Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 µg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-µg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-µg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-µg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-µg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.

Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD-11 trial.

AIM: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add-on to metformin in subgroups defined by age (<65 and ≥65 years). MATERIALS AND METHODS: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent-to-treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population. RESULTS: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment-by-age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups. CONCLUSION: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose-related improvements in HbA1c and BW with no significant treatment-by-age interactions, and with a similar safety profile across age subgroups.

Metabolic parameters in smokers undergoing smoking reduction.

INTRODUCTION: Few human studies have explored the mechanisms of smoking-induced insulin resistance. Aims: To prospectively examine the metabolic changes of smoking reduction. METHODS: Cigarette smokers (n = 22; ½-2 packs per day) were enrolled in a smoking reduction program (counseling plus bupropion × 8 weeks; Phase I) followed by monitoring only (no counseling or bupropion × 16 weeks; Phase II). We serially measured exhaled carbon monoxide (CO) and urine nicotine metabolites; fat distribution, and metabolic parameters by hyperinsulinemic clamps including hepatic glucose output (HGO) and indirect calorimetry, adjusted for total caloric intake and expenditure. RESULTS: CO and nicotine metabolite levels fell with smoking reduction during Phase I (all p < 0.05), without any further changes through Phase II. Central-to-peripheral fat ratio increased during Phase I, but then fell during Phase II (all p < 0.05). Over 24 weeks, basal HGO fell (p = 0.02); and falling CO and nicotine metabolite levels correlated inversely with changes in glucose oxidation, and directly with changes in weight (all p < 0.05). CONCLUSIONS: Smoking reduction produced a transient worsening of central fat redistribution followed by a more significant improvement; along with other net beneficial metabolic effects.

Results of a Study Comparing Glycated Albumin to Other Glycemic Indices.

CONTEXT: Intermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C. OBJECTIVE: Compare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices. DESIGN: 24-week prospective study of assay performance. SETTING: 8 US clinics. PARTICIPANTS: Subjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52). INTERVENTIONS: GA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles. MAIN OUTCOME MEASURES: Primary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management. RESULTS: GA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively. CONCLUSIONS: Compared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773).

Differences in cholesterol management among states in relation to health insurance and race/ethnicity across the United States.

BACKGROUND: Across the United States, hyperlipidemia remains inadequately controlled and may vary across states according to differences in health insurance coverage and/or race/ethnicity. OBJECTIVE: To examine relationships between states' health insurance and race/ethnicity characteristics with measures of hyperlipidemia management across the 50 U.S. states and the District of Columbia. METHODS: Cross-validated, multiple linear regression modeling was used to analyze associations between states' health insurance patterns or proportions of racial minorities (from the 2010 U.S. Census data) and states' aggregate frequency of checking cholesterol within the previous 5 years or prescriptions written for lipid-lowering medications (from national survey and population-adjusted retail prescription data, respectively), with adjustments for age, sex, body mass index, race/ethnicity, and poverty. RESULTS: In states with proportionately more uninsured, cholesterol levels are checked less often, but in states with proportionately more private, Medicare, or Medicaid coverage, providers are not necessarily more likely to check cholesterol or to write more prescriptions. In states with proportionately more African-Americans and/or Hispanics, cholesterol is more likely to be checked, but in states with more African-Americans, more prescriptions were written, whereas in states with more Hispanics, fewer statin prescriptions were written. CONCLUSION: Variations across states in insurance and racial/ethnicity mix are associated with variations in hyperlipidemia management; less-insured states may be less effective whereas states with more private, Medicare, or Medicaid coverage may not be more effective. In states with proportionately more African-Americans vs. Hispanics, lipid medications may be prescribed differently. Our findings warrant further investigations.

Psychological insulin resistance among low-income, U.S. racial minority patients with type 2 diabetes.

