Risk factors for hypoglycemia in patients with type 2 diabetes, hospitalized in internal medicine wards: Findings from the FADOI-DIAMOND study.

AIMS: Hypoglycemia is a potential risk in the management of patients suffering from type 2 diabetes (T2DM) and hospitalized in internal medicine units (IMUs). The aim of this analysis was to evaluate incidence of hypoglycemia and related risk factors in a group of patients admitted to IMUs. METHODS: We used the FADOI-DIAMOND study carried out in 53 Italian IMUs. The DIAMOND design included two cross-sectional surveys interspersed with an educational program. In both phases each center reviewed the charts of the last 30 hospitalized patients with known T2DM (n=3167), including information about hypoglycemia during hospital stay. The association between occurrence of hypoglycemia and potential predictors was evaluated by means of a multivariable logistic regression analysis. RESULTS: A total of 385 symptomatic hypoglycemic events were observed (rate=12%). Advanced age, cognitive dysfunction, and nephropathy were associated with hypoglycemia. Hypoglycemia occurred in 19.4% of patients treated according to the insulin sliding-scale method versus 11.4% of patients treated with basal bolus (p<0.01). More patients with hypoglycemia received sulfonylureas versus the no-hypoglycemia group (28.3% versus 20.6%, p<0.001). Significantly longer length of hospital stay and increased in-hospital mortality were found in the group with hypoglycemia compared with the no-hypoglycemia group (12.7±10.9 versus 9.6±6.5 days; 8.8% versus 4.8%, p<0.01). CONCLUSIONS: Hypoglycemia in hospitalized patients with diabetes is associated with increased length of hospitalization and in-hospital mortality. Identification of patients at increased risk of hypoglycemia may be important for optimally adapting treatment and patient management.

Intensification to biphasic insulin aspart 30/70 (BIAsp 30, NovoMix 30) can improve glycaemic control in patients treated with basal insulins: a subgroup analysis of the IMPROVE observational study.

AIMS: The international IMPROVE observational study investigated the safety profile and effectiveness of biphasic insulin aspart 30/70 (BIAsp 30) in the routine treatment of patients with type 2 diabetes. We present analyses for the subgroup of patients who switched from basal insulin to BIAsp 30. METHODS: Patients in routine care who started insulin therapy with or switched to BIAsp 30 from existing insulin regimens were eligible for this 26-week study. This analysis includes only patients previously treated with basal insulin. Outcomes including adverse events, hypoglycaemic events and glycaemic profile were recorded from patients' notes, recall and diaries. RESULTS: Of the 748 patients included (age 59.7+/-11.8 years, diabetes duration 11.4+/-7.3 years, baseline HbA1c 9.1+/-1.6%), 497 were previously using human neutral protamine Hagedorn (NPH) insulin and 245 analogue basal insulin. Overall, major and minor hypoglycaemia rates decreased from baseline to final visit (major: 0.171 to 0.011; minor: 9.70 to 5.89 events/patient-year) and were similar between the subgroups. HbA1c and fasting blood glucose were significantly reduced from baseline (NPH prestudy: -1.6%, -2.4 mmol/l; analogue basal prestudy: -1.8%, -2.4 mmol/l), as was postprandial blood glucose, with 33.8% of patients achieving the HbA1c target < 7% without hypoglycaemia. Insulin dose increased slightly from prestudy (0.33+/-0.21 U/kg), baseline (0.40+/-0.20 U/kg) to final visit (0.52+/-0.26 U/kg); most patients (76%) followed a twice-daily regimen at final visit. Body weight did not change significantly and treatment satisfaction increased. CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on basal insulins may improve their glycaemic control by intensification to BIAsp 30 therapy.

Safety and effectiveness of biphasic insulin aspart 30/70 (NovoMix 30) when switching from human premix insulin in patients with type 2 diabetes: subgroup analysis from the 6-month IMPROVE observational study.

AIMS: IMPROVE is an open-label, multinational, non-randomised, 26-week observational study designed to evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in routine clinical practice. Here, we report data for patients switching to BIAsp 30 from human premixed insulin. METHODS: Patients (n = 3856) with type 2 diabetes previously receiving human premixed insulin with or without oral antidiabetic drugs were eligible for inclusion. Demographic data, efficacy end-points (HbA(1c), fasting blood glucose and postprandial blood glucose) and safety end-points (serious adverse drug reactions, hypoglycaemia and adverse events) were collected at baseline and final visit. A subgroup analysis of mean dose change was also undertaken. RESULTS: Switching patients to BIAsp 30 resulted in significant improvements in glycaemic control combined with a reduced risk of hypoglycaemia. Patients who reached the HbA(1c) target (< 7%) had shorter diabetes duration, lower HbA(1c) at baseline and needed less insulin. Over 30% of patients were able to reach this target without experiencing hypoglycaemia over the 26-week period. Compared with asymmetric dose switching, unit-for-unit switching resulted in the highest proportion of patients reaching HbA(1c) target and incurred the least amount of dose titration. CONCLUSIONS: A unit-for-unit switch is the most effective as well as the simplest approach when transferring patients from biphasic human insulin 30 to BIAsp 30.

Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study.

AIMS: The IMPROVE observational study evaluated the safety profile and effectiveness of biphasic insulin aspart 30/70 (BIAsp 30) in patients with type 2 diabetes in routine practice in 11 countries. METHODS: Patients who initiated insulin therapy with, or switched existing insulin therapy to, BIAsp 30 in routine care were eligible for this 26-week, non-interventional observational study. Data on adverse events, hypoglycaemia and glycaemic parameters were obtained from patients' diaries and medical notes. Questionnaire-based patient treatment satisfaction was also measured. We report global results and, uniquely for a diabetes observational study, country-specific data. RESULTS: A total of 52,419 patients were enrolled from three prestudy treatment groups: no pharmaceutical therapy (n = 8966, diabetes duration 2.0 years, baseline HbA1c 9.9%), oral antidiabetic drugs (OADs) only (n = 33,797, diabetes duration 7.4 years, baseline HbA1c 9.2%) and insulin +/- OADs (n = 9568, diabetes duration 10.4 years, baseline HbA1c 9.3%). At final visit, HbA1c, fasting and postprandial blood glucose were significantly reduced from baseline in all subgroups (no pharmaceutical therapy: -3.1%, -5.9 and -9.0 mmol/l, respectively; OADs-only: -2.1%, -4.1 and -6.1 mmol/l; insulin +/- OADs: -2.0%, -3.3 and -5.1 mmol/l). Major hypoglycaemia rates decreased in all subgroups; minor hypoglycaemia increased in the insulin-naïve groups. There was no mean weight gain across subgroups. Across all countries, glycaemic parameters and major hypoglycaemia were reduced; weight increases were seen in some countries. Treatment satisfaction increased in all subgroups and countries following BIAsp 30 therapy. CONCLUSIONS: Initiating insulin with, or switching insulin therapy to, BIAsp 30 in routine care resulted in improved glycaemic control, reduced major hypoglycaemia and greater treatment satisfaction.

The IMPROVE study--a multinational, observational study in type 2 diabetes: baseline characteristics from eight national cohorts.

AIMS: The IMPROVE study is a multinational, open-label, non-randomised, 26-week observational study assessing the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) treatment in type 2 diabetes in routine clinical practice. The principal aims of this report were to characterise the baseline population and physicians' treatment decisions. METHODS: Patients with type 2 diabetes who required insulin and whose physician had decided to initiate BIAsp 30 were eligible. At baseline, demographic data and detailed medical histories were collected and physicians recorded their reasons for starting BIAsp 30, the glycaemic targets set and the regimens chosen. RESULTS: Data from 51,286 patients were included in analyses. Baseline glycaemic control was poor in all eight countries in the present analysis and in all prestudy treatment groups [no therapy, oral antidiabetic drugs (OADs) only, insulin with or without OADs], and the rates of vascular complications were high. Although the management of each of the three main measures of glycaemic control were key reasons for starting BIAsp 30, target-setting for postprandial glucose levels was variable. A twice-daily regimen was used to start BIAsp 30 therapy for 80% or more of patients. CONCLUSIONS: The IMPROVE baseline data reaffirm the global nature of poor glycaemic control in type 2 diabetes and echo the concerns that initiation of therapy, particularly insulin, is commonly delayed in clinical practice. Although postprandial glucose control was a key driver for physicians' choice of BIAsp 30, this was not consistently reflected in the targets set.

Low-dose bedtime NPH insulin in treatment of secondary failure to glyburide.

Secondary failure to oral hypoglycemic agents (OHAs) is a possible outcome for non-insulin-dependent diabetes mellitus (NIDDM) patients and poses a serious therapeutic problem. In this study, we evaluated the effect of adding a single bedtime low-dose NPH insulin injection to the previous ineffective sulfonylurea therapy in 23 NIDDM patients with true secondary failure to OHAs. This treatment schedule was conducted for 3 mo by 18 patients (78%) who completed the study. In these patients, the addition of NPH insulin (0.2 +/- 0.01 IU/kg body wt) greatly decreased fasting and postprandial plasma glucose (P less than .001) and glycosylated hemoglobin (P less than .005). No weight gain was observed in any of the patients studied. Five patients dropped out: 2 patients (9%) due to insufficient compliance, 2 patients (9%) due to the multiple insulin injections required to achieve good metabolic control, and 1 patient (4%) due to recurrent hypoglycemic episodes. No correlation was observed between glucagon-stimulated C-peptide values and amelioration of metabolic control. In conclusion, most NIDDM patients with secondary failure to OHAs may be successfully treated with the addition of a single low-dose bedtime NPH insulin injection, and residual beta-cell function evaluation is not able to predict the effectiveness of the combined treatment.

