Severe hypoglycemia in an elderly patient treated with metformin.

UNLABELLED: The following case of severe hypoglycemia was reported during a systematic evaluation of hospital admissions caused by adverse drug reactions (supported by BfArM). HISTORY AND FINDINGS ON ADMISSION: A 79-year-old diabetic woman was admitted to hospital in a stuporous and unresponsive state. The initial physical examination revealed no other abnormal findings. Serum blood glucose was found to be 2.0 mmol/l and HbA1c was 4.6%. The patient had been started on antidiabetic therapy with metformin 2 months earlier. Treatment with other drugs being taken at that time, an ACE inhibitor, an NSAID and nitrofurantoin, remained unchanged. DIAGNOSIS, TREATMENT AND FOLLOW-UP: Laboratory tests excluded lactic acidosis and renal insufficiency. Cerebral computed tomography findings were normal. The patient improved dramatically following administration of glucose. Other laboratory findings confirmed the diagnosis of hypoglycemia. Blood glucose concentrations ranged between 4.0 and 10.0 mmol/l in the subsequent days and the patient could be discharged in full health. CONCLUSIONS: Drug-induced hypoglycemia is possible even in diabetics not receiving insulin or oral antidiabetic agents increasing insulin secretion. The risk of drug-induced hypoglycemia should be particularly considered when drugs containing blood glucose-lowering components are combined. Metformin does not usually cause hypoglycemia when administered as monotherapy. We suspected that hypoglycemia in this patient was caused by additional blood glucose-lowering effects of the ACE inhibitor and the NSAID possibly combined with a suboptimal nutrition. The indications for metformin administration undergo critical scrutiny.

[Doxycycline--the forgotten antibiotic]. / Doxycyclin--das vergessene Antibiotikum.

BACKGROUND: Doxycycline is an broad-spectrum antimicrobial agent, it remains an inexpensive alternative for the treatment of community-acquired respiratory infections and urinary tract infections. Despite these clinical data the use of doxycycline has decreased during the last years. PHARMACOLOGY: Adverse effects and resistance to therapy are infrequent and not different to fluoroquinolones and macrolide antibiotics. Gastrointestinal and phototoxic side effects are of importance. After oral administration 75% will be absorbed and largely eliminated by the hepatic and intestinal way. Contraindications are severe liver dysfunction and treatment in childhood. CLINICAL INDICATIONS: Bacterial resistance to doxycycline has a low incidence in Germany. A therapeutic success can be expected in respiratory and urinary tract infections in about 80%. Doxycycline is the drug of choice for treating infections caused by Rickettsia, Borrelia, Ehrlichia. It shows good activity against Plasmodium falciparum as one part in a combination therapy. Daily costs of therapy are low, in oral administration DM 0.80 per day, in i.v. administration DM 22,-per day. CONCLUSION: Despite competition from new antibiotics, doxycycline can retain an important place in the treatment of many infectious diseases.

Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.

The Diabetes Intervention Study (DIS) is a prospective population-based multicentre trial of newly detected cases of non-insulin-dependent diabetes mellitus (NIDDM). This report analyses the risk factors for subsequent coronary heart disease and all-cause death during the 11-year follow-up. The prognostic significance of the categories of the NIDDM Policy Group was validated with respect to the incidence of coronary heart disease and mortality. At baseline 1139 subjects, aged 30-55 years at the time of diabetes detection and classified as diet controlled after a 6-week screening phase, were included. Of the patients 112 (15.2%) suffered from myocardial infarction, 197 (19.82%) of 994 had died. The odds ratio for all-cause mortality compared to the general population for males at the age of 36-45 years was 5.1 and for females 7.0. In multivariate analysis age, blood pressure and smoking were independent risk factors for myocardial infarction and male sex, age, blood pressure, triglycerides, postprandial blood glucose and smoking for death, respectively. The categories of the NIDDM Policy Group target parameters for blood glucose, triglycerides and blood pressure were significant predictors of both CHD and death. Thus, it appears that in NIDDM good control of blood glucose, blood pressure and triglycerides is associated with a lower incidence of coronary heart disease and death rate respectively.

