Cardiovascular Benefits of Semaglutide Use for Weight Reduction
Among patients with a body mass index (BMI) of 27 or greater and preexisting CV disease but without diabetes, treatment with once-weekly semaglutide reduced the risk of a composite of death from CV causes, nonfatal MI, or nonfatal stroke by 20%. These results of SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity Trial) were presented at the 2023 American Heart Association's Scientific Sessions and were published simultaneously in the New England Journal of Medicine. Overweight and obesity are independently associated with an increased risk of CV events; semaglutide is known to reduce the risk of adverse CV events in adults with diabetes, but it's unknown if using the medication to treat overweight or obesity in the absence of diabetes will produce such effects.
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SELECT was a multicenter, double-blind, placebo-controlled trial conducted at 804 sites across 41 countries, and included 17,604 patients, mean age 61.6 years, 72.3% men, with mean BMI of 33.3 and mean Hb A1c of 5.8%; 71.5% of patients in the study were classified as having obesity (BMI of at least 30), and 67% met the criteria for prediabetes (Hb A1c 5.7% to 6.4%). Established CV disease was defined as previous MI, previous stroke, or symptomatic peripheral arterial disease. Patients were receiving other medications to manage their CV disease, including lipid-lowering medications, antiplatelet drugs, beta blockers, ACE inhibitors, and angiotensin receptor blockers. Patients were randomized to once-weekly semaglutide, titrated to a target dose of 2.4 mg (n = 8,803) or placebo (n = 8,801), while continuing their standard CV care.
Use of semaglutide resulted in a 20% relative risk reduction in the composite endpoint of death from CV causes, nonfatal MI, and nonfatal stroke. A primary endpoint event occurred in 6.5% (n = 569) of those taking the GLP-1 receptor agonist and to 8.0% (n = 701) in placebo-treated patients. Findings for each element of the composite endpoint were:
- CV death: 2.5% with semaglutide versus 3.0% with placebo; hazard ratio (HR), 0.85
- Nonfatal MI: 2.7% with semaglutide versus 3.7% with placebo, HR, 0.72
- Nonfatal stroke: 1.7% with semaglutide versus 1.9% with placebo; HR, 0.93.
Only the difference in nonfatal MI reached significance. Among secondary endpoints, heart failure events occurred in 3.4% with semaglutide versus 4.1% with placebo (HR, 0.82); all-cause death occurred in 4.3% with semaglutide versus 5.2% with placebo (HR, 0.81); and need for coronary revascularization was seen in 5.4% with semaglutide versus 6.9% with placebo (HR, 0.77). Patients receiving semaglutide were significantly less likely to progress to diabetes, defined as Hb A1c of 6.5% or higher (3.5% of patients receiving semaglutide versus 12.0% of those on placebo; HR, 0.27). Semaglutide reduced body weight by a mean of 15.2% among these patients. The mean change in body weight over 104 weeks was −9.39% with semaglutide vs. −0.88% with placebo, for an estimated treatment difference of −8.51 percentage points.
What's important about the risk reduction seen with semaglutide is that the participants' CV disease was already reasonably well-controlled. Notably, the reduction in risk occurred early, before substantial weight loss could be achieved. It's worth exploring the mechanisms of such effects. (Neale, T. (2023). Full SELECT results affirm CV risk reduction with semaglutide in nondiabetics. tctMD.com. Retrieved November 2023 from https://www.tctmd.com/news/full-select-results-affirm-cv-risk-reduction-semaglutide-nondiabetics; Lincoff, A. M., et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New Engl J Med. Advanced online publication. Retrieved November 2023 from https://www.nejm.org/doi/10.1056/NEJMoa2307563?logout=true)
Released: December 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Effect of Adding Tirzepatide to Basal Insulin in Type 2 Diabetes
In patients with inadequately controlled type 2 diabetes mellitus treated with basal insulin, adding weekly tirzepatide as adjunctive treatment resulted in greater reduction in glycated hemoglobin (Hb A1c), accompanied by more weight loss and fewer incidents of hypoglycemia, than adding prandial insulin to the regimen. Basal insulins are typically the first injectable treatment option for patients with type 2 diabetes mellitus who have inadequate glycemic control on oral antidiabetic medications. Current guidelines, however, suggest adding an injectable incretin-related treatment: a glucagon-like peptide-1 receptor agonist such as tirzepatide.
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SURPASS-6, a 52-week, open-label, multicenter, phase 3b trial conducted at 135 sites in 15 countries, enrolled 1,248 adults with type 2 diabetes mellitus. Patients were randomized to once-weekly (subcutaneous injections of tirzepatide in three dosage strengths:5 mg (n = 243), 10 mg (n = 238), and 15 mg (n = 236)–or to twice daily prandial insulin lispro (n = 708). Eligible participants had Hb A1c levels of 7.5% to 11% at visit 1 and body mass index of 23 to 45. Patients were instructed to switch their diabetes treatment to insulin glargine and to discontinue other glucose-lowering medications, except for metformin, 10 weeks before randomization. At randomization, the insulin glargine dose was reduced by 30% to lower the risk of hypoglycemia, then titrated to meet an early-morning blood glucose target of 100 to 125 mg/dL.