NADPH-forming dehydrogenases in the adipose tissue of obese and nonobese diabetics.

The activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) of adipose tissue was markedly decreased, both on a protein and on a fat cell number basis, in nonobese diabetics compared to control subjects, but was unchanged in obese diabetics. Average value in the obese diabetics was about fourfold higher than in nonobese diabetics. On the other hand, the activity of malate dehydrogenase (decarboxylating) (NADP) (EC 1.1.1.40) was reduced by about 50% in both groups of diabetics. These findings suggest that in obese diabetics NADPH-generation in the adipose tissue, necessary for several biosynthetic processes, might be less severely depressed than in lean diabetics.

Enzymes related to lipogenesis in the adipose tissue of obese subjects.

In a group of ten adult obese subjects, maintained for 15 days on a normal caloric intake and balanced diet, the activity of hexokinase (EC 2.7.1.1),6-phosphofructokinase (EC 2.7.1.11), and ATP citratelyase (EC 4.1.3.8) in the adipose tissue was significantly increased, both on a protein and on a fat cell number basis, compared to matched normal subjects. The activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), malate dehydrogenase (EC 1.1.1.37), and malate dehydrogenase (decarboxylating) (NADP) (EC 1.1.1.40), on the other hand, was unchanged. Since both hexokinase and 6-phosphofructokinase are rate-limiting in glycolysis, their enhanced activity would indicate the occurrence of an increased capacity to metabolize glucose and therefore to generate alpha-glycerophosphate. The elevation of ATP citrate-lyase would suggest increased lipogenesis, owing to the regulatory role that this enzyme plays in fatty acid synthesis. The normal activity of glucose-6-phosphate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), which supply NADPH for the reduction of acetyl-CoA to fatty acids, would suggest that the change in lipogenesis is of moderate degree, thereb) affecting only the most rate-limiting enzyme, ATP citrate-lyase. These data, on the whole, are consistent with the occurrence of enhanced triglyceride formation. Whether the enzyme changes observed are adaptive or genetic in nature remains to be clarified.

Enzymes of glucose metabolism and of the citrate cleavage pathway in adipose tissue of normal and diabetic subjects.

Enzyme activities operative in glucose degradation and citrate cleavage pathway were studied in the adipose tissue of twenty-four patients with adult-onset diabetes and normal body weight, aged 59+/-9 years, and twenty-four matched controls. In normal tissue, type II (heat-inactivated) hexokinase moderately predominated over type I (heat-resistant). 6-Phosphofructokinase had an extremely low activity, which was by far the lowest among the ten glycolytic enzyme activities investigated, and which therefore might greatly limit the glycolytic rate. The level of glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase (decarboxylating) was elevated above that occurring in other tissues. This, especially if considered together with the low 6-phosphofructokinase activity, would suggest a major role of pentose cycle in glucose degradation. Of the citrate cleavage pathway enzymes, ATP citrate-lyase, although having a lower activity than malate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), was readily measurable, which contrasts with previous data by others. This finding is consistent with the occurrence of lipogenetic capacity in human adipose tissue. In diabetic tissue, there was a decreased activity, both on a protein and on a wet-weight basis, of enzymes concerned with the glucose entry into metabolic pathways, namely hexokinase (both type I and, especially, type II) and pentose cycle dehydrogenases, as well as of pyruvate kinase. This could be connected with the defective glucose utilization by adipose tissue in diabetes. Beside the above-mentioned dehydrogenases, malate dehydrogenase (decarboxylating) (NADP) was also diminished. The reduction of these NADPH-forming enzymes, which supply reducing equivalents for fatty acid synthesis, would suggest a depressed lipogenesis.

Enzyme activities of NADPH-forming metabolic pathways in normal and leukemic leukocytes.

With respect to the enzymes of NADPH-forming metabolic pathways in human leukocytes: (a) Glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase (decarboxylating) were less active in leukocytes (mostly myeloblasts) from eight patients with acute myeloblastic leukemia (I) than in leukocytes (mostly granulocytes) from 16 normal subjects (II). (b) Of the enzymes of the citrate cleavage pathway, ATP citrate lyase and malate dehydrogenase (decarboxylating) (NADP+) were virtually absent in the cells studied. (c) Isocitrate dehydrogenase (NADP+), aspartate aminotransferase, and alanine aminotransferase, which, together with the much more active malate dehydrogenase, constitute a newly proposed NADPH-forming metabolic cycle, showed a higher activity in I than in II or III, and therefore could compensate, as concerns NADPH-generation, for the low activity of pentose cycle dehydrogenases. We are not sure whether the enzymatic characteristic of I cells is attributable to their immaturity or to their leukemic nature.