AIMS: To examine psychological insulin resistance (PIR), the unwillingness to accept insulin therapy, within a unique U.S. population of patients with diabetes. METHODS: A cross-sectional survey of PIR among low-income, U.S. Latino and African-American (AA) patients with type 2 diabetes recruited from a diabetes specialty clinic. RESULTS: Data from 136 insulin-naïve respondents (57% female, 69% Latino, mean age 51.1 ± 10.3 years; $200-$1000 median monthly household income; grade 8-12 median education) revealed a 48% prevalence of complete unwillingness to begin insulin. In comparing Latinos to AA, Latino respondents were younger, lived fewer years in the U.S., had less education, were more likely unwilling to use insulin (53% vs. 30%, p = 0.03), and reported a more negative attitude to 8 of 9 PIR domains (p ≤ 0.01 for each). Fewer years in the U.S. predicted greater unwillingness and a more negative attitude on 8 of 9 PIR domains (p ≤ 0.03 for each); and less education predicted greater feelings of unfairness (p = 0.01). CONCLUSIONS: PIR is highly prevalent among low income, U.S. Latino patients with type 2 diabetes. Our data may help to better guide culturally appropriate counseling regarding insulin use.

The endocrine effects of nicotine and cigarette smoke.

With a current prevalence of approximately 20%, smoking continues to impact negatively upon health. Tobacco or nicotine use influences the endocrine system, with important clinical implications. In this review we critically evaluate the literature concerning the impact of nicotine as well as tobacco use on several parameters of the endocrine system and on glucose and lipid homeostasis. Emphasis is on the effect of smoking on diabetes mellitus and obesity and the consequences of smoking cessation on these disorders. Understanding the effects of nicotine and cigarettes on the endocrine system and how these changes contribute to the pathogenesis of various endocrine diseases will allow for targeted therapies and more effective approaches for smoking cessation.

Sitagliptin compared with thiazolidinediones as a third-line oral antihyperglycemic agent in type 2 diabetes mellitus.

OBJECTIVE: To compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus. METHODS: In an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A1c levels less than 7.5% at 4 months continued through 1 year of follow-up. RESULTS: One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptin- and thiazolidinedione-treated patients had identical hemoglobin A1c levels (mean ± SD) (9.4 ± 1.8% and 9.4 ± 1.9%, respectively) and similar known diabetes duration (6.7 ± 5.0 years and 7.6 ± 5.8 years, respectively). Hemoglobin A1c was reduced in both groups at 4 months (P<.001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 ± 1.7% vs -1.3 ± 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated. CONCLUSIONS: Among ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, third-line add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months.

Insulin glargine compared to NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients.

AIMS: We compared basal regimens of glargine or NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients who were sub-optimally controlled on maximally tolerated doses of combination oral agents. METHODS: Eighty-five subjects were randomized to 26 weeks of open-label, add-on therapy using single doses of bedtime NPH, bedtime glargine, or morning glargine; initially through an 8-week dose titration phase, followed by a 16-week maintenance phase during which insulin doses were adjusted only to avoid symptomatic hypoglycemia. RESULTS: All three groups were comparable at baseline (mean HbA(1c) 9.3 ± 1.4%), and improved their HbA(1c) (to 7.8 ± 1.3%), fasting, and pre-supper glucose readings, with no significant between-group differences. Weight gain was greater with either glargine regimen (+3.1 ± 4.1 kg and +1.7 ± 4.2 kg) compared to NPH (-0.2 ± 3.9 kg), despite comparable total insulin doses. Pre-supper hypoglycemia occurred more frequently with morning glargine, but nocturnal hypoglycemia and improvements in treatment satisfaction did not differ among groups. CONCLUSIONS: Among inner city ethnic minority type 2 diabetic patients in the U.S., we found no differences in basal glycemic control or nocturnal hypoglycemia between glargine and NPH, although glargine precipitated greater weight gain.

A population-based, cross-sectional comparison of lipid-related indexes for symptoms of atherosclerotic disease.

