Oral contraception and GLP-1 agonists.

This work is a continuation of an earlier article published in this journal (no. 91/1: “Current aspects of polycystic ovary syndrome I: definition, pathophysiology, clinical manifestations, diagnosis and complications”). As the pathology of polycystic ovary syndrome is not fully known, the treatments used do not constitute a causal therapy, only pathogenetical interventions to break the vicious circles of pathological events. It does not currently have a universal therapeutic procedure or an approved specific drug. Treatment may be aimed at reducing hyperandrogenism, inducing ovulation and preventing complications. The patient’s complaints and desire for becoming pregnant should also be taken into account. In mild cases, an appropriate lifestyle (prevention/treatment of obesity) is sufficient, i.e. a 5-10% reduction in body weight can already result in significant improvement and also serves to prevent late complications (diabetes, hypertension, cardiovascular disease, hyperlipidemia). Oral contraceptives and antiandrogens are mainly used to treat hyperandrogenism (hirsutism, acne, and alopecia). A contraceptive whose progestogen component has antiandrogenic properties, or at least is androgen-neutral, is preferred, such as third-generation contraceptives. However, combined contraceptives (containing gestodene, desogestrel, drospirenone and cyproterone acetate) may increase the risk of venous thromboembolism and are therefore contraindicated in case of hypercoagulability. Antiandrogens (cyproterone acetate, spironolactone, finasteride, etc.) can also be used independently, but only with effective contraception (as these can cause feminization of the male fetus). Insulin resistance plays a crucial role in the development of this disease. Metformin is used as primary therapy, as it also has many other beneficial effects (e.g. cardiovascular and anti-cancer) described in recent years. These pleiotropic effects and their subtle mechanisms are discussed in detail. We highlight the possibilities of avoiding side effects and the current interpretation of rare contraindications (acidosis, hypoxic conditions, renal damage). Insulin resistance lowering agents include thiazolidinediones, acarbose, GLP-1 agonists, vitamin D, resveratrol, octreotide, but the beneficial effects of myoinositol and D-chiro-inositol are also mentioned. In the last part of the paper, the treatment options for infertility are discussed, highlighting the efficacy of clomiphene citrate, gonadotropins (“step-up”, “step- down” methods), IVF techniques, and ovarian drilling used for ovulation induction. We detail the importance and possibilities of the prevention of ovarian hyperstimulation syndrome and multiple pregnancies.

Type 2 diabetes is a progressive disease where in case of unsuccessful behavioral modifications and metformin monotherapy treatment needs to be intensified by adding some other oral agents and/or GLP-1 agonists and/ /or basal insulin. After some years of treatment with increasing defect of beta cells, there is a necessity to start or intensify insulin therapy with prandial insulin, premixed insulin, basal-bolus regimen or multiple injections of insulin. Patient’s treatment should be individualized but there are no direct recommendations which type of insulin to choose — human or analogue one. This article summarizes clinical situations in which one could consider using human insulin. When selecting a suitable insulin, the type of dietary habits, especially eating snacks, the presence of gastroparesis and economic issues should be taken into account. It turnes out that for patients with type 2 diabetes both human and analogue insulins are equally safe and efficient in terms of risk of severe hypoglycaemia. Undoubtedly, analogue insulin has uncontestable advantages, but in some clinical cases human insulin seems to be a better option.

