H. Keen

Mortality and causes of death in the WHO multinational study of vascular disease in diabetes

Abstract.Aims/hypothesis: We aimed to examine the mortality rates, excess mortality and causes of death in diabetic patients from ten centres throughout the world. Methods: A mortality follow-up of 4713 WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participants from ten centres was carried out, causes of death were ascertained and age-adjusted mortality rates were calculated by centre, sex and type of diabetes. Excess mortality, compared with the background population, was assessed in terms of standardised mortality ratios (SMRs) for each of the 10 cohorts. Results: Cardiovascular disease was the most common underlying cause of death, accounting for 44 % of deaths in Type I (insulin-dependent) diabetes mellitus and 52 % of deaths in Type II (non-insulin-dependent) diabetes mellitus. Renal disease accounted for 21 % of deaths in Type I diabetes and 11 % in Type II diabetes. For Type I diabetes, all-cause mortality rates were highest in Berlin men and Warsaw women, and lowest in London men and Zagreb women. For Type II diabetes, rates were highest in Warsaw men and Oklahoma women and lowest in Tokyo men and women. Age adjusted mortality rates and SMRs were generally higher in patients with Type I diabetes compared with those with Type II diabetes. Men and women in the Tokyo cohort had a very low excess mortality when compared with the background population. Conclusion/interpretation: This study confirms the importance of cardiovascular disease as the major cause of death in people with both types of diabetes. The low excess mortality in the Japanese cohort could have implications for the possible reduction of the burden of mortality associated with diabetes in other parts of the world. [Diabetologia (2001) 44 [Suppl 2]: S 14–S 21]

CORONARY-HEART-DISEASE RISK AND IMPAIRED GLUCOSE TOLERANCE The Whitehall Study

In the Whitehall Study of 18,403 male civil servants aged 40--64 years, 7 1/2 year coronary-heart-disease (CHD) mortality has been examined in relation to blood-sugar concentration 2 h after a 50 g oral glucose load. CHD mortality was approximately doubled for subjects with inpaired glucose tolerance (IGT), defined as a blood-sugar above the 95th centile (greater than or equal to 96 mg/dl). There was no trend of CHD mortality with blood-sugar below the 95th centile. Within the IGT group, age, systolic blood-pressure, and ECG abnormality (Whitehall criteria) were significantly predictive of subsequent CHD mortality. These findings are relevant to discussions on the criteria for diabetes which include the definition of an IGT category with increased risk of large-vessel disease, but without the high risk of small-vessel disease as occurs in diabetes mellitus.

Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia.

A study was performed to examine the feasibility of achieving long periods of near-normoglycaemia in patients with diabetes mellitus by giving a continuous subcutaneous infusion of insulin solution from a miniature, battery-driven, syringe pump. Twelve insulin-dependent diabetics had their insulin pumped through a subcutaneously implanted, fine nylon cannula; the basal infusion rate was electronically stepped up eightfold before meals. The blood glucose profile of these patients was closely monitored during the 24 hours of the subcutaneous infusion and compared with the profile on a control day, when the patients were managed with their usual subcutaneous insulin. Diet and exercise were standardised on both days. In five out of 14 studies the subcutaneous insulin infusion significantly lowered the mean blood glucose concentration without producing hypoglycaemic symptoms; in another six patients the mean blood glucose concentration was maintained. As assessed by the M value the level of control was statistically improved in six out of 14 studies by the infusion method and maintained in six other patients. To assess the effects of blood glucose control on diabetic microvascular disease it will be necessary to achieve long-term normoglycaemia in selected diabetics. The results of this preliminary study suggest that a continuous subcutaneous insulin infusion may be a means of maining physiological glucose concentrations in diabetics. Though several problems remain--for example, in determining the rate of infusion--longer-term studies with the miniature infusion pumps are now needed.