Determinants for coronary heart disease in non-insulin-dependent diabetes mellitus: lessons from the diabetes intervention study.

In NIDDM a clustering of established coronary risk factors, e.g. the metabolic syndrome is responsible for excessive incidence of myocardial infarction. The harmful effects of these risk factors are aggravated by poor glucose control. Hyperinsulinaemia is associated with a higher level of risk factors for coronary heart disease. Individuals with subsequent myocardial infarction exhibit higher levels of serum insulin at entry. However, insulin in multivariate analysis was no independent risk factor. Perfect control of blood glucose, triglycerides and blood pressure was associated with a lower incidence of coronary heart disease. By extrapolation an integrated approach to correct the anomalies of the metabolic syndrome seems to be necessary to prevent macroangiopathy and improve life expectancy.

Retinopathy and nephropathy in 772 insulin-treated diabetic patients in relation to the type of diabetes.

Using the register of the centralized Diabetes Care system in former GDR as run until 1989, the frequency of diabetic retinopathy and nephropathy and related factors were investigated in insulin-treated diabetic patients. Retinopathy was diagnosed by ophthalmoscopy, nephropathy was evaluated on the estimation of macroproteinuria. Out of the total of 1058 insulin-treated patients, 772 subjects (286 males, 486 females) who had undergone ophthalmoscopic examination during the previous year were selected for this study. According to clinical criteria, there were 238 patients with Type 1 and 534 patients with Type 2 diabetes. Their mean age was 43.3 and 64.5 years, respectively, and duration of diabetes was 13.2 and 14.0 years. Essential results: (1) Retinopathy was diagnosed in 52.5% of Type 1 and in 50.3% of insulin-treated Type 2 diabetic patients. There were no differences in the degree of retinopathy between the two groups. (2) The Type 1 diabetic patients with retinopathy were significantly older than those without retinopathy (49 vs. 37 years), but no such difference could be ascertained in Type 2 diabetes (64 vs. 65 years). (3) Duration of diabetes was longer in patients with retinopathy both in Type 1 (18 vs. 8 years) and in Type 2 diabetes (16 vs. 12 years). (4) Subjects of either group with retinopathy exhibited significantly higher systolic blood pressure values. (5) There was no difference in postprandial blood sugar or in applied insulin doses between the patients with or without retinopathy. (6) Clinical nephropathy was more frequent in Type 2 (22%) than in Type 1 diabetes (16.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

[Coronary heart disease and insulin concentration in type II diabetic patients--results of a diabetes intervention study]. / Koronare Herzkrankheit und Insulinkonzentration bei Typ II-Diabetikern--Ergebnisse der Diabetesinterventions-studie (DIS).

There is experimental, clinical and epidemiological evidence that elevated insulin levels are associated with development of atherosclerosis. Early results came from studies in non-diabetics, but the situation with respect to diabetes is more complex and not so clear. The Diabetes Intervention Study is a population-based follow-up study in newly detected type II diabetics (30- to 55-yr-old). After 5 years 431 men and 320 women received a complex check up with oral glucose tolerance tests and measurements of plasma insulin and glucose levels, fasting and 2h post-load. Regarding the metabolic parameters, the fasting and postprandial insulin levels were higher among the patients having coronary heart disease (15% of men, 36% of women), as compared to patients without this disease. In multivariate analysis sex, age, antihypertensive treatment, blood pressure, body mass index, and fasting insulin levels were independently associated with the prevalence of coronary heart disease in patients with non-insulin dependent diabetes mellitus (NIDDM) treated with diet and/or oral antidiabetics. Body mass index and triglycerides were the only variables that independently correlated to insulin: fasting insulin = 0.4 (body mass index) + 0.1 (triglycerides) - 4,2. In future prospective studies of diabetics relating insulin concentrations to the development of vascular disease are of particular interest and necessity. Because hyperinsulinemia may contribute to accelerated atherosclerosis in NIDDM-patients, the aim of the treatment of type II-diabetes should be to correct hyperglycemia without aggravating insulin levels and other cardiovascular risk factors.

