infused angiotensin II (0.3 to 3 ng · kg−1 · min −1) was investigated in six normotensive patients with Type 1 (insulin-dependent) diabetes free of complications and in six healthy subjects matched for age, sex and weight. Basal blood pressures (111/68 and 114/72 mmHg) and basal plasma angiotensin II levels (18.0±5.2 and 14.1±2.4 pmol/l; mean + SD) were similar in the diabetic and control groups as were 24 h urinary excretions of sodium (157±88 and 154±84 mmol/24h). Equal increments in plasma angiotensin II were produced during the infusions in the two groups. Increases in both diastolic and systolic blood pressure were significantly greater in the diabetic patients throughout the infusion. Mean diastolic increments were: 6.7 versus 1.3 mmHg (0.3 ng dose), 11.0 versus 6.9 mmHg (1 ng dose) and 16.7 versus 12.3 mmHg (3 ng dose) (p<0.001). Corresponding figures for systolic pressure were: 8.7 versus 1.3mmHg, 10.3 versus 3.7mmHg and 15.3 versus 8.7mmHg (p<0.001). Vasopressor responsiveness to angiotensin II is thus increased in Type 1 diabetic patients without complications; it may, therefore, be a consequence of the diabetes rather than of the presence of microvascular disease or hypertension.

Derivation and Validation of a New Cardiovascular Risk Score for People With Type 2 Diabetes: The New Zealand Diabetes Cohort Study

OBJECTIVE To derive a 5-year cardiovascular disease (CVD) risk equation from usual-care data that is appropriate for people with type 2 diabetes from a wide range of ethnic groups, variable glycemic control, and high rates of albuminuria in New Zealand. RESEARCH DESIGN AND METHODS This prospective open-cohort study used primary-care data from 36,127 people with type 2 diabetes without previous CVD to derive a CVD equation using Cox proportional hazards regression models. Data from 12,626 people from a geographically different area were used for validation. Outcome measure was time to first fatal or nonfatal cardiovascular event, derived from national hospitalization and mortality records. Risk factors were age at diagnosis, diabetes duration, sex, systolic blood pressure, smoking status, total cholesterol–to–HDL ratio, ethnicity, glycated hemoglobin (A1C), and urine albumin-to-creatinine ratio. RESULTS Baseline median age was 59 years, 51% were women, 55% were of non-European ethnicity, and 33% had micro- or macroalbuminuria. Median follow-up was 3.9 years (141,169 person-years), including 10,030 individuals followed for at least 5 years. At total of 6,479 first cardiovascular events occurred during follow-up. The 5-year observed risk was 20.8% (95% CI 20.3–21.3). Risk increased with each 1% A1C (adjusted hazard ratio 1.06 [95% CI 1.05–1.08]), when macroalbuminuria was present (2.04 [1.89–2.21]), and in Indo-Asians (1.29 [1.14–1.46]) and Maori (1.23 [1.14–1.32]) compared with Europeans. The derived risk equations performed well on the validation cohort compared with other risk equations. CONCLUSIONS Renal function, ethnicity, and glycemic control contribute significantly to cardiovascular risk prediction. Population-appropriate risk equations can be derived from routinely collected data.

Accurate Estimation of Glomerular Filtration Rate in Diabetic Nephropathy From Age, Body Weight, and Serum Creatinine

Objective To assess, in diabetic nephropathy, the accuracy of a method that estimates glomerular function with age, body weight, and serum creatinine as parameters. Research Desihn and Methods Glomerular filtration rate (GFR) was measured 57 times in 20 subjects with insulin-dependent diabetes mellitus and nephropathy with a single injection of 51Cr-EDTA. At the same time, the estimated creatinine clearance (ml/min) was calculated with the Cockroft-Gault formula These values were then corrected for body surface area (1.73 m2). Results For GFR measurements <100 ml · min−1 · 1.73 m−2 (n = 41), there was a strong positive correlation with the estimated creatinine clearance corrected for body surface area (r = 0.94, P <0.0001). The slope of this regression line did not differ significantly from identity or the y-intercept from zero. On average, the Cockroft-Gault formula (corrected for body surface area) underestimated the GFR by only 3.1 ml·min−1·1.73 m−2 (9.7 SD). Conclusions This formula, corrected for body surface area, gives accurate estimates of GFR when GFR <100 ml·min−1·1.73 m–2. This formula could be used with an acceptable degree of confidence when repeated isotope assessments of renal function in diabetic nephropathy are impracticable.

