Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes.

AIM: To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. METHODS: A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. RESULTS: The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. CONCLUSIONS: The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic events than other insulin regimens.

A comparison between sitagliptin or glibenclamide in addition to metformin + pioglitazone on glycaemic control and ß-cell function: the triple oral therapy.

AIMS: To evaluate which triple oral therapy between metformin + pioglitazone + sitagliptin and metformin + pioglitazone + glibenclamide can be more useful in improving glycaemic control and should be preferred in clinical practice. METHODS: During the 2-year run-in period, patients were instructed to take metformin monotherapy for the first year, then a combination of metformin and pioglitazone for the second year, then patients were randomized to add glibenclamide or sitagliptin to the dual combination of metformin and pioglitazone for another year. RESULTS: Body weight reached with sitagliptin at 36 months was lower than that reached with glibenclamide. Fasting plasma insulin and homeostasis model assessment of insulin resistance were significantly increased by triple therapy with glibenclamide and decreased by that with sitagliptin. While sitagliptin did not change homeostasis model assessment of ß-cell function, this value was significantly increased by glibenclamide. Fasting plasma proinsulin was not influenced by triple oral therapy including glibenclamide, while it was decreased by the therapy including sitagliptin compared to glibenclamide. Triple oral therapy with sitagliptin better improved ß-cell function measures compared with the glibenclamide therapy. CONCLUSIONS: Sitagliptin should be preferred to glibenclamide as an addition to the metformin + pioglitazone combination for its better protection of ß-cell secretion and its neutral effect on body weight.

Exenatide plus metformin compared with metformin alone on ß-cell function in patients with Type 2 diabetes.

AIM: To quantify how much exenatide added to metformin improves ß-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone. METHODS: A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 µg twice a day for the first 4 weeks and forced titration to 10 µg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and ß-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor-α. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation. RESULTS: Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment ß-cell function index (HOMA-ß) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-α. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin. CONCLUSION: Exenatide is effective not only on glycaemic control, but also in protecting ß-cells and in reducing inflammation.

Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients.

The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients (T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters.

Efficacy and safety of ezetimibe/simvastatin association on non-diabetic and diabetic patients with polygenic hypercholesterolemia or combined hyperlipidemia and previously intolerant to standard statin treatment.

BACKGROUND AND OBJECTIVE: One of the problems associated with reaching the low-density lipoprotein cholesterol (LDL-C) target during statin treatment is the emergence of laboratory or clinical side effects. The aim of our study was to evaluate the prevalence of statin-associated adverse events in diabetic and non-diabetic patients affected by polygenic hypercholesterolemia or combined hyperlipidemia and the efficacy and tolerability of treatment with ezetimibe/simvastatin 10/10 mg/day on the same subjects experiencing the adverse events. METHODS: Consecutively enrollment of patients affected by polygenic hypercholesterolemia or combined hyperlipidemia with or without type 2 diabetes mellitus. Each Centre used any of the available statins on the basis of current clinical judgement and monitored enrolled patients for adverse events during the following 2 years. Those patients with moderate adverse events suspended the current statin therapy for 1 month (washout period), and then were shifted to treatment with ezetimibe/simvastatin 10/10 mg/day and again monitored for adverse events in the following 6 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, creatinine phosphokinase and monitored adverse events such as asthenia and myalgia. RESULTS AND DISCUSSION: All 1170 Caucasian patients affected by polygenic hypercholesterolemia obtained a significant reduction in LDL-C during the observation period (P < 0*05), while those with combined hyperlipidemia also showed a reduction in TG plasma level (P < 0*05) and a significant increase in HDL-C (P < 0*05). Patients affected by polygenic hypercholesterolemia experiencing adverse event under statin treatment obtained a significantly lower reduction than those tolerating the treatment (P < 0*001). The prevalence of adverse events under statin treatment was 4*9% in non-diabetic patients with polygenic hypercholesterolemia, 8*6% in those with combined hyperlipidemia, 7*1% in diabetic patients with polygenic hypercholesterolemia and 7*6% in those with combined hyperlipidemia. Six months after the shift to treatment with ezetimibe/simvastatin 10/10 mg, all patients experienced a significant improvement in LDL-C, TG and HDL-C plasma level. No adverse event was registered during the ezetimibe/simvastatin 10/10 mg treatment period. It seems that previous side effects observed with statins did not re-appear with the administration of ezetimibe/simvastatin 10/10 mg/day. CONCLUSIONS: The efficacy and adverse effect profile of the ezetimibe and simvastatin combination appear to be good for both diabetic and nondiabetic patients, and in both conditions.

Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience.

