Drug Whisperer (March-June 2023)

  1. Lp(a) May Be More Than A Cardiovascular Risk Marker. It Is Also Associated With Kidney Function Decline in Diabetics. Or Maybe Atherosclerosis Is The Basis For Kidney Function Decline?
  2. Are Verapamil’s Potential Benefits Greater Than Potential Harms In Newly Diagnosed Type 1 Diabetics?
  3. Is Intranasal Delivery Of Epinephrine Close To Being A Reality?


1. Lp(a) May Be More Than A Cardiovascular Risk Marker. It Is Also Associated With Kidney Function Decline in Diabetics. Or Maybe Atherosclerosis Is The Basis For Kidney Function Decline?

OBJECTIVE: Little is currently known about the role of lipid metabolism in diabetic kidney disease (DKD), warranting further study. The present study sought to investigate the correlation between lipid metabolism and renal function as well as renal pathological grade/score in DKD patients.

METHODS: A total of 224 patients diagnosed with DKD by pathological examination were retrospectively analyzed, of which 74 patients were further evaluated by DKD pathological grade/score. ANOVA was used to investigate serum lipoprotein (a) [Lp (a)] levels in DKD patients with different chronic kidney disease (CKD) stages. Spearman correlation analysis was used to evaluate the relationship between Lp (a) and renal function-related indicators. The DKD pathological grade/score was also evaluated with this method. The receiver operating characteristic (ROC) curve was used to analyze the value of Lp (a) in assessing renal function and pathological changes.

RESULTS: There were significant differences in Lp (a) levels among different CKD stages (H = 17.063, p = 0.002) and glomerular grades (H = 12.965, p = 0.005). Lp (a) levels correlated with serum creatinine (p = 0.000), blood urea nitrogen (p = 0.000), estimated glomerular filtration rate (p = 0.000), 24-h proteinuria (24hUPro, p = 0.000), urine microalbumin (p = 0.000), urine albumin creatinine ratio (p = 0.000), glomerular basement membrane thickness (p = 0.003), and glomerular grade (p = 0.039). ROC curve demonstrated good performance of Lp (a) as an indicator to assess CKD stage 4-5 (AUC = 0.684, p = 0.000), 24hUPro > 3.5 g (AUC = 0.720, p = 0.000), and glomerular grade III-IV (AUC = 0.695, p = 0.012).

CONCLUSIONS: Elevated levels of Lp (a) are associated with decreased GFR, increased proteinuria, and renal pathological progression, suggesting they could be used to monitor changes in DKD patients.

Wang A, et al. Study on the relationship between lipoprotein (a) and diabetic kidney disease. J Diabetes Complications. 2023 Jan;37(1):108378.  doi: 10.1016/j.jdiacomp.2022.108378. Epub 2022 Dec 15.

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2. Are Verapamil’s Potential Benefits Greater Than Potential Harms In Newly Diagnosed Type 1 Diabetics?

IMPORTANCE: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes.

OBJECTIVE: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes.

DESIGN, SETTING & PARTICIPANTS: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022.

INTERVENTIONS: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care.

MAIN OUTCOMES AND MEASURES: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes.

RESULTS: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a non serious adverse event considered to be related to treatment.

CONCLUSIONS AND RELEVANCE: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.

Forlenza GP, et al. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.  JAMA. 2023 Mar 28;329(12):990-999. doi: 10.1001/jama.2023.2064.

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3. Is Intranasal Delivery Of Epinephrine Close To Being A Reality?

BACKGROUND: Manual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles.

OBJECTIVE: To compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray.

METHODS: This integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy).

RESULTS: Data from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively).

CONCLUSION: Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

Tanimoto S, et al. Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis. Ann Allergy Asthma Immunol. 2023 Apr;130(4):508-514.e1. doi: 10.1016/j.anai.2022.10.024. Epub 2022 Nov 2.

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