Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial.

AIMS: To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin. MATERIALS AND METHODS: A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5-9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint. RESULTS: Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [-1.14% vs. -0.54%; estimated mean treatment difference (ETD): -0.61% (95% CI -0.82 to -0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [-3.31 kg vs. -1.64 kg; ETD: -1.67 kg (95% CI -2.34 to -0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode. CONCLUSIONS: Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy.

Multidisciplinary approach to patients with poorly controlled type 2 diabetes mellitus: a prospective, randomized study.

Practicing physicians as well as diabetes specialists are confronted with the often-frustrating experience of dealing with patients with poorly controlled diabetes. It is not always obvious why these patients fail to improve. The aims of this study were two-fold: (a). to determine if the interdisciplinary approach offered by the Western Negev Mobile Clinic Diabetes Program (WNMDCP) is of benefit in patients with poorly controlled type 2 diabetes and (b). to more fully characterize patients refractory to treatment. Two primary-care clinics of the Western Negev were randomly selected as control and intervention. All patients from both clinics with hemoglobin (HbA(1C)) >or=10% (tested during June-July 2000) were studied for 6 months. Patients from the control clinic continued the usual treatment. Patients from the intervention clinic received the interdisciplinary approach offered by WNMCDP. The rate of improvement of diabetes control, measured as a decrease in HbA(1C) values of at least 0.5%, and compliance to treatment were determined. Overall, 48 of 258 patients in the intervention clinic and 34 of 179 patients in the control clinic met the inclusion criteria. At the 6-month follow-up, we observed significant improvements in plasma glucose (-1.5 mmol/l; p=0.003) and HbA(1C) (-1.8%; p=0.00001) in the intervention group but not in the control group. The compliance and response rates were 85% and 71% for the intervention group and 32% and 35% for the control group, respectively. Patients from the intervention clinic showed significant improvement in the endpoints compared to patients from the control clinic. More than 70% of patients with poorly controlled diabetes mellitus responded to the interdisciplinary treatment approach offered by WNMDCP. The group of non-responders comprised patients with poor compliance (15%) and those with serious concomitant diseases or limitations of mobility.

Western Negev Mobile Diabetes Care Program: a model for interdisciplinary diabetes care in a semi-rural setting.

We describe a mobile diabetes clinic aimed to provide comprehensive, interdisciplinary care to patients with diabetes resident on a semi-rural area. A mobile, tertiary care diabetes clinic, composed of a diabetologist, a diabetes nurse-educator and a dietitian, was created. The clinic regularly visited the primary-care facilities of 3 towns of the Western Negev, a semi-rural area of southern Israel. A standardized, computer-based clinical protocol was applied. Analysis of data was performed on records of all patients who had had at least 2 visits to the clinic. Of 492 patients who met the inclusion criteria, 93.6% were diagnosed with type 2 diabetes, 58% were female, the mean age was 60 years and the mean time after diagnosis of diabetes was 10 years. Most patients had not visited a diabetes center before implementation of the mobile clinic. Parameters of clinical practice such as nutritional advice by a dietitian, interaction with a diabetes nurse-educator, performance of periodic ophthalmologic examination, and measurement of microalbumin excretion improved dramatically after opening of the mobile clinic. Modifiable clinical variables such as body mass index (p<0.0001), systolic (p<0.001) and diastolic (p<0.05) blood pressures, fasting plasma glucose (p<0.001), hemoglobin A1c (p<0.01), LDL-cholesterol (p<0.01) and HDL-cholesterol (p<0.0001) improved significantly after implementation of the program. The implementation of a mobile diabetes care program in an area of low-density population is feasible. Significant improvement in parameters of clinical practice and of modifiable variables of diabetes control was achieved. The mobile diabetes clinic brought the interdisciplinary diabetes-care team to the patients' area of residence. Limited manpower answered the requirement of a geographically spread population.

Miglitol combined with metformin improves glycaemic control in type 2 diabetes.