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Possible synergistic effect of metformin and enalapril on the development of hyperkaliemic lactic acidosis.

A 71 year old hypertensive, non insulin-dependent diabetic patient with moderate renal insufficiency taking 500 mg/d of metformin and 5 mg/d of enalapril, developed metabolic acidosis characterized by fairly elevated anion gap, hyperchloremia, severe hyperkaliemia, normal plasma level of 3-hydroxybutyric acid, absence of ketonuria and high plasma level of lactic acid. This biochemical feature allowed us to ascribe the pathogenesis of metabolic acidosis, both to the increased plasma level of lactic acid and to the type IV renal tubular acidosis syndrome, the precipitating factor being an infection of urinary tract (as we assumed on the basis of the urine culture). The patient was dehydrated and lethargic; the ECG revealed the presence of nonparoxysmal junctional tachycardia. The clinical evolution was favorable under the treatment with an infusion of isotonic saline solutions, mild alkalinizing solutions, low-dose regular insulin and antibiotics. It is likely that metformin and enalapril, regularly taken by this nephropathic patient, could have played an iatrogenic role, even if the doses were low. This case highlights the importance of complying with the contraindications of these drugs, to avoid the rare but reported life-threatening complications of metformin administration.

[Lactic acidosis and severe hyperkalemia in a diabetic patient treated with metformin and enalapril: influence of acute renal disease and drugs]. / Acidosi lattica ed iperpotassiemia grave in un paziente diabetico in terapia con metformina ed enalapril: influenza di patologia renale acuta e farmaci.

A 71 year old hypertensive and non insulin-dependent diabetic patients with moderate renal insufficiency taking 500 mg/d of metformin and 5 mg/d of enalapril, developed metabolic acidosis characterized by fairly elevated anion gap, hyperchloremia, severe hyperkalemia, normal plasma level of beta-hydroxybutyric acid, absence of ketonuria and high plasma level of lactic acid. This biochemical feature allowed us to ascribe the pathogenesis of metabolic acidosis both to the increased plasma level of lactic acid and to the type IV renal tubular acidosis syndrome, the precipitating factor being an infection of urinary tract (as we assumed on the basis of the urine culture). The patient was dehydrated and lethargic; the ECG revealed the presence of nonparoxysmal junctional tachycardia. The clinical evolution was favorable thanks to the treatment with the infusion of isotonic saline solutions, mild alkalinizing solutions, low-dose regular insulin and antibiotics. It is likely that metformin and enalapril, regularly assumed by the patient, could have played a iatrogenic role even if they were taken in low dosages. This event points out the importance of complying with the indications and especially the contraindications of these drugs, to avoid life threatening complications as that one occurred in this case.

Quality of Life, Wishes, and Needs in Women with Gestational Diabetes: Italian DAWN Pregnancy Study.

The DAWN (Diabetes Attitudes, Wishes and Needs) study is a survey promoted by the International Diabetes Federation to recognize the perceptions and attitudes of people suffering from diabetes mellitus. In this context, we evaluated the quality of life of Italian and immigrant women with gestational diabetes mellitus (GDM). Information was gathered using a structured questionnaire for patients' self-compilation. In a 3-month period, a 51-item questionnaire was submitted to 198 Italians and 88 immigrants (from 27 different foreign nationalities). Italian women were older and had higher education than the immigrants. 60% of the Italians and 38% of the immigrants had a family history of diabetes mellitus. In both groups, the diagnosis of GDM caused anxiety; one-third of women feared their child could contract diabetes at delivery and/or have congenital malformations. Some women had trouble in following treatment regimens: the major concern being dietary advice and blood glucose testing. Most women were satisfied (34%) or highly satisfied (60%) with the quality of care, although the degree of cooperation between diabetes specialists and gynaecologists was considered sometimes unsatisfactory. In order to optimize maternal and foetal outcomes, educational projects and improved communication between patients and the healthcare provider team are recommended.

Exenatide versus glibenclamide in patients with diabetes.

BACKGROUND: Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes. METHODS: One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months. RESULTS: Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide. CONCLUSIONS: Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Serum lipid pattern as severity indicator of angiographically assessed coronary artery disease.

In this study we compared the relative utility of plasma lipid and apolipoprotein pattern as predictor of extent of Coronary Artery Disease as angiographically established. The lipid and apolipoprotein values were plotted in multiple stepwise analysis against coronary score determined as follows: at least 1 coronary artery system (left, anterior, descendent, circumflex, right) with a >/= 25% stenosis 1 point, number of involved vessel 1, 2, 3, .... adjunctive points; sequential lesions +1 point; < = %50% stenosis +1 point; 75-95 % +2 points; > 95% +3 points. The statistical analysis demonstrate a strong influence on extent of disease by total-cholesterol, % HDL-cholesterol on total cholesterol and by the difference between LDL and HDL-cholesterol. We conclude that, in predicting the extension of CAD, is important to know how total cholesterol is distributed in plasma apolipoprotein system.