The mean change from baseline Hb A1c at week 52 with tirzepatide (pooled data) was −2.1%, and with insulin lispro was −1.1%. Final mean Hb A1c levels were 6.7% versus 7.7%, an estimated treatment difference of −0.98%. This difference was statistically significant. The mean change and estimated treatment difference compared to insulin lispro with each dosage strength was as follows:
- 5-mg tirzepatide: −1.9%; treatment difference −0.79%
- 10-mg tirzepatide: −2.2%; treatment difference −1.01%
- 15-mg tirzepatide: −2.3%; treatment difference −1.13%
Estimated mean change in body weight was −9.0 kg with tirzepatide and +3.2 kg with insulin lispro, a treatment difference of −12.2 kg. Mean change in body weight was −6.7 kg with 5-mg tirzepatide, −9.2 kg with 10-mg tirzepatide, and −11.0 kg with 15-mg tirzepatide. The percentage of patients reaching the target of Hb A1c <7.0% was 68% for tirzepatide and 36% for insulin lispro, for an odds ratio of 4.2. The percentage reaching Hb A1c <6.5% was 56% for tirzepatide and 22% for insulin lispro; for <5.7% was 56% for tirzepatide and 22% for insulin lispro.
In addition, these effects on glycemic control enabled a decrease in the mean daily basal insulin dose, from a baseline of 46 IU to the following:
- 13 IU with pooled tirzepatide
- 20 IU with 5 mg tirzepatide
- 12 IU with 10 mg tirzepatide
- 8 IU with 15 mg tirzepatide.
Depending on the tirzepatide dosage, 8% to 19% of patients were able to completely discontinue insulin glargine treatment by week 52.
The most common adverse events were mild to moderate GI symptoms. The most serious was hypoglycemia. Rates of hypoglycemic events (blood glucose level <54 mg/dL) were 0.4 events/patient-year with tirzepatide and 4.4 events/patient-year with insulin lispro. Severe hypoglycemia was reported in 30 insulin lispro-treated patients and in 3 tirzepatide-treated patients. The incidence of clinically significant hypoglycemia was 12% in the 5-mg group, 9% in the 10-mg group, and 11% in the 15-mg group compared to 48% in the prandial insulin lispro group.
The researchers hypothesized that the body weight loss induced by tirzepatide may have led to an improvement in insulin sensitivity. Sustained weight loss of more than 10% has known disease-modifying effects, including remission of type 2 diabetes. In exploratory analysis of the data, 32% to 57% of tirzepatide users met that goal. (Rosenstock, J., et al. (2023). Tirzepatide vs insulin lispro added to basal insulin in type 2 diabetes: The SURPASS-6 randomized clinical trial. JAMA, 330(17), 1631–1640. Retrieved November 2023 from https://jamanetwork.com/journals/jama/fullarticle/2810386)
Released: December 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
First Fixed-Dose Triple Combination Therapy for Acne
Acne pathogenesis follows multiple pathways, including abnormal keratinization, increased inflammation and sebum production, and follicular proliferation of Cutibacterium acnes (Propionibacterium acnes). Fixed-dose combination treatments that target those multiple pathways can provide better efficacy and adherence in patients with moderate to severe acne. IDP-126, a fixed-dose, triple-combination topical gel, was demonstrated to be effective and well tolerated in two clinical studies discussed in the Journal of the American Academy of Dermatology.
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The topical gel contains clindamycin phosphate 1.2%, adapalene 1.15%, and benzoyl peroxide 3.1%. Clindamycin is a lincosamide antibiotic; adapalene is a retinoid that modulates cellular differentiation, proliferation, and keratinization; and benzoyl peroxide is an antibacterial with keratolytic and mild comedolytic effects. In the phase 3 double-blind studies, each enrolling approximately 180 participants aged at least 9 years with moderate to severe acne, participants were randomized to IDP-126 gel or vehicle gel, applied once daily for 12 weeks (Study 1: IDP-126 [n = 122], vehicle gel [n = 61]; Study 2: IDP-126 [n = 120], vehicle gel [n = 60]). Treatment success was defined as achieving at least a 2-grade reduction from baseline on the Evaluator's Global Severity Score.
At week 12, about half of those using IDP-126 achieved treatment success: 49.6% and 50.5% of those using the triple-combination gel reported such improvement compared to 24.9% and 20.5% using the vehicle gel in the two studies, respectively. IDP-126 also provided significantly greater reductions in lesion counts compared to the vehicle gel: 72.7% and 80.1% versus 47.6% and 59.6%, respectively, in the two studies. IDP-126 gel showed rapid reductions in lesion counts as early as week 4 and was superior to the vehicle gel in all efficacy assessments at week 12.
In addition, in both studies, mean cutaneous safety and tolerability scores with the triple-combination gel were below 1 (mild) for all assessments at all visits. Most treatment-emergent adverse events were mild to moderate in severity. (Stein Gold, L., et al. (2023). Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel for moderate-to-severe acne: Efficacy and safety results from two randomized phase 3 trials. J Am Acad Dermatol, 89(5), 927–935. Retrieved November 2023 from https://www.jaad.org/article/S0190-9622(23)01201-X/fulltext)
Released: December 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer