The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

BACKGROUND: To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. DESIGN AND METHODS: Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. RESULTS: Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. CONCLUSIONS: Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.     

Prevalence of exocrine pancreatic insufficiency in type 2 diabetes mellitus with poor glycemic control

ObjectivesTo evaluate the relationship between exocrine pancreatic insufficiency and the level of glycemic control in diabetes (DM).MethodsPatients with type 2 DM treated in our clinic were prospectively recruited into the study. Pancreatic diabetes was excluded. Cases with HbA1c ≥7% formed Group A (n = 59), and with HbA1c <7% Group B (n = 42). The fecal level of pancreatic elastase (PE-1) was measured and morphological examinations of the pancreas were performed.ResultsThe PE-1 level was significantly lower in Group A than in Group B (385.9 ± 171.1 μg/g, vs. 454.6 ± 147.3 μg/g, p = 0.038). The PE-1 level was not correlated with HbA1c (r = −0.132, p = 0.187), the duration of DM (r = −0.046, p = 0.65), age (r = 0.010, p = 0.921), BMI (r = 0.203, p = 0.059), or pancreatic steatosis (r = 0.117, p = 0.244). The size of the pancreas did not differ significantly between Groups A and B.ConclusionsAn exocrine pancreatic insufficiency demonstrated by fecal PE-1 determination is more frequent in type 2 DM patients with poor glycemic control. The impaired exocrine pancreatic function cannot be explained by an alteration in the size of the pancreas or by pancreatic steatosis.     

Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.     

Effect of glycemic control on left ventricular diastolic function in type 1 diabetes mellitus

Left ventricular (LV) diastolic dysfunction is a main feature of diabetic heart disease. The aim of this prospective study was to evaluate the influence of glycemic control on diastolic function in type 1 diabetes mellitus. Thirty-six normotensive (24-hour blood pressure <130/80 mm Hg) subjects with inadequately controlled (glycated hemoglobin >7%) type 1 diabetes, without clinically detectable heart disease, were enrolled. After the basal evaluation, insulin therapy was modified to improve glycemic control. Glycated hemoglobin, LV echocardiography, 24-hour blood pressure monitoring, and laboratory tests were repeated after 6 months in all patients and after 12 months in 27 patients. At the basal evaluation, LV anatomy and systolic function were normal in all, and diastolic function was impaired in 14 patients. After 6 months, the mean values of body mass index, 24-hour blood pressure, and LV anatomy and systolic function were unchanged; mean glycated hemoglobin was decreased (p < 0.001), and mean values of diastolic parameters were significantly improved. After 12 months, the mean values of all blood pressure, metabolic, and LV parameters were unchanged. Percent changes of diastolic parameters were inversely correlated with percent changes of glycated hemoglobin, considering changes from the basal to the 6-month evaluation, as well as changes from the 6- to the 12-month evaluation. In conclusion, in normotensive patients with type 1 diabetes, a close relation was found between glycemic control and LV diastolic function, which improves when glycemic control improves. Therefore, diastolic dysfunction can be prevented or reversed, at least partly, by tight glycemic control.     

Effects of rapid-acting insulin analogs on overall glycemic control in type 1 and type 2 diabetes mellitus

The altered pharmacokinetics of new rapid-acting insulin analogs make them very effective in controlling blood glucose peaks after meals. However, simple replacement of regular human insulin by rapid-acting analogs may not be sufficiently effective for overall daily glycemic control. Both basal and bolus insulins need to be addressed with overall changes in insulin regimens for long-term reductions of glycated hemoglobin (HbA(1c)) levels. Clinical studies in patients with type 1 diabetes have shown that better control of postprandial peaks together with optimal use of basal insulin, in multiple injection regimens or with continuous subcutaneous insulin infusion, resulted in improved HbA(1c) levels of 0.3-0.4% in comparison with regular human insulin. In patients with type 2 diabetes the combination therapy of insulin lispro with an oral agent improved metabolic control in the range of 1.5-2.5%. Such decreases in HbA(1c) should lead to a reduction in risk of complications with both type 1 and type 2 diabetes. The better overall metabolic control with rapid-acting insulin analogs was not accompanied by any increased risk for hypoglycemia.     

F2 isoprostane is already increased at the onset of type 1 diabetes mellitus: effect of glycemic control

Much evidence has suggested that oxidative stress (OS) may play a role in the pathogenesis of diabetic complications. However, the relationship between hyperglycemia and OS is inconsistent in diabetic clinical studies. The aim of this study was to evaluate the effect of normalization of blood glucose levels on urinary 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) excretion at the onset of type 1 diabetes. We studied 14 type 1 diabetic patients (50% males; mean age, 24.3 +/- 4.9 years) and 14 control subjects matched by age and body mass index. A 24-hour urine collection was performed to determine 8-epi-PGF(2alpha) as an integrated index of OS production at baseline, before starting insulin therapy, and 16 weeks later. Insulin treatment induced a significant reduction in glycosylated hemoglobin (HbA(1c)) (from 11.5% to 5.4% P =.0001), triglycerides (from 1.0 to 0.8 mmol/L, P =.002), and an increase in high-density lipoprotein (HDL)-cholesterol levels (from 1.1 to 1.5 nmol/L, P =.01) at week 16. This improvement in metabolic control was associated with a statistically significant reduction in 8-epi-PGF(2alpha) values (from 92.0 +/- 41.5 to 66.9 +/- 28.9 pg/mg urinary reatinine excretion, P =.015), although compared with the control group, 8-epi-PGF(2alpha) values remained higher in diabetic patients (66.9 +/- 28.9 v 39.1 +/- 13.8 pg/mg creatinine, P =.004). Enhanced OS is present in early clinical phases of type 1 diabetes, and the amelioration in metabolic control is associated with improvement in this pathogenic pathway.     

Lipid profile correlates with glycemic control in young patients with type 1 diabetes mellitus

Data on dyslipidemia in type 1 diabetes is scarce. The authors aimed to evaluate the lipid profile in patients with type 1 diabetes and its correlation to glycemic control. Ninety-four subjects (53.2% males), aged 15.4+/-4.7 (3.6-21.9 years), with disease duration of 5.0+/-3.6 years (0.3-17 years) were evaluated for heart rate, blood pressure, height, and weight. Laboratory data included total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs), glycemia, glycosylated hemoglobin (HbA1c), creatinine, thyroid-stimulating hormone, antithyroid antibodies, and 24-hour microalbuminuria. Correlations were performed by the Spearman rank correlation test, and the significance level was <0.05. Mean values were TC, 168.6+/-46.6 mg/d; HDL, 43.1+/-15.3 mg/dL; LDL, 110.9+/-40.6 mg/dL; TGs, 78.3+/-48.6 mg/dL; glycemia, 204.6+/-116.7 mg/dL; and HbA1c, 11.2%+/-2.9%. High TC (43.9% vs. 10.7%; p<0.002) and LDL (51.5% vs. 10.7%; p<0.01) were more prevalent in patients 19 years and younger (n=66). HbA1c correlated with TC (r=0.30; p=0.004), LDL (r=0.28; p=0.008), TG (r=0.31; p=0.003), and TG/HDL ratio (r=0.25; p=0.01). Duration of diabetes correlated with LDL (r=0.21; p=0.04) and insulin daily doses with TG (r=0.23; p=0.04) and body mass index expressed as z scores (r=-0.28; p=0.007). There was a high prevalence of hypercholesterolemia (54.6%) in these diabetic patients, and lipid fraction levels were correlated with HbA1c. Good management of diabetes seems to be of paramount importance in controlling dyslipidemia.     

Periodontal disease and type 1 diabetes mellitus: Associations with glycemic control and complications: An Indian perspective

AimTo evaluate the frequency of periodontal disease in a group of patients with type 1 diabetes mellitus and its relationship with diabetic metabolic control, duration and complications.Materials and methodsA comparison was made of periodontal parameters (plaque index, bleeding index, pocket depth and attachment loss) in a group of diabetic patients versus a group of non-diabetics (n = 20). Statistical analysis was performed to evaluate the relationship between periodontal parameters and degree of metabolic control, the duration of the disease and the appearance of complications.ResultsDiabetics had greater bleeding index (p < 0.001), probing pocket depth (p < 0.001) and clinical attachment level (p = 0.001). Patients diagnosed for diabetes for shorter duration of time (4–7 years) showed bleeding index-disease severity correlation to be 1.760 ± 0.434.ConclusionPatients with type 1 diabetes have increased periodontal disease susceptibility. Periodontal inflammation is greatly increased in subjects with longer disease course, poor metabolic control and diabetic complications.     