Current lipid guidelines recommend that therapy be targeted primarily at low-density lipoprotein (LDL) cholesterol, and that other lipid indexes may be used as secondary or supplementary targets. Emerging data have suggested that measures such as non-high-density lipoprotein (HDL) cholesterol, apolipoprotein-B, or the total/HDL cholesterol ratio may be more predictive of cardiovascular risk than LDL cholesterol. We conducted a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey to directly compare the strengths of the associations among various lipid-related indexes and clinical features consistent with atherosclerotic disease. From approximately 9,500 data sets in the overall analysis, the apolipoprotein-B/HDL cholesterol ratio emerged as the strongest correlate (odds ratio 1.177 per 1 mg/dl increment, 95% confidence interval 1.063 to 1.302, p <0.01), followed by the total or non-HDL cholesterol/HDL cholesterol ratio (odds ratio for each 1.070 per 1 mg/dl increment, 95% confidence interval 1.024 to 1.118, p <0.01), followed by the triglyceride/HDL cholesterol ratio (odds ratio 1.033 per 1 mg/dl increment, 95% confidence interval 1.011 to 1.056, p <0.01). Neither LDL cholesterol nor the LDL/HDL cholesterol ratio correlated significantly. Parallel analyses comparing tertile extremes and analyses in subgroups determined by gender, age, and body mass index revealed similar findings. The LDL/HDL cholesterol ratio was only significant for lean patients. In conclusion, these observations add to the published data suggesting that LDL cholesterol may not be the best target of lipid-lowering treatment strategies.

Effects of transdermal testosterone administration on insulin sensitivity, fat mass and distribution, and markers of inflammation and thrombolysis in human immunodeficiency virus-infected women with mild to moderate weight loss.

OBJECTIVE: To determine the effects of raising serum T levels into the high normal female range by transdermal T administration on insulin sensitivity, fat volume, and markers of inflammation and thrombolysis in HIV-infected women with recent weight loss. DESIGN: Placebo-controlled, randomized clinical trial. SETTING: Academic clinical research center. PATIENT(S): Fifty-two HIV-infected, menstruating women with >5% weight loss over the prior 6 months and current T<33 ng/dL. INTERVENTION(S): Placebo or T patches twice weekly for 24 weeks to achieve nominal delivery of 300 microg T daily. MAIN OUTCOME MEASURE(S): Testosterone by liquid chromatography-tandem mass spectrometry, insulin sensitivity by the frequently sampled intravenous glucose tolerance test (FSIVGT), abdominal and thigh fat volumes by magnetic resonance imaging (MRI), and C-reactive protein (CRP) as a measure of inflammation and plasminogen-activated inhibitor-1 (PAI-1) levels as a marker of thrombolysis. RESULT(S): Serum and free T levels significantly increased into the high normal female range in T-treated but not placebo-treated women. Insulin sensitivity by FSIVGT, whole body, thigh SC, and intra-abdominal fat volumes, and CRP and PAI-1 levels did not change significantly in either group and were not significantly different between the two groups. Fasting insulin increased in the placebo group and fell slightly in the T group, resulting in significant differences in change between groups. CONCLUSION(S): Twenty-four weeks of elevation of serum T levels into the high normal female range in HIV-infected women with mild to moderate weight loss by transdermal T patches did not adversely affect insulin sensitivity, whole-body fat mass or regional fat distribution, or markers of inflammation and thrombolysis. More prolonged and larger studies are needed to determine the effects of higher doses of T on body composition and insulin sensitivity in women.

Effect of Pancreas Tonic (an ayurvedic herbal supplement) in type 2 diabetes mellitus.

Although there is widespread use of herbal dietary supplements that are believed to benefit type 2 diabetes mellitus, few have been proven to do so in properly designed randomized trials; their efficacy for intermediate-term glucose control remains unclear. Pancreas Tonic is a botanical mixture of traditional Indian Ayurvedic herbs currently available as a dietary supplement. We report the results of a single-center, randomized, double-blind, placebo-controlled 3-month trial of Pancreas Tonic in type 2 diabetic patients inadequately treated with diet/lifestyle or stable doses of sulfonylureas and/or metformin for at least 3 months. Patients with type 2 diabetes for >/= 1 year were entered into 2 strata of hemoglobin A(1c) (HbA(1c)) levels (stratum 1: 8.0% to 9.9%; stratum 2: 10.0% to 12.0%). All subjects began a 1-month single-blind placebo run-in phase, followed by randomization in a 2:1 ratio of active treatment: placebo, to 3 months of double-blind treatment with either Pancreas Tonic or matching placebo (2 capsules 3 times a day). Concurrent oral agents were continued unchanged throughout the study. The primary outcome was the change in HbA(1c) from randomization; results of each stratum were analyzed independently. The baseline characteristics of 36 subjects who completed the study were comparable between treatment groups. Nineteen subjects entered stratum 1 and 17 entered stratum 2. A statistically significant reduction of HbA(1c) from randomization to end-of-study was seen in the stratum 2 subjects (Pancreas Tonic: 10.1% +/- 1.0% to 8.8% +/- 1.9%, P =.004; placebo: 10.8% +/- 1.4% to 11.2% +/- 1.8%, not significant [NS]). No significant HbA(1c) reductions were seen in the stratum 1 subjects. There were no significant treatment-related differences in the fasting plasma glucose (FPG), lipids, body mass index (BMI), body composition, blood pressure, insulin sensitivity estimates using the minimal model, glucose and insulin responses to a meal challenge, quality of life, adverse events, or other safety indices between treatment groups. Pancreas Tonic was well tolerated. Treatment with Pancreas Tonic (2 capsules 3 times per day) for 3 months significantly improved glucose control in type 2 diabetic patients with HbA(1c) levels between 10.0% to 12.0%. This study represents the first properly designed, prospective intervention trial of therapy with an Ayurvedic herbal supplement for intermediate-term glucose control in type 2 diabetes.

Annexin II is a thiazolidinedione-responsive gene involved in insulin-induced glucose transporter isoform 4 translocation in 3T3-L1 adipocytes.

The target genes of peroxisomal proliferator-activated receptor-gamma ligands that lead to insulin sensitization are not fully understood. In this study, we have found that the thiazolidinedione, troglitazone, increases expression of annexin II at both the mRNA and protein levels, raising the possibility that annexin II plays a role in insulin-stimulated glucose transporter isoform 4 (GLUT4) translocation and glucose transport. To assess this, we microinjected annexin II antibody or annexin II small interfering RNA into 3T3-L1 adipocytes and found that insulin-stimulated GLUT4 translocation was inhibited by 54 and 60%, respectively. Furthermore, microinjection of annexin II antibody inhibited constitutively active Galphaq (Q209L-Galphaq)-induced but not osmotic shock-induced GLUT4 translocation. When cells were cotransfected with wild-type annexin II, along with an enhanced green fluorescent protein-cmyc-GLUT4 construct, and the percentage of cells expressing cmyc-GLUT4 at the cell surface was measured by immunofluorescence microscopy, there was a marked increase in the ability of insulin to stimulate recruitment of cmyc-GLUT4 protein to the cell surface. In summary, our results show that annexin II is a newly described thiazolidinedione response gene involved in insulin-induced GLUT4 translocation in 3T3-L1 adipocytes.

Established therapies for diabetes mellitus.

Traditional oral anti-diabetic agents for the treatment of diabetes mellitus include the sulfonylureas, metformin, and the alpha-glucosidase inhibitors. Insulin has traditionally been used in various forms with an aim to mimic physiological insulin secretion patterns. Combinations of any of these treatment classes have also been utilized for their additive effects. All of these options have specific advantages and disadvantages, making them ideal for certain patients and less ideal for others. Each of these treatment classes is briefly discussed with respect to mechanisms of action, clinical efficacy, side-effects and current controversies associated with their use. Newer agents (such as the thiazolidinediones, newer insulin secretagogues, and insulin analogues) will be discussed elsewhere.