Diabetes Intervention Study. Multi-intervention trial in newly diagnosed NIDDM.

OBJECTIVE: In a randomized 5-yr multi-intervention trial, we tested the efficacy of intensified health education (IHE) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease (IHD). RESEARCH DESIGN AND METHODS: Within the intervention group, the benefit of clofibric acid was evaluated in a double-blind study. One thousand one hundred thirty-nine newly diagnosed middle-aged (30- to 55-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) entered the study. They were classified as diet controlled after a 6-wk screening phase with conventional dietary treatment. During the follow-up, the control group (n = 378) was cared for at different diabetes outpatient clinics with a standardized surveillance. The intervention group (n = 761) had a structured IHE that included dietary advice, antismoking and antialcohol education, and ways to enhance physical activity. RESULTS: Randomly, 379 of the IHE patients received 1.6 g clofibric acid/day, and the others received placebo. IHE resulted in improved glucose control (adjusted fasting blood glucose) levels after 5 yr (control subjects 9.27 mM, IHE group 8.71 mM, and IHE plus clofibric acid group 8.60 mM, P less than 0.01). The better glycemic control was achieved with fewer antidiabetic drugs. After 5 yr, antidiabetic drugs were prescribed to 47% of the control subjects, 28% of the IHE group, and 34% of the IHE plus clofibric acid group (cutoff limit for drug application was postprandial blood glucose of greater than or equal to 13.87 mM). The ratio of polyunsaturated to saturated fatty acids (0.26 vs. 0.40, P less than 0.01) and physical activity (174 vs. 327 scores, P less than 0.01) were increased, and blood pressure, tobacco, and alcohol consumption were significantly reduced by IHE. However, IHE had no effect on calorie intake, percentage of fat in the diet (45%), and body weight. The most important finding was the significant increase of blood cholesterol in all three groups (+0.47, +0.36, and +0.34 mM, respectively). Clofibric acid only prevented the increase of triglyceride levels (+0.56, +0.24, and +0.05 mM, respectively). The incidence rate per 1000 for myocardial infarction was 30.3 for control subjects, 53.6 for the IHE group, and 55.6 for the IHE plus clofibric acid group. The corresponding rates for IHD incidence were 90.9, 97.8, and 98.8, respectively. Men suffered more frequently from myocardial infarction, whereas women developed ECG criteria for IHD more frequently. Among the 35 cases of death, besides cardiovascular diseases, liver cirrhosis and neoplasia were the predominant causes. The death rate per 1000 in control subjects was 46.2, 30.6 in the IHE group, and 27 among patients with IHE plus clofibric acid. CONCLUSIONS: IHE was of substantial benefit for the control of glycemia, significantly diminished the need for antidiabetic drugs, and reduced a cluster of risk factors but had no effect on the control of blood lipids. This could be one major reason for the failure of IHE, effective lowering of blood pressure, and clofibric acid to prevent cardiovascular complications. Clofibric acid was only effective in reducing triglycerides.

[Coronary heart diseases and associated risk factors in newly manifested type II diabetic patients over the course of 5 years]. / Koronare Herzkrankheit und assoziierte Risikofaktoren bei frisch manifestierten Typ-II-Diabetikern im 5-Jahres-Ablauf.

Using the baseline data of the diabetes intervention study (DIS) from 1126 newly manifested type II-diabetics our analysis demonstrates higher mean-values of some components of the so-called metabolic syndrome in patients with ECG-abnormalities indicating coronary heart disease (CHD) in diagnosis of diabetes compared with subjects without ECG-findings. The impact of general risk factors for the prevalence of CHD in diagnosis and after a 5-year follow-up is obviously different in both sexes. In multivariate analysis only systolic blood pressure was persistently a significant predictor in both sex groups. With increasing age life-duration gets as time-related factor importance for the development of CHD. The mathematically demonstrated association of triglyceride levels to the presence of ECG-abnormalities agrees with the results of WHO multinational study of vascular disease in diabetes mellitus. In the interventions as well as in the control-groups diabetic subjects with CHD after 5 year follow-up showed in comparison to diabetics without CHD higher levels of investigated risk factors which develop their pathogenetic effect probably by their clustering impact, because the differences of their mean-values are only in some cases significant. The common lower level of the most risk factors at the intervention group compared with the conventionally treated group is the result of the intervention measures.