AIM: To investigate the efficacy and safety of miglitol vs. placebo in type 2 diabetic outpatients insufficiently controlled (HbA1c between 7.5 and 10.5%) with diet and metformin. METHODS: Patients treated with diet and metformin (1500-2250 mg/day) were randomized to receive additional treatment with either miglitol or placebo for 32 weeks. The dosages were force-titrated: 4 weeks at 25 mg miglitol t.i.d., 12 weeks at 50 mg miglitol t.i.d., and 16 weeks at 100 mg miglitol t.i.d. or matching placebo. If the highest dosage could not be tolerated, patients could be down-titrated to 50 mg t.i.d. The primary efficacy criterion was the change in glycated haemoglobin (HbA1c). Secondary efficacy parameters included fasting and 1 h postprandial blood glucose, serum insulin, and fasting and 1 h postprandial triglyceride levels. Safety and tolerability were evaluated by the incidence of adverse events and changes in vital signs or routine biochemical and haematological parameters. RESULTS: One hundred and fifty-two patients were valid for the intent-to-treat (ITT) analysis. There was a significant decrease in HbA1c on adding miglitol to metformin compared to adding placebo (miglitol treatment effect, - 0.21%; placebo treatment effect, + 0.22%; p = 0.011). Postprandial blood glucose declined in both the miglitol/metformin and placebo/metformin groups with a statistically significant difference in favour of miglitol/metformin (end of treatment adjusted means 13.8 mmol/l for miglitol vs. 15.8 mmol/l for placebo, p = 0.0007). Adverse events (AEs) were reported by only 8% more patients in the miglitol/metformin group than placebo/metformin. No cases of hypoglycaemia were reported. CONCLUSIONS: Miglitol can safely and effectively be added to diet and metformin in patients whose type 2 diabetes is insufficiently controlled, and improves glycaemic control by significantly reducing HbA1c and postprandial blood glucose levels.

Splanchnic and systemic hemodynamic effects of sustained euglycemic hyperinsulinemia in rats.

Insulin, in addition to its metabolic function, was found to induce skeletal muscle vasodilatation after acute administration. The vasoactive effects of sustained euglycemic hyperinsulinemia, especially in the splanchnic circulation, are less well known. The aim of this study was to evaluate the systemic and splanchnic hemodynamic effects of sustained euglycemic hyperinsulinemia. Hyperinsulinemia was induced by a sustained-release insulin implant in the scurf area of male rats (release rate -1 U/day). Beginning on the 3rd day, the study group was fed a glucose-rich diet. Hemodynamic studies were performed on the 5th day using the radioactive microsphere technique. Serum insulin was measured by radioimmunoassay. At the time of the hemodynamic measurements, plasma insulin level was higher in the insulin-treated (n=8) compared to control rats (n=8) (23.6 +/- 4.7 vs. 13.2+/-3.9 microu/mL, respectively; p<0.001). Plasma glucose level of the two groups was similar (5.43 +/- 1.07 vs. 5.83 +/- 1.44 mmol/L, respectively). Abdominal skeletal muscle blood flow was higher in the insulin-treated group (0.11 +/- 0.05 vs. 0.05 +/- 0.04 mL x min(-1) x g(-1), respectively; p<0.02). No significant changes were observed in cardiac output and renal blood flow. In the splanchnic circulation: stomach, pancreatic, intestinal, splenic, hepatic arterial and total hepatic blood flow were also not significantly different. In summary, short-term, sustained euglycemic hyperinsulinemia in rats increased blood flow to skeletal muscle but had no hemodynamic effects on cardiac output or splanchnic circulation.

Prolactin serum level in patients with breast cancer.

BACKGROUND: Previous studies have suggested that prolactin may serve as an indicator of disease progression in breast cancer. OBJECTIVES: To evaluate the use of PRL as a serum tumor marker in patients with breast cancer. METHODS: PRL serum level was determined in 99 breast cancer patients and compared with CA 15-3 serum level. RESULTS: Elevated serum level of PRL (> 20 ng/ml) was found in 8 of 99 patients (8.1%). A stratified analysis of prolactin levels according to therapy revealed that PRL levels was increased in 8 of 55 untreated patients (14.5%), but not in patients who received hormonal or chemotherapy in the 3 months preceding the test (0/42 patients, P = 0.009). However, mean PRL level was similar in patients with no evidence of disease activity and in patients with active disease (10.2 vs. 8.2 ng/ml, NS). In comparison, CA 15-3 mean level was significantly lower in patients with no evidence of disease as compared to patients with active disease (18.2 vs. 144.7 units/ml, P < 0.001). PRL level was increased in 6 of 60 patients (10%) with no evidence of disease and in 2 of 39 (5.2%) with active disease (NS). In comparison, CA 15-3 level was increased in 3 of 60 patients (5%) with no evidence of disease and in 24 of 39 (61.5%) with active disease (P < 0.001). CONCLUSIONS: PRL levels are decreased following hormonal or chemotherapy in patients with breast cancer and there is no correlation between PRL serum level and the state of disease. Further studies are needed to clarify a possible clinical significance of hyperprolactinemia in a subset of patients with breast cancer.

Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.

BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Gorging and plasma HDL-cholesterol--the Ramadan model.

OBJECTIVES: To evaluate the effect of a single evening meal (gorging) on plasma lipids and lipoproteins in normal individuals observing the Ramadan Fast. During the Ramadan month, Muslims refrain from food and liquids during the day and eat a large meal after sundown. DESIGN: Sequential measurement of plasma lipids and lipoproteins in Muslims observing the Ramadan Fast and non-fasting individuals. SETTING: The study was conducted in the Bedouin town of Rahat, in the northern Negev area of Israel. SUBJECTS: Twenty-two healthy subjects who fasted during Ramadan and 16 non-fasting laboratory workers, were studied before Ramadan, at week 1, 2 and 4 of the Ramadan month, and again four weeks after the end of Ramadan. RESULTS: Plasma high-density lipoprotein cholesterol (HDL) rose significantly (P < 0.001) at the week 4 measurement, returning to basal levels 4 weeks after the end of Ramadan. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), very-low density lipoprotein cholesterol (VLDL), and lipoprotein (a) [Lp(a)] did not change significantly. CONCLUSIONS: Plasma HDL increased by 23% after four weeks of gorging. The dietary change did not affect the composition of other lipoproteins, such as LDL, VLDL or Lp(a), other plasma biochemical parameters, or BMI. Prolonged gorging, well tolerated by all individuals, is a very effective non-pharmacological method to increase plasma HDL-cholesterol.

Serum prolactin in coeliac disease: a marker for disease activity.

Prolactin, a polypeptide hormone of anterior pituitary origin, has pronounced physiological effects on growth, reproduction, and osmoregulation. Increasing evidence indicates that prolactin also has an immunomodulatory influence on the immune system. The status of prolactin in patients with coeliac disease was investigated by obtaining serum samples from 48 patients with active and non-active coeliac disease. These were compared with samples from 20 children with familial Mediterranean fever and 65 normal controls. Serum prolactin in patients with active coeliac disease was significantly higher than in the other groups studied and reference values. Serum prolactin correlated well with the degree of mucosal atrophy and with the serum concentration of antiendomysial antibodies. Prolactin may play a part in immune modulation in the intestinal damage of coeliac disease and serve as a potential marker for disease activity.

Association of diabetic retinopathy, ischemic heart disease, and albuminuria with diabetic treatment in type 2 diabetic patients. A population-based study.

The management of type 2 diabetes has been a controversial issue. The objective of the present study was to estimate patients' characteristics, particularly diabetes treatment, associated with retinopathy, coronary heart disease, and microalbuminuria in an unselected population of 532 type 2 diabetic individuals from three communities. Questionnaires, clinic record review, and physical examination were used for the assessment of the three conditions. Fasting C-peptide was measured in all insulin-treated participants to establish type 2 diabetes. Patients with and without each of the studied complications were matched for age at diagnosis of diabetes and duration of diabetes. Univariate matched and multivariate conditional logistic regression analyses were used to estimate the independent association between each of the various factors studied and the three complications. Insulin treatment was the only factor independently associated with all three complications (odds ratios 3.3, 3.4, and 5.3 for diabetic retinopathy, coronary heart disease, and albuminuria, respectively). Glycosylated hemoglobin, uric acid, systolic blood pressure levels, and body mass index were also independently associated with at least one of the complications but not with all of them. Although no cause-effect relationship can be established from this cross-sectional design, insulin therapy seems to be a marker of severer diabetes from the time of diagnosis.

Hemodynamic characterization of the diabetic Psammomys obesus--an animal model of type II diabetes mellitus.

