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Introduction: Medications used to treat type 2 diabetes (T2D) often require dose escalation to optimize effectiveness. Physician and patient perceptions of treatment characteristics of T2D medications have previously been examined, but little is known about perceptions of escalation to the optimal dose for each patient. This study examined physicians' perceptions of dose escalation for medications used to treat T2D. Methods: Data on dose escalation and other factors influencing decision-making for treatment of T2D were collected via an online survey of endocrinologists and primary care physicians in the USA. Results: The sample included 501 physicians (348 primary care physicians and 153 endocrinologists). Dose escalation was not frequently considered by physicians as a primary factor keeping patients' from reaching treatment goals (mentioned as a factor by only 7.6% of the sample) or a barrier to prescribing T2D medication (16.2%). Factors more likely to keep patients from reaching treatment goals included an unhealthy diet (86.6%) and medication adherence (77.4%). The most common reasons that physicians reported for escalating dose levels were the need for better glycemic control (reported by 89.8% of the sample), ability to decrease the total number of medications by increasing the dose of one medication (39.9%), and the need for the patient to lose weight (39.3%). Data reported by primary care physicians and endocrinologists followed similar patterns. Conclusions: Although common with T2D treatments, escalating the dose of T2D medication was not perceived by physicians to be a significant barrier to attaining treatment goals or prescribing medication. Multiple factors contribute to the decision to escalate the dose of T2D medication. Plain Language Summary: In early phases of initiating medication treatment for a patient with type 2 diabetes (T2D), it is common for physicians to increase from a lower initial dose to a higher end dose to maximize treatment benefit. This process is known as dose escalation. The purpose of this study was to examine physicians' perceptions of dose escalation for medications used to treat T2D. An online survey was designed to identify reasons why physicians in the US may choose to escalate or not escalate a dose of medication for T2D. In addition, physicians were asked about factors that keep patients from reaching treatment goals to identify whether the requirement for dose escalation is perceived to be a common barrier to successful treatment. The sample included 501 physicians (348 primary care, 153 endocrinologists). Dose escalation was not frequently considered to be a primary factor keeping patients' from reaching treatment goals or a barrier to prescribing medication for T2D. Dose escalation decisions are complex, driven by a range of factors such as glycemic control medication tolerability, the patient's body mass index, treatment guidelines, comorbidities, characteristics of the patient's entire treatment regimen, and potential cardiovascular benefits. [ABSTRACT FROM AUTHOR]

Context Efficacy and safety of tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, have been studied in patients with type 2 diabetes in the global phase 3 SURPASS program. Objective This work aimed to assess the efficacy and safety of tirzepatide in Hispanic/Latino and non-Hispanic/Latino patients in SURPASS-1 to -4 clinical trials. Methods A total of 5679 patients were included, 2895 of self-reported Hispanic/Latino ethnicity, in this exploratory analysis of SURPASS-1 to -4 trial data. Interventions included tirzepatide 5, 10, or 15 mg, placebo, or active comparator (semaglutide 1 mg, insulin degludec, and insulin glargine). Change in glycated hemoglobin A1c (HbA1c) and body weight from baseline to week 40 (SURPASS-1 and -2) and to week 52 (SURPASS-3 and -4), and other efficacy and safety outcomes were evaluated within Hispanic/Latino and non-Hispanic/Latino subgroups. Results Among Hispanic/Latino and non-Hispanic/Latino patients treated with tirzepatide, respectively, HbA1c decreased significantly from baseline, ranging from 1.9% to 2.7% and 1.7% to 2.5%, and body weight decreased significantly from baseline, ranging from 5.3 kg to 12.4 and 6.5 kg to 17.1 kg (both P <.05) vs comparators across all trials. Subgroup trends were consistent with the overall trial populations. Treatment-emergent adverse events were reported in similar proportions across the subgroups and were primarily gastrointestinal disorders. The incidence of hypoglycemia was low. Conclusion Tirzepatide significatively reduced HbA1c and body weight in Hispanic/Latino and non-Hispanic/Latino patients. Tirzepatide was generally well tolerated in both subgroups. Efficacy and safety trends were comparable between subgroups and within the overall trial populations. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison. Materials and Methods: Using SURMOUNT‐1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching‐adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points. Results: Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: −4.67% [95% CI −5.91%, −3.43%]; tirzepatide 15 mg mean difference: −5.92% [95% CI −7.16%, −4.68%]; both P <.001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P <.001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P <.001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P =.074). Conclusions: Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching‐adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg. [ABSTRACT FROM AUTHOR]

Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chowfed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas [NPY.sub.1] receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85[alpha]) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85[alpha] expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity. development; hypothalamus; obesity doi: 10.1152/ajpregu.90585.2008

Objective: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin.Research Design and Methods: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients.Results: Mean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%).Conclusions: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile. [ABSTRACT FROM AUTHOR]