[The value of hypertension and metabolic factors on the development of coronary heart disease in type II diabetic patients]. / Zur Wertigkeit von Hypertonie und metabolischen Einflussfaktoren auf die Entstehung der koronaren Herzkrankheit bei Typ-II-Diabetikern.

In 1,126 newly manifested type II diabetics of the diabetes intervention study (628 male, 498 female) between 30 and 55 years of age by a univariate and multivariate analysis the influence of atherogenic risk factors on the development of the coronary heart disease was tested. The diagnosis coronary heart disease is based on the ECG at rest (Minnesota-code), in 796 test persons an exercise electrocardiogram was made. In a manifestation of diabetes males with coronary heart disease showed higher mean values for systolic and diastolic blood pressure, body mass index and serum triglycerides than the control group free of coronary heart disease. In females systolic and diastolic blood pressure, uric acid level and age were significantly increased. By means of multidimensional analysis of variance as to the major findings in the ECG at rest (Q/QS type) in males the diastolic blood pressure, in females the systolic blood pressure and the serum uric acid proved to be significant. Minor findings (above all disturbances of repolarisation) were in males significantly associated with the triglycerides and the diastolic blood pressure, in the females with the systolic blood pressure and the age. Test persons with a stage of coronary heart disease which is to be recognized only in the exercise ECG in the behaviour of the mean value of the atherogenic risk factors did not differ from the control group free of findings with the exception of the increased serum triglycerides in the females.

[Cardiologic findings in newly manifested type II diabetics of the diabetes intervention study]. / Kardiologische Befunde bei frisch manifestierten Typ-II-Diabetikern der Diabetesinterventionsstudie.

In 1,126 newly manifested primarily purely dietetic manageable type II-diabetics (628 men, 498 women) of the diabetes intervention study (DIS) at the age from 30 to 55 years the prevalence of the ischaemic heart disease was established with the help of the ECG in rest (Minnesota code) and in 70% of the test persons by an additional electrocardiography after work. Including the two parameters in 9.2% of the diabetic men and 26.1% of the women electrocardiographic findings of an ischaemic heart disease could be proved. The proportion of pathological findings of the ECG increased with age. While the proportion of a probable ischaemic heart disease (code 1.1-1.2) in the ECG in rest and with 1.4% the same size in the two sexes, in women, the percentage of a possible ischaemic heart disease (code 1.3, 4.1-4.3/5-5.3/8.3) prevailed with statistical significance after the 45th year of age. The at present numerically largest study on newly detected diabetics of type II gives evidences to the previous cardial lesion when the diabetes is manifest at medium age on the basis of the homogeneity of the number of patients.

[Longitudinal studies on the prognostic significance of plasma fibrinogen in diabetes mellitus]. / Längsschnittuntersuchungen zur prognostischen Bedeutung des Plasmafibrinogens beim Diabetes mellitus.

In 243 diabetics of different duration of the disease the prognostic value of an initial estimation of plasma fibrinogen for life expectancy and development of macroangiopathy was controlled over a period of ten years. Diabetics with a cardiovascular cause of death showed at the beginning with 3.68 in contrast to 3.24 g/l weakly significantly higher fibrinogen values than the surviving patients. In analogy to this in the surviving patients the diabetics with a meanwhile appearing myocardial infarction, chronic ischaemic heart disease or manifest disturbances of the peripheral blood supply differed by higher fibrinogen concentrations from test persons without manifest macroangiopathy. There was a close correlation between plasma fibrinogen level and development of hypertension. The increase of plasma fibrinogen is apparently associated with the atherogenesis without rendering a secure prognosis in the individual case on account of a critical limiting value.

