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.
Tirzepatide (TZP) is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (on metformin) Phase 3 ...trials, TZP substantially reduced HbA1c and body weight (BW) in people with T2D. Exploratory post hoc analyses examined the predictive value of HOMA2-IR (insulin) and HOMA2-B (C-peptide) by quartiles low (lower beta-cell function or insulin resistance) Q1 to high Q4 for achieving HbA1c (<5.7%, ≤6.5%) and BW reduction (≥10%, ≥15%) targets for those adherent to TZP treatment at Week 40. Odds ratios (OR) were calculated from logistic regression models using the overall mean as the reference. The results showed that TZP was equally likely to achieve BW and HbA1c targets in S-1 and S-2 regardless of baseline HOMA2-B and -IR quartiles, with the exception of S-2 where subjects with Q1 HOMA2-B (lowest beta-cell function) were significantly less likely and those with Q4 HOMA2-B (highest beta-cell function) were significantly more likely to reach HbA1c ≤6.5% (Figure). We conclude that baseline HOMA2-B, but not HOMA2-IR, may predict the likelihood of subjects achieving the HbA1c target ≤6.5% for patients enrolled in S-2 not controlled with metformin alone.
Disclosure
S.H.Hsia: Research Support; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. H.Wang: None. J.Peleshok: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
Abstract
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).
Orforglipron OFG (LY3502970) is an oral, non-peptide, glucagon-like peptide-1 receptor agonist (GLP-1 RA).
The 26-week, randomized, double-blind, double placebo, phase 2 study enrolled 383 patients ...with type 2 diabetes (T2D) treated with diet, exercise, ± metformin. At baseline, mean age was 58.9 yr, HbA1c was 8.1%, and body weight (BW) was 100.3 kg. Patients were randomly assigned to OFG 3, 12, 24, 36, or 45 mg once daily, placebo (PBO), or dulaglutide 1.5 mg (dula). Protocols guided the initial OFG dose and escalation schemes. Primary endpoint was HbA1c change from baseline (CFB) at wk 26 for OFG vs PBO. Secondary endpoints included CFB at wk 26 in HbA1c for OFG vs dula, and CFB in fasting blood glucose (FBG) and body weight (BW) for OFG vs PBO and dula.
OFG resulted in improvements in glycemic control and BW (table). At wk 26, HbA1c reduction with OFG ranged from 1.19 to 2.10% vs PBO 0.43% (P<0.001, all doses vs PBO). Significantly greater reductions in HbA1c were also noted with 12, 24, 36, and 45 mg OFG vs dula (p<0.001). Most adverse events (AE) were gastrointestinal (nausea: PBO 5.5%, OFG 30.6%, dula 18.0%) and mild or moderate in severity.
OFG resulted in significant reductions in HbA1c, FBG, and BW with an AE profile consistent with other GLP-1RAs. OFG does not have food or water administration restrictions and may provide a safe, effective, and convenient oral treatment option for patients with T2D.
Disclosure
J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.A.Robins: None. S.H.Hsia: Research Support; Eli Lilly and Company. S.Eyde: None. R.Liu: None. X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Konig: None. C.M.Kazda: Employee; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company.
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.
Highlights
The anti‐inflammatory agent, hydroxychloroquine, improved glycemic control in type 2 diabetes patients when used as a third‐line agent added to metformin and a sulfonylurea.
In comparison ...to pioglitazone, hydroxychloroquine lowered hemoglobin A1c levels less effectively and did not improve insulin sensitivity, but also did not cause any weight gain, hypoglycemia, or pedal edema.
In this small, proof‐of‐concept study, hydroxychloroquine was well tolerated and may be an alternative treatment choice in combination with other agents.
Abstract 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 HbA1c 9.3 ± 1.4%), and improved their HbA1c (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.
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
versus placebo (-7.8 U l
) and tropifexor 140- and 200-μg groups were -18.0 U l
and -23.0 U l
, respectively, versus placebo (-8.3 U l
)) 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.
Few human studies have explored the mechanisms of smoking-induced insulin resistance. Aims: To prospectively examine the metabolic changes of smoking reduction.
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.
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).
Smoking reduction produced a transient worsening of central fat redistribution followed by a more significant improvement; along with other net beneficial metabolic effects.
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.
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