The hemodynamic changes occurring early in the course of non-insulin-dependent diabetes mellitus (Type II, NIDDM) are not well understood. We applied the radioactive microspheres technique at an early stage of diabetes in Psammomys abesus (sand rat), an established animal model of spontaneous NIDDM. Ten diabetic and 7 control male animals were studied. Plasma glucose and insulin levels in the diabetic group were significantly higher than in the control group (21.3 +/- 2.1 vs. 6.2 +/- 1.1 mmol/l, and 2,650 +/- 480 vs. 770 +/- 120 pmol/l, respectively). Mean arterial blood pressure, heart rate, cardiac output, splanchnic blood flow, muscular blood flow, and total peripheral resistance were not statistically different between the two groups. Renal blood flow was significantly lower in the diabetic group (7.45 +/- 0.32 vs. 10.48 +/- 0.99 ml/min) and renal arterial resistance was higher (11.65 +/- 0.93 vs. 8.33 +/- 0.76 mm Hg.min/ml) compared with the control group. These results suggest that increased renal resistance and decreased renal blood flow may be the initial hemodynamic alterations in NIDDM. The combination of this animal model with the radioactive microspheres technique provides a new tool for studying the physiopathology, the natural history of hemodynamic changes, and possible therapeutic interventions of Type II diabetes.

Gestational diabetes complicated by severe hypertriglyceridemia and acute pancreatitis.

We present a case of severe acute pancreatitis in pregnancy associated with hypertriglyceridemia, gestational diabetes, sepsis and Adult Respiratory Distress Syndrome. The patient was successfully treated by antibiotics, parenteral feeding, intravenous insulin and bezafibrate and gave birth to a healthy boy at 40 weeks gestation.

Massive splenomegaly responsive to proguanil and with features of hairy cell leukaemia.

A recent Ethiopian immigrant to Israel presented with pneumococcal sepsis, massive splenomegaly and lymph-adenopathy. Investigations revealed many features of both hairy cell leukaemia (HCL) and hyperreactive malarious splenomegaly (HMS). Proguanil therapy for HMS was followed by rapid, marked decrease in spleen size, disappearance of the tartrate-resistant acid phosphatase-positive cells characteristic of HCL, and increasing eosinophilia, but unchanged lymphadenopathy.

Marked increase in plasma high-density-lipoprotein cholesterol after prolonged fasting during Ramadan.

We evaluated the effect of the Ramadan fasting on plasma lipids and lipoproteins in normal individuals. Twenty-four healthy subjects were studied before the end of the Ramadan month (Ram) and for 1 mo thereafter. Plasma total cholesterol (TC), triglycerides, low-density-lipoprotein cholesterol (LDL-C), and very-low-density-lipoprotein cholesterol (VLDL-C) did not change. High-density-lipoprotein cholesterol (HDL-C) was 30% higher (P < 0.005) at the end of Ram; apolipoprotein A-I also increased (P < 0.0001). Both the ratios of TC to HDL-C and LDL-C to HDL-C (P < 0.001) decreased at Ram. There was a striking nonpharmacologic improvement in plasma HDL-C and ratios of TC to HDL-C and LDL-C to HDL-C, which were most probably induced by eating one large evening meal a day. Further studies to determine the mechanism of this observation are underway.

Diabetic ketoacidosis. A rare complication of gestational diabetes.

OBJECTIVE: To describe a case of severe DKA in an otherwise healthy pregnant woman. RESEARCH DESIGN AND METHODS: We describe 2.5 yr of close follow-up of a Bedouin woman who was hospitalized for DKA while pregnant with her 11th child. Plasma glucose returned to normal levels immediately after delivery of a dead conceptus. Four months later, while normoglycemic, the patient became pregnant again. During the subsequent pregnancy, GDM was diagnosed at week 20 of gestation. Tight plasma glucose control was achieved with an insulin regimen, and the patient delivered a healthy girl at term. Plasma glucose again returned to normal and remained so to date, 18 mo postpartum. An OGTT and a euglycemic hyperinsulinemic clamp were performed between pregnancies; another OGTT was performed at week 14 of the last pregnancy. Plasma glucose, insulin, and C-peptide were measured in blood samples during these procedures. RESULTS: We established beyond doubt that the patient developed GDM and returned to essentially normal glucose tolerance after her last (12th) delivery. During the 11th pregnancy, gestational diabetes was complicated by severe DKA. CONCLUSIONS: GDM is a common abnormality of glucose metabolism during pregnancy, which affects fetal development and leads to peripartum complications. Our report stresses that under certain circumstances, gestational diabetes can be complicated by DKA and become life-threatening to the mother and fetus.