The Bedford Survey: Ten year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk indices for coronary heart disease in borderline diabetics

SummaryMortality rates from coronary heart disease and from all causes have been ascertained over ten years in three groups of people participating in the Bedford Survey — newly-diagnosed diabetics, borderline diabetics and control subjects with normal glucose tolerance. Age corrected mortality rates, from all causes and coronary heart disease, were highest in the diabetics and intermediate in the borderline diabetics and in both groups were similar in men and women. When statistical allowance was made for baseline differences in age, blood pressure and obesity, female borderline diabetics still had a significantly increased risk over their controls of death from ‘all causes’. Much of the difference appeared to be due to a relative excess of deaths due to coronary heart disease. It is concluded that borderline diabetes (or impaired glucose tolerance) is associated with a relatively greater increase in mortality risk in women than men. During the 10-year follow-up of the Bedford borderline diabetics, coronary heart disease morbidity and mortality rates were similar in men and women. Age at entry to the study was the major independent and significant predictor of mortality from all causes. The level of systolic blood pressure and current cigarette smoking at baseline were statistically significant predictors only of mortality due to coronary heart disease.

The British Diabetic Association Cohort Study, II: cause‐specific mortality in patients with insulin‐treated diabetes mellitus

Aims To assess mortality in patients with diabetes incident under the age of 30 years.

Prospective Study of Microalbuminuria as Predictor of Mortality in NIDDM

Retrospective studies of patients with non-insulin-dependent diabetes mellitus (NIDDM) have suggested that microalbuminuria predicts early all-cause (mainly cardiovascular) mortality independently of arterial blood pressure. These findings have not been confirmed in prospective studies, and it is not known whether the predictive power of microalbuminuria is independent of other major cardiovascular risk factors. During 1985–1987, we examined a representative group of 141 nonproteinuric patients with NIDDM for the prevalence of coronary heart disease and several of its established and putative risk factors, including raised urinary albumin excretion (UAE) rate. Thirty-six patients had microalbuminuria (UAE 20–200 μg/min), and 105 had normal UAE (< 20 μg/min). At follow-up, an average of 3.4 yr later, 14 patients had died. There was a highly significant excess mortality (chiefly from cardiovascular disease) among those with microalbuminuria (28%) compared to those without microalbuminuria (4%, P < 0.001). In univariate survival analysis, significant predictors of all-cause mortality included microalbuminuria (P < 0.001), hypercholesterolemia (P < 0.01), hypertriglyceridemia (P < 0.05), and preexisting coronary heart disease (P < 0.05). The predictive power of microalbuminuria persisted after adjustment for the effects of other major risk factors (P < 0.05). We conclude that microalbuminuria is a significant risk marker for mortality in NIDDM, independent of the other risk factors examined. Its presence can be regarded as an index of increased cardiovascular vulnerability and a signal for vigorous efforts at correction of known risk factors.

Raised arterial pressure in parents of proteinuric insulin dependent diabetics.

Arterial pressure is raised early in the subset of insulin dependent diabetics at risk of later development of progressive renal failure, suggesting that liability to arterial hypertension may play a part in the aetiology of diabetic kidney disease. Evidence for a genetic basis was therefore sought by measuring the blood pressures of the 26 surviving parents of 17 insulin dependent diabetic patients with proteinuria and comparing them with those of the parents of 17 matched insulin dependent diabetic patients without proteinuria selected from the same cohort. Systolic and diastolic pressures were significantly higher in parents of the proteinuric (mean (SD) 161 (27)/94 (14) mm Hg) than in parents of the non-proteinuric patients (146 (21)/86 (11) mm Hg). The difference between the sample mean blood pressures was 15 mm Hg (95% confidence interval 3.3 to 26.7 mm Hg) for systolic pressure and 8 mm Hg (95% confidence interval 0.8 to 15.2 mm Hg) for diastolic pressure. These differences were independent of age, sex, and adiposity. There was a significant correlation between the mean arterial pressures in the proteinuric patients and the higher mean blood pressure in their parents. High blood pressure in non-diabetic parents may be a marker of susceptibility to clinical nephropathy in their insulin dependent diabetic offspring.