Metabolic variations with oral antidiabetic drugs in patients with Type 2 diabetes: comparison between glimepiride and metformin.

Patients with Type 2 diabetes (T2DM) are at high risk of morbidity and mortality from cardiovascular complications, and hypoglycaemia increases this risk. Furthermore, other metabolic parameters exacerbate cardiovascular risk in these patients. The aim of the study was to compare the metabolic effects of glimepiride and metformin in patients with T2DM. We evaluated 164 patients with T2DM (80 males, 84 females) in a multicentre, randomised, controlled, open, parallel group study comparing glimepiride with metformin. Eighty-one patients (aged 56+/-10 yr) received glimepiride (3+/-1 mg/d); 83 patients (aged 58+/-9 yr) received metformin (2500+/-500 mg/d). Patients had been diagnosed for < or = 6 months; they were non-smokers; had no hypertension or coronary heart disease; were not taking hypolipidaemic drugs, diuretics, beta-blockers or thyroxin; and had normal renal function. Metabolic parameters were measured after 6 and 12 months of treatment. Glimepiride significantly lowered lipoprotein(a) [Lp(a)] and homocysteine levels (HCT) at 6 and 12 months. Both glimepiride and metformin lowered plasminogen activator inhibitor Type 1 (PAI-1) at 12 months and significantly improved levels of glycosylated haemoglobin, fasting plasma glucose and post-prandial plasma glucose after 6 and 12 months. Metformin significantly lowered fasting plasma insulin and postprandial plasma insulin. Glimepiride and metformin also reduced levels of other metabolic parameters in patients with T2DM. In particular, glimepiride significantly reduced HCT, Lp(a), and PAI-1 levels, important metabolic risk factors for atherosclerotic vascular disease. These reductions may be owing to improved glucose metabolism, but it cannot be excluded that these drugs have a direct effect on additional metabolic parameters.

Mental arithmetic stress as a test for evaluation of diabetic sympathetic autonomic neuropathy.

The effects of a 1-min mental arithmetic stress test on heart rate change were studied in 72 Type 1 diabetic patients, 36 without and 36 with diabetic autonomic neuropathy (mean age 33 and 44 yr, respectively), and in 80 matched normal subjects. Variation in hand skin temperature was also recorded in 25 normal subjects and 30 diabetic patients without and 32 with autonomic neuropathy. While mental arithmetic rapidly reduced skin temperature of normal volunteers and of patients without autonomic neuropathy, no effect was found in autonomic neuropath (a drop of 0.63 +/- 0.05 (+/- SE), 0.52 +/- 0.04 and 0.16 +/- 0.02 degrees C (p less than 0.001), respectively). In control subjects and in diabetic patients without and with autonomic neuropathy the heart rate increase was 22.9 +/- 6.8 (+/- SD), 21.4 +/- 8.4 and 7.0 +/- 3.7 beats min-1, respectively (p less than 0.001). The ratio between maximum mental arithmetic-induced heart rate and basal heart rate was 1.29 +/- 0.10, 1.24 +/- 0.10 and 1.07 +/- 0.05 (p less than 0.001) for healthy subjects, non-neuropathic patients, and neuropathic patients. Cut-off values (the low normal limit for these variables) are proposed: skin temperature 0.23 degrees C, heart rate increase 11.6 beats min-1 and heart rate ratio 1.12. Anxiety state, blood glucose concentration (excluding hypoglycaemia), body position, basal heart rate, and age did not interfere with responses to mental arithmetic stress.

Epidural spinal electrostimulatory system (ESES) in the management of diabetic foot and peripheral arteriopathies.

Epidural spinal electrostimulatory system (ESES) or dorsal column stimulation (DCS) may be used for the treatment of peripheral vascular diseases of the lower extremities. ESES has been used in our metabolic and surgical department as a way to ameliorate inadequate blood supply in patients suffering from diabetic foot (seven patients), painful chronic arterial narrowing, or inoperable occlusions (25 patients). The continuous stimulation by an implantable apparatus (Medtronic model Itrel, Medtronic, Inc., Minneapolis, MN, USA) led to a reduction or disappearance of pain, an improvement in plethysmographic curves, functional performance, and trophic lesions in about 75% of the patients. The system is safe and well-tolerated by patients.