Predictors of glycemic control in Japanese subjects with type 2 diabetes mellitus

The purpose of this study was to investigate which pathophysiological and demographic characteristics of Japanese subjects with type 2 diabetes mellitus were associated with poor glycemic control and to propose a statistical model for predicting their glycemic control. A total of 220 subjects with type 2 diabetes mellitus were enrolled in this study. Frequently sampled intravenous glucose tolerance test was performed to determine the first-phase C-peptide secretion rate (CS1) and insulin sensitivity index. Multiple regression analysis in a stepwise manner was carried out to identify independent regulators of glycemic control. Upon stepwise linear regression analysis with hemoglobin A1c as a dependent parameter, fasting plasma glucose concentration (FPG), CS1, and onset age remained as predictors, explaining 41.0% of glycemic control. The young-onset group (onset age < or =48 years) had significantly higher hemoglobin A1c than the old-onset group (onset age >48 years) (P = .0148), although the present age was significantly older in the old-onset group; and there were no significant differences in duration of diabetes, treatment, body mass index, FPG, fasting insulin level, homeostasis model assessment of insulin resistance, CS1, and log(insulin sensitivity index) between them. Worsening factors of glycemic control in Japanese subjects with type 2 diabetes mellitus were elevated FPG, impaired first-phase insulin secretion, and young age of onset of the disease. Because glycemic control in the subjects with young-onset diabetes tends to be worse, early and aggressive intervention should be required for those with young-onset diabetes to prevent long-term complications.     

Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context

Type 2 diabetes mellitus is the consequence of both insulin resistance and impaired insulin secretion. In the progression from normal glucose tolerance to diabetes, postprandial glucose (PPG) levels often rise before fasting plasma glucose (FPG) levels increase above 126 mg/dL (7.0 mmol/L). Numerous epidemiologic studies have shown that impaired glucose tolerance is associated with increased risk for macrovascular disease and that isolated postchallenge hyperglycemia is an independent factor for increased mortality. Reducing the risk for microvascular complications by improving glycosylated hemoglobin (HbA(1c)) levels is well documented. Emerging data now support the relationship between glycemic control and macrovascular disease. Epidemiologic studies documenting postprandial hyperglycemia and the risk for increased mortality suggest that lowering PPG levels might be beneficial. Optimizing both FPG and PPG is important in achieving normal/near-normal glucose levels. Many patients with type 2 diabetes have difficulty attaining the recommended HbA(1c) goal despite normal/near-normal FPG levels; thus, pharmacologic treatment targeting PPG levels may prove beneficial.     

The relationship between glycemic control and platelet activity in type 2 diabetes mellitus

AimsPlatelet activity and aggregation potential, which are essential components of thrombogenesis and atherosclerosis, can be conveniently estimated by measuring mean platelet volume (MPV) as part of whole blood count. It has been shown that MPV was significantly higher in diabetes mellitus (DM); however, the effect of glycemic control on MPV has not been studied. The aim of this study was to investigate the relationship among MPV, glycemic control, and micro- and macrovascular complications in type 2 DM.MethodsSeventy patients with type 2 DM and 40 age- and sex-matched healthy individuals were enrolled. Diabetic patients were grouped into those with glycated hemoglobin (HbA1c) levels ≤7% (Group A, n=35 patients) and those with HbA1c >7% (Group B, n=35 patients). Initially, both groups were compared with regard to MPV, HbA1c, serum lipid levels, coronary artery disease, retinopathy, neuropathy, and nephropathy. Thereafter, Group B was called to monthly visits to obtain improved control glycemic control, which was defined as achievement of HbA1c ≤7%. At the end of 3 months of follow-up, Group B was reevaluated.ResultsMPV was significantly higher in patients with DM than in controls (8.7±0.8 fl vs. 8.2±0.7 fl, P=.002). In diabetic patients, there was a significant positive correlation between MPV and HbA1c levels (r=.39, P=.001) but not diabetic vascular complications. When we compared the two diabetic groups, Group B patients had significantly higher MPV than Group A (9.0±0.7 fl vs. 8.4±0.8 fl, P=.01). Thirty patients (86%) of Group B achieved improved glycemic control at the end of the 3 months. MPV of the patients with improved glycemic control were significantly decreased compared to baseline MPV (8.4±0.8 fl vs. 9.0±0.7 fl, P=.003).ConclusionsOur results suggested a close relationship between poor glycemic control and increased platelet activity in patients with type 2 DM. Furthermore, platelet activity recovered through improved glycemic control, which may prevent the possible role of platelets in cardiovascular events in these patients.     

Alogliptin: a novel molecule for improving glycemic control in type II diabetes mellitus

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. It is characterized by high circulating levels of glucose resulting from insulin resistance and impaired insulin secretion. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. The results of Phase II and Phase III human studies, upon evaluation for clinical efficacy, safety and tolerability in patients with type 2 diabetes, have demonstrated that Alogliptin is effective and well tolerated as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin, with an excellent safety profile.     

Improved glycemic control induces regression of left ventricular mass in patients with type 1 diabetes mellitus

BACKGROUND: Diabetes mellitus has been associated with abnormalities of cardiac function and left ventricular hypertrophy. We sought to determine whether improved glycemic control in patients with type 1 diabetes mellitus will induce reversal of those abnormalities. METHODS: We prospectively studied 19 patients (mean age 40+/-9 years) with longstanding type 1 diabetes mellitus (28+/-4 years), who participated in a program of stringent glycemic control. Glycemic control was monitored with hemoglobin A1c levels, and improvement was defined as >1% (absolute) decrease of hemoglobin A1c. Two-dimensional and Doppler echocardiograms and ambulatory 24-h blood pressures were obtained at baseline and after 1 year. Left ventricular mass was determined using the area-length method. RESULTS: In the patients with improved glycemic control (n=12), hemoglobin A1c decreased from 9.8% to 7.8% (p< or =0.0001), interventricular septal thickness decreased from 10.3 to 9.4 mm (p< or =0.05), and left ventricular mass regressed from 205 to 182 g (p< or =0.05). Septal thickness and left ventricular mass remained unchanged in the patients who did not achieve improvement of glycemic control. Left ventricular internal diameters, posterior wall thickness, fractional shortening, E/A ratio of mitral inflow, E-wave deceleration time (DT), and ambulatory 24-h blood pressures did not change significantly after 1 year in either group. CONCLUSIONS: Improved glycemic control in patients with type 1 diabetes mellitus is associated with regression of septal thickness and left ventricular mass without significant effect on systolic or diastolic function, in the absence of significant alterations in ambulatory 24-h blood pressures.     

Glucose sensor evaluation of glycemic instability in pediatric type 1 diabetes mellitus

Maintaining blood glucose (BG) levels within the target range can be an elusive goal in children with type 1 diabetes mellitus (DM). To identify factor(s) that may contribute to glycemic instability, we analyzed the Continuous Glucose Monitoring System (CGMS) (Medtronic MiniMed, Northridge, CA) profiles of a group of children with type 1 DM and a history of frequent BG fluctuations and hypoglycemia. A total of 30 (17 girls, 13 boys) pediatric patients with a history of frequent BG fluctuations and hypoglycemia (mean age, 10.5 +/- 0.7 years; duration, 5.0 +/- 0.6 years), on three to four injections of insulin daily or insulin pump therapy, were evaluated by the CGMS. The mean BG (MBG), absolute means of daily differences (MODD), mean amplitude of glycemic excursion (MAGE), and number of hypoglycemic events (BG <60 mg/dL) for 48 h were calculated in each patient. There was a significant correlation between MBG and glycosylated hemoglobin (HbA1c) (r(2) = 0.22, p < 0.009). There was also a significant correlation between severity of lipohypertrophy and glycemic control (HbA1c) (r(2) = 0.20, p < 0.01). The MODD values had a positive correlation with the severity of injection site lipohypertrophy (r(2) = 0.37, p < 0.0003). The MAGE values had a positive correlation with bolus:basal insulin ratio (r(2) = 0.22, p < 0.009) and number of hypoglycemic events (r(2) = 0.21, p < 0.008), independent of age, MBG, and glycemic control. The 48-h CGMS profile can help characterize day-to-day and within-day BG variability and identify factors influencing glycemic instability in pediatric type 1 DM.     

The effect of real-time continuous glucose monitoring on glycemic control in patients with type 2 diabetes mellitus

Background:

Real-time continuous glucose monitoring (RT-CGM) improves hemoglobin A1c (A1C) and hypoglycemia in people with type 1 diabetes mellitus and those with type 2 diabetes mellitus (T2DM) on prandial insulin; however, it has not been tested in people with T2DM not taking prandial insulin. We evaluated the utility of RT-CGM in people with T2DM on a variety of treatment modalities except prandial insulin.

Methods:

We conducted a prospective, 52-week, two-arm, randomized trial comparing RT-CGM (n = 50) versus self-monitoring of blood glucose (SMBG) (n = 50) in people with T2DM not taking prandial insulin. Real-time continuous glucose monitoring was used for four 2-week cycles (2 weeks on/1 week off). All patients were managed by their usual provider. This article reports on changes in A1C 0–12 weeks.

Results:

Mean (±standard deviation) decline in A1C at 12 weeks was 1.0% (±1.1%) in the RT-CGM group and 0.5% (±0.8%) in the SMBG group (p = .006). There were no group differences in the net change in number or dosage of hypoglycemic medications. Those who used the RT-CGM for ≥48 days (per protocol) reduced their A1C by 1.2% (±1.1%) versus 0.6% (±1.1%) in those who used it <48 days (p = .003). Multiple regression analyses statistically adjusting for baseline A1C, an indicator for usage, and known confounders confirmed the observed differences between treatment groups were robust (p = .009). There was no improvement in weight or blood pressure.

Conclusions:

Real-time continuous glucose monitoring significantly improves A1C compared with SMBG in patients with T2DM not taking prandial insulin. This technology might benefit a wider population of people with diabetes than previously thought.