Type 2 diabetes mellitus and diabetic complications have sharply increased and have become an important issue to resolve. The goal of treatment of type 2 diabetes is to prevent the development and progress of diabetic complications by successful glycemic control. Various treatment modalities are used in the glycemic control of diabetic patients, such as lifestyle modification, oral hypoglycemic agent, insulin, insulin analogues, and GLP-1 agonist. Although there are many treatment guidelines for glycemic control, the key to successful therapy for type 2 diabetes is precise insight on the nature of the disease, characteristics of the patient, and knowledge of the therapy. Therefore, it is important to learn about antihyperglycemic drug therapy. Sulfonylurea, metformin, α-glucosidase inhibitor, glinide, thiazolidinedione, and SGLT2 inhibitor are used in monotherapy for the glycemic control of diabetic patients. However, the failure rate of monotherapy is not low at the beginning or during the course of treatment. When monotherapy fails, the next step is combination therapy. A well-chosen combination treatment method will help to achieve the glycemic goal before the use of insulin. In conclusion, it is essential to achieve a precise insight into the characteristics of the drug, considerations in drug choice, and the advantages/disadvantages of combination therapy. The most important thing is the appropriate individualization of the treatment after understanding the current state of diabetic patients, such as diabetic complications, age, lifestyle, body weight, hypoglycemia risk, and economic state.

To compare insulin and GLP-1 analogues therapy on glycemic control in poorly controlled Type 2 diabetes (T2DM) subjects failing on oral therapy. The electronic database PubMed was systematically searched for randomized controlled trial (RCT) with duration >16 weeks comparing the addition of insulin therapy vs glucagon-like peptide (GLP-1) analogues in poorly controlled T2DM subjects on oral therapy. We identified 7 RCT with 2199 patients of whom 1119 were assigned to insulin therapy and 1080 received a GLP-1 analogue. Both insulin and GLP-1 analogues were effective in lowering glycated hemoglobin (HbA(1c)) with no statistically significant difference between the mean decreases in HbA(1c). However, insulin was more effective than GLP-1 analogues in lowering the fasting plasma glucose concentration, while GLP-1 agonists were more effective in lowering the postprandial glucose concentration. Insulin therapy was associated with weight gain while GLP-1 analogues consistently caused weight loss and the difference between the mean change in body weight between the two therapies was highly statistically significant. Despite a similar decrease in HbA(1c), the risk of hypoglycemia was 35% lower (p=0.001) with GLP-1 therapy compared to insulin. Compared to insulin, GLP-1 analogues caused a significant decrease in systolic blood pressure and were associated with greater rate of gastrointestinal adverse events. In poorly controlled T2DM subjects on oral therapy, GLP-1 analogues and insulin are equally effective in lowering the HbA(1c). However, GLP-1 analogues have additional non-glycemic benefits and lower risk of hypoglycemia. Thus, GLP-1 analogues should be considered as a treatment option in this group of diabetic individuals.

Polycystic ovarian syndrome-current pharmacotherapy and clinical implications

Annals for Educators - 5 February 2019.

Disclosure: M.M. Bethea: None. S. da Silva Teixeira: None. T.M. Cook: None. J. Hendrix: None. D. Sandoval: None. Oral formulations, such as the first and only FDA-approved oral GLP-1 analog (semaglutide), have the advantage of improving patient adherence and quality of life. Yet, how these oral GLP-1 receptor (GLP-1R) agonists mediate their glucose-lowering effects is unknown. Because systemic administration of GLP-1R analogs likely targets different GLP-1R populations than that of oral administration, it is imperative that we advance our understanding of the key GLP-1Rs needed for the metabolic benefits of orally administered GLP-1 therapies. We have preliminary data demonstrating that the oral administration of free Ex-4 significantly enhances glucose tolerance in fasted non-diabetic mice, strongly suggesting that oral Ex-4 is bioactive after transit through the GI system. Importantly, we have additional evidence that shows the oral administration of either Ex-4 or GLP-1 does not lead to detectable circulating levels of either peptide, suggesting that a local source is mediating this effect. Furthermore, using a GLP-1R Cre mouse crossed with a tdTomato reporter mouse, we see that the GLP-1R is expressed on epithelial cells within the intestine, yet oral Ex-4 administration in mice lacking GLP-1R in intestinal enterocytes elicited glycemic improvements. We hypothesized that neuronal GLP-1R populations within the gastrointestinal tract mediate the glycemic improvements of orally administered GