Cardiovascular drugs as antidiabetic agents: evidence for the prevention of type 2 diabetes.

Given the long-term health consequences and increasing incidence of type 2 diabetes, there is great interest to potentially prevent or delay its onset. Primary prevention studies have demonstrated that intensive exercise and weight reduction, and to a lesser extent certain antidiabetic agents, can reduce new onset diabetes in at-risk individuals. Results from post hoc analyses and secondary end-point outcomes of large randomized controlled trials of cardiovascular drugs suggest that these may also have beneficial effects, reducing the incidence of new onset diabetes in addition to their proven cardiovascular benefits. Multiple meta-analyses confirm that drugs primarily acting on the renin-angiotensin system (RAS) reduce the incidence of diabetes in the populations studied, perhaps via improved insulin sensitivity and/or effects on pancreatic beta cells. However, results from the recent Diabetes REduction Approaches with Medication study specifically failed to show a significant reduction in the incidence of diabetes with ramipril in individuals with abnormal glucose tolerance at baseline. There is only limited evidence that statins improve glucose tolerance, and although beta-blockers tend to have detrimental effects on glucose tolerance, newer agents with vasodilatory properties may confer benefits. With current guidelines, the use of cardiovascular drugs modifying the RAS will increase in at-risk individuals, but at present, they cannot be recommended to prevent diabetes.

Oral antidiabetic agents as cardiovascular drugs.

The increased risk of cardiovascular disease associated with type 2 diabetes is well documented. Lesser degrees of abnormal glucose metabolism including impaired fasting glycaemia and impaired glucose tolerance are also associated with increased cardiovascular risk. Studies showing improved cardiovascular outcomes with oral antidiabetic agents are limited, with the UKPDS demonstrating improved macrovascular outcomes only in a subgroup of obese patients with type 2 diabetes treated with metformin, and the heavily criticized STOP NIDDM trial showing a reduction in the number of cardiovascular events with the alpha glucosidase inhibitor acarbose. In recent years there has been an increase in the number of oral antidiabetic drugs available to treat the hyperglycaemia of diabetes. Some of these drugs have complex metabolic properties, additional to their antihyperglycaemic effect, improving endothelial function and markers of atherogenesis, with the potential to reduce cardiovascular morbidity and mortality, as supported by the recently published results of the PROACTIVE study. The results of further long-term cardiovascular outcome studies with these newer agents are awaited.

Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD.

BACKGROUND: Abeta42-immunization reduces plaque burden and improves cognition in transgenic mouse models of Alzheimer disease (AD). This phase 1 study evaluated the safety, tolerability, and immunogenicity of AN1792 (human aggregated Abeta42) in patients with mild to moderate AD. METHODS: Twenty patients were enrolled into each of four dose groups and randomly assigned to receive IM AN1792 (50 or 225 microg) with QS-21 adjuvant (50 or 100 microg) or QS-21 only (control) in a 4:1 active:control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and exploratory evidence of efficacy were evaluated. RESULTS: Treatment-related adverse events were reported in 19 (23.8%) patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencephalitis that was diagnosed after death (not directly related to study treatment) and 219 days after discontinuing from the study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment. During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer (an anti-AN1792 antibody titer of > or =1:1,000). This increased to 58.8% after additional injections with the modified formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients at week 84 (p = 0.002). No treatment differences were observed in three other efficacy measures. CONCLUSIONS: AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.

Intensified treatment of patients with type 2 diabetes mellitus and overt nephropathy.

BACKGROUND: Diabetic nephropathy is the single most common cause of chronic renal failure requiring dialysis. Effective treatment exists, but no clinical audit or large trial has reduced the rate of loss of renal function as effectively as in small groups of intensively managed patients. AIM: To determine the effect of intensive vs. standard medical management on the rate of progression of renal failure in patients with diabetic nephropathy. DESIGN: Prospective randomized controlled study. METHODS: Patients with type 2 diabetes and nephropathy were randomly allocated to an intensive group (n = 47) or control group (n = 43). Treatment targets were the same for both groups, but the intensive group were seen as often as required to meet the targets; controls were seen at their normal clinics. The primary end-point was the rate of progression of renal disease in the second year. RESULTS: The groups were well matched at baseline. During follow-up, the intensive group had lower mean SBP, DBP and cholesterol. Median rate of progression of renal failure in the intensive group fell from 0.44 ml/min/month in the first year to 0.14 ml/min/month in the second year, compared to 0.49 ml/min/month and 0.53 ml/min/month in the control group (p = 0.04 for second year). Patients in the intensive group spent significantly less time in hospital. DISCUSSION: Intensive treatment slowed progression of renal disease within 2 years in patients with established diabetic nephropathy. Mean creatinine clearance at the start of the trial was 55 ml/min, so assuming that the rates of progression achieved at the end of the second year persisted, onset of dialysis would be delayed by 20 years in the intensive group compared with the control group.

Mortality study of 18 000 patients treated with omeprazole.

BACKGROUND: The long term safety of potent gastric acid suppressive therapy has yet to be established. METHOD: General practice record review at a median interval of 26 months followed by retrieval of details of all deaths within four years using the UK National Health Service Central Registers in 17 936 patients prescribed omeprazole in 1993-1995. Death rates were compared with general population rates. RESULTS: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received further scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. All cause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals (CI) 1.34-1.55); p<0.0001) but had fallen to population expectation by the fourth year. There were significant mortality increases in the first year, falling to or below population expectation by the fourth year, for deaths ascribed to neoplasms (1.82 (95% CI 1.58-2.08); p<0.0001), circulatory diseases (1.27 (95% CI 1.13-1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12-1.64); p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87-3.43); p<0.0001) persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60-6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84-2.18); p=0.075), and trachea, bronchus, and lung (1.64 (95% CI 1.19-2.19); p<0.01) seen in the first year had disappeared by the fourth year but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20-10.09) (p<0.0001) in year 1; 2.88 (95% CI 1.62-4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of Barrett's disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17-4.80)). Six deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37-2.22)) and five in patients without oesophageal disease (O/E 0.77 (95% CI 0.25-1.80)). No relationships were detected with numbers of omeprazole scripts received. CONCLUSIONS: Increases in mortality associated with treatment are due to pre- existing illness, including pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesophageal adenocarcinoma in those without oesophageal mucosal damage recorded at registration.

Diabetic nephropathy: how effective is treatment in clinical practice?

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal failure in patients starting dialysis in the developed world. In clinical trials, interventions, particularly blood pressure control, have achieved major reductions in the rate of decline in renal function. AIM: To investigate whether results from clinical trials can be achieved in routine clinical practice. DESIGN: Observational study of 170 consecutive patients referred to a combined diabetic-renal clinic over a 10 year period. METHODS: We collected demographic and laboratory data from the electronic patient record. RESULTS: Median serum creatinine at referral was 170 micromol/l and was >350 micromol/l in 26% of patients. Mean blood pressure (BP) was 159/85. The publication of guidelines by the Scottish Intercollegiate Guidelines Network in 1997, recommending more active intervention and earlier referral, had no impact on referral BP and creatinine. In the 125 patients with at least 1 year follow-up, significant improvements in BP, albuminuria, HbA(1c) and serum cholesterol were seen. In the 63 patients followed up for 3 years (median creatinine 120 micromol/l), the median rate of decline in renal function slowed from 0.52 ml/min/month (first year) to 0.27 ml/min/month (third year) (p=0.003), nearly doubling the time to end-stage renal failure. DISCUSSION: Patients referred early to a combined diabetic-renal clinic benefited by slowing in the rate of decline of renal function. A challenging but achievable standard for audit would be to reduce the rate of progression to <0.25 ml/min/month in 70% of patients with diabetic nephropathy presenting with a serum creatinine <150 micromol/l.

Postmarketing surveillance of the safety of cimetidine: 15-year mortality report.

The pattern of mortality after 15 years of observation is reported among almost 10,000 patients who were taking cimetidine when they were first recruited between 1977 and 1980. Many took the drug for a number of years, some switching to other antisecretory agents as the study progressed. The findings are reassuring and provide no evidence of any long-term adverse effects of cimetidine which might be detected by monitoring mortality rates. The data have also been used to examine the possible positive relationships between aluminium ingestion and Alzheimer's disease and H. pylori infection and ischaemic heart disease. No significant evidence was obtained in support of the existence of these relationships.

Glomerular charge selectivity in type 1 (insulin-dependent) diabetes mellitus.

Glomerular charge selectivity was assessed using the ratio of the clearance of pancreatic isoamylase to the clearance of the more anionic salivary isoamylase (CPAm/CSAm) in 12 normal subjects and 50 patients with Type 1 diabetes: 13 with normal albumin excretion and short duration of diabetes (< 5 years), 15 with normal albumin excretion and long duration of diabetes (> 15 years), 13 with microalbuminuria, and 9 with clinical nephropathy. None had serum creatinine > 200 mumol l-1. There were no significant differences in CPAm/CSAm between the normal subjects and the two groups of normoalbuminuric patients with Type 1 diabetes. CPAm/CSAm was significantly lower in diabetic patients with microalbuminuria or clinical nephropathy than in normoalbuminuric patients with Type 1 diabetes. When the 37 patients with normoalbuminuria and long-standing diabetes, microalbuminuria, and nephropathy were considered together, there was a significant negative correlation between CPAm/CSAm and albumin excretion rate (rs = 0.71, p < 0.001). Progressive impairment of glomerular charge selectivity at the molecular size of amylase (molecular mass 56 kDa) accompanies increasing albuminuria in Type 1 diabetes.

European postmarketing surveillance of ramipril in hypertension. 1. Feasibility and study cohort.

A prospective observational cohort study of the angiotensin inhibitor, ramipril, was undertaken in four countries within the European Community-Netherlands, United Kingdom, Germany and Belgium. A total of 10,377 consecutive patients with essential hypertension were recruited to the study with the aim of follow-up for one year. Overall 37% of doctors who agreed to participate in the study actually enrolled at least one patient. One third of the doctors who enrolled patients in the study entered two thirds of patients studied. Some 15% of participating males and 27% of females were aged over 70 years. Newly diagnosed hypertensives comprised 22% of the study cohort, the proportion being highest in UK and Netherlands, whereas 53% were established hypertensives of two or more years' duration, the proportion being highest in Germany and Belgium. There were substantial differences among the participating countries in the concurrent treatment these patients were receiving for hypertension, with two or more co-therapies being most frequent in Germany and Belgium. There were also substantial differences in co-therapies for concurrent diseases among the participating countries, reflecting both standard therapeutic practices in local areas and differences in marketing of drugs in the different countries. This report describes the initial findings of this multinational study and emphasises the need to consider several major potentially confounding variables in the analysis of the outcome events both in this study and in other collaborative observational international monitoring schemes for adverse drug reactions.

Population screening for diabetes mellitus. Professional Advisory Committee of the British Diabetic Association.

The role and value of screening for diabetes mellitus is still unclear. If asymptomatic subjects are to be screened, then a fasting plasma glucose > 6.6 mmol l-1 or a venous plasma glucose 2 h after a 75 g oral glucose load > 8.0 mmol l-1 or the presence of any glucose in a urine sample passed 2 h after a main meal should be regarded as a positive result. A fasting plasma glucose in the range 5.5-6.6 mmol l-1 is an equivocal result which should lead to retesting in 6-12 months if there is any risk factor for diabetes (obesity, family history of diabetes, Asian/African racial origin). Other screening tests or combinations of tests are not recommended. Screening should be restricted to subjects between 40 and 75 years and should be undertaken only every 5 years (3 years if a risk factor for diabetes is present), ideally in parallel with other health screening test; subjects with a positive result should have further investigations as necessary to reach a diagnosis in line with WHO criteria.

Psychological factors and their relationship to diabetes control.

Thirty-nine Type 1 diabetic patients were asked to complete an Eysenck Personality Questionnaire (EPQ). A significant relationship was found between neuroticism scores and glycosylated haemoglobin concentrations (r = 0.43, p < 0.01) and also fructosamine (r = 0.45, p < 0.01). Patients with glycosylated haemoglobin concentrations greater than or equal to 10 (n = 13) had significantly higher neuroticism scores than patients with glycosylated haemoglobin results less than or equal to 8 (n = 11) (p < 0.01).