Glycaemia, arterial pressure and micro-albuminuria in Type 1 (insulin-dependent) diabetes mellitus

SummaryPlasma glucose control and arterial pressure were assessed in 28 Type 1 (insulin-dependent) diabetic patients with different degrees of micro-albuminuria. They were divided into two groups according to their urinary albumin excretion rate: a low micro-albuminuria group (n= 16) with albumin excretion ranging between 12.1 and 28.9 μg/min and a high micro-albuminuria group (n= 12) with albumin excretion between 32.4 and 91.3 μg/min. The groups were matched for age, sex and duration of diabetes with the same number of normo-albuminuric (2.0–10.4 μg/min) diabetic control subjects. Both the low and high micro-albuminuria groups had significantly higher glycosylated haemoglobin levels and mean plasma glucose concentrations during a 24-h profile than their respective normo-albuminuric control subjects. A correlation between glycosylated haemoglobin level and urinary albumin excretion rate was found in the whole study group (r= 0.48; p< 0.001). Arterial pressure (both systolic and diastolic) was significantly higher in the high micro-albuminuria group than in either the control group or the low microalbuminuria group. A significant correlation was found between arterial pressure and albumin excretion rate in the whole study population (r= 0.49; p< 0.001) as well as in the pooled micro-albuminuria groups (r= 0.43; p< 0.05). Multiple regression analysis showed that glycosylated haemoglobin and arterial pressure levels were independently correlated with albumin excretion rates. Diabetic patients with micro-albuminuria of any degree have worse glycaemic control than normo-albuminuric patients. Higher levels of arterial pressure, though often sub-hypertensive, are associated with levels of micro-albuminuria predictive of later development of clinical proteinuria. Thus high plasma glucose and high arterial pressure, or both, characterise those diabetic patients at increased risk of nephropathy. These indices of risk are potentially reversible.

The ten-year follow-up of the Bedford Survey (1962–1972): Glucose tolerance and diabetes

SummaryIn a 10-year prospective study of 241 people with ‘borderline diabetes” (impaired glucose tolerance) identified by screening of the Bedford adult population, 36 (15%) worsened to diabetes and 128 (53%) substantially improved their glucose tolerance. The major predictor of worsening to diabetes was the level of blood glucose at baseline. This was statistically significant (p < 0.05), independent of other factors, both for deterioration in the first and in the second five years of observation. Body mass index, a measure of adiposity, did not predict worsening to diabetes during the first five years, but was an independent and significant predictor of worsening during the second five years (p < 0.05). The apparent effect of adiposity was complex, for it was also significantly related to improvement in glucose tolerance during the 10-year follow-up. Persons with impaired glucose tolerance are a heterogeneous group and with present knowledge the ability to predict metabolic deterioration is limited.

Long term correction of hyperglycaemia and progression of renal failure in insulin dependent diabetes

The effect of long term correction of hyperglycaemia on the rate of deterioration of renal function was studied in six insulin dependent diabetics with proteinuria due to diabetic nephropathy. After a planned run in observation period of 10 to 24 months patients entered a programme of continuous subcutaneous insulin infusion for up to 24 months. Glycaemic control was promptly and significantly improved and optimal glycaemic values sustained throughout the study. Blood pressure was maintained stable. A control group of six nephropathic diabetics was studied receiving conventional insulin injection treatment but also with blood pressure control over the same period. Despite greatly improved metabolic control in the infusion treated group no significant change in the rate of decline of glomerular filtration rate could be shown, the plasma creatinine concentrations continued to increase, and the fractional clearance of albumin and IgG rose progressively, indicating progression of glomerular damage. The conventionally treated control group behaved similarly. In a single patient receiving the continuous infusion the rate of decline of the glomerular filtration rate slowed considerably, suggesting that the response to strict diabetic control may differ in some patients. These findings suggest that by the time glomerular function has started to fail in diabetic nephropathy the process culminating in end stage renal failure has become self perpetuating and is little influenced by the degree of metabolic control. A new definition of potential clinical diabetic nephropathy is proposed that will permit identification of patients at risk and earlier intervention by glycaemic correction in an attempt to arrest diabetic renal disease.