Defining the ideal injection techniques when using 5-mm needles in children and adults

OBJECTIVE We aimed to establish the ideal injection techniques using 5-mm needles to reliably inject insulin into the subcutaneous fat in both children and adults and to quantify the associated pain and leakage of the test medium. RESEARCH DESIGN AND METHODS A total of 259 subjects (122 children/adolescents and 137 adults) were injected with sterile air corresponding to 20 IU insulin (200 μl) with 32-G 5-mm needles at 90° or 45°, in the abdomen and thigh, and with or without a pinched skin fold. Injection depth was assessed via ultrasonography. Subjects rated pain on a visual analog scale. Test medium injections into the abdomen and thigh (0.2–0.6 ml) were also administered to assess injection leakage. RESULTS Among children, 5.5% of injections were intramuscular (IM) and 0.5% were intradermal, while in adults, the incidence was 1.3 and 0.6%, respectively. The frequency of IM injections was greater in boys and negligible among adult women. Subcutaneous fat thickness was the primary predictor of the likelihood of IM injections (P < 0.001). A third of all patients reported experiencing no pain during insulin injection, with children/adolescents experiencing considerably more discomfort than adults. Some leakage of medium was observed, but was unrelated to injection volume and was generally minimal. CONCLUSIONS 5-mm needles are reliably inserted into subcutaneous fat in both adults and children. These needles were associated with reduced pain and minimal leakage. We recommend an angled injection with a pinched skin fold for children, while in adults, the technique should be left to patient preference.

Glycemic Control Over 5 Years in 4,900 People With Type 2 Diabetes: Real-world diabetes therapy in a clinical trial cohort

OBJECTIVE Glycemic control in type 2 diabetes generally worsens over time, requiring intensification of therapy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial provided the opportunity to observe glycemic control in a real-world setting. We assessed the adequacy of metformin, sulfonylureas, and insulin to maintain glycemic control and their effects on weight. RESEARCH DESIGN AND METHODS Diabetes control was measured at baseline and yearly for a median of 5 years in the 4,900 patients from the nonintervention arm of this study allocated to placebo. RESULTS Median HbA1c was 6.9% at baseline and increased by an average of 0.22% over 5 years (P < 0.001). Median weight was 86.3 kg at baseline and decreased by 0.4 kg over 5 years (P = 0.002). Baseline therapy was lifestyle measures only in 27%, oral agents without insulin in 59%, and insulin in 14% (7% also taking oral agents). Over 5 years, insulin use increased to 32% (21% also taking oral agents). Use of oral agents remained similar at 56%. Only 2% of patients at baseline and 4% after 5 years were taking oral agents other than metformin or sulfonylureas. Initiation of insulin therapy in 855 patients produced a sustained reduction of HbA1c from a median of 8.2 to 7.7%, with a weight gain of 4.6 kg over 5 years. CONCLUSIONS With intensification of traditional therapies, glycemic control deteriorated very little over 5 years in a large cohort of type 2 diabetes. However, the requirement for insulin therapy doubled, at the expense of significant weight gain and risk of hypoglycemia.

Blood pressure in children, adolescents and young adults with Type 1 (insulin-dependent) diabetes

SummaryBlood pressure has been measured by a single observer using a standardised technique in 163 Type 1 (insulin-dependent) diabetic patients aged 4 to 32 years, 232 of their non-diabetic siblings in the same age range and in 292 of their natural parents. Results for each sex were examined separately by analysis of variance. Systolic pressures were not significantly different overall nor in any single 4-year age band. In contrast, phase IV diastolic pressure was slightly but significantly higher in the diabetic males than in their sibling group overall (increment= +2.8 mmHg; p<0.03), a difference also shown individually within the 16–20 year age band (81.3 versus 76.5 mmHg, p<0.025). There were no significant differences in diastolic pressure between the female groups, and no effect of duration of diabetes on blood pressure was shown in either sex. Eighteen of 97 male diabetic patients (19%) had mean blood pressures above the 90th centile for age, derived from the sibling data, compared with 12 of 137 siblings (9%, p=0.05). The higher blood pressures among the diabetic males could not be explained solely by early nephropathy; familial factors appeared to be important in the determination of elevated blood pressure in this group as well as in the siblings. Alone, these small differences in blood pressure are unlikely to make a major contribution to the incidence of diabetic vascular disease, but the isolated increase in diastolic pressure may indicate altered vascular regulation in Type 1 diabetes.