[Prognostic significance of the resting ECG of diabetics--results of a 10-year analysis]. / Zur prognostischen Aussagefähigkeit des Ruhe-Ekg bei Diabetikern--Ergebnis einer 10-Jahres-Analyse.

On 226 diabetics at the age of greater than or equal to 40 years the prognostic evidence of the ECG after resting using the Minnesota code was prospectively analysed with regard to the life expectancy in the subsequent 10 years. During this period 65 diabetics died, 46 of them of vascular and 19 of another cause of death. Essential results of the analysis are Diabetics with Q/QS types (code 1.1-1.2) as well as repolarisation disturbances (code 4.1-4.3/5.1-5.3) in the ECG showed a higher lethality rate in the observation period (48.8%) than those ones with an ECG unsuspicious of ischaemic heart disease (15.9%). When a hypertension is simultaneously present the prognosis is additionally loaded. The proportion of ECG-findings suspicious of ischaemic heart disease was initially only 62.3% in diabetics with coronary cause of death. A relation between codation pattern and year of death in a temporary interval to the ECG-registration could not be established.

[Comparative analysis of electrocardiographic findings in diabetics and metabolically healthy persons]. / Vergleichende Analysen elektrokardiographischer Befunde bei Diabetikern und Stoffwechselgesunden

The electrocardiograms of 447 diabetics and of the same number of non-diabetic test persons who were coordinated as biostatic twins, taking into consideration age, sex, and weight, were evaluated according to the Minnesota-code and compared. The cardiac endangering of the diabetics was most clearly expressed in the larger frequency of infarctions and the chronic-ischaemic heart disease which can be proved in all age groups. Diabetic males with short duration of diabetes showed the highest frequency of infarctions. The frequency of coronaropathy which is not increased in most age groups in the long-term diabetics compared with the control persons characterizes them as a positive selection of diabetics with an apparantly primarily low atherogenic potency. Hypertonus and/or adiposity were concomitant with a nearly doubled frequency of the ischaemic heart disease. The breadth of the P-wave as a possible reference to angiopathic changes in the region of the atrium was significantly larger in the diabetics in all age groups than in the control group.

[Long-term diabetes--a special form of diabetes]. / Der Langzeitdiabetes-eine besondere Verlaufsform der Zuckerkrankheit

Two hundred and eight long-term diabetics from the diabetic population of one district were examined thoroughly by physicians of the several special branches and compared with a control group consisting of biostatic twins with a healthy metabolism. Case control was performed for 5 years. The frequent absence of pathological findings in the coronary, peripheric and cerebral regions as well as a significantly high percentage of standard weight and underweight were found to be characteristic signs in that patients who survived their diabetes for several tens of years. Five years after the first registration, 68 long-term diabetics and 23 subjects of the control group had been died. However, the excess mortality does not surpass the mortality of subjects diseased for a short period. Besides the age and the duration of the manifestation, the survival rate was found to be dependent on the degree of the micro- and macroangiopathies, hypertension and over-weight. On the other hand, the duration of the diabetes and the metabolic condition did not exert any perceptible influence.

[The effect of an ambulatory long term training on performance, metabolic and coagulation parameters after myocardial infarct]. / Zur Beeinflussung von Leistungs-, Stoffwechsel- und Gerinnungsparametern durch ein ambulantes Langzeittraining nach Myokardinfarkt

It is reported on the results of a training treatment for outpatients after myocardial infarction which was carried out twice a week during one and a half year, compared to a control group without physical conditioning. Out of 30 patients 14 continuously took part in the training lessons. In contrast to the control group in the training group a clear increase of the working capacity, a slight decrease of the body-weight, of the blood pressure in rest and of the triglycerides in the serum as well as a favourable influence on the glucose tolerance could be proved. The serum cholesterol level and the coagulation parameters did not change significantly. One patient of the training group and one of the control group died. One patient of the training group and one patient of the control group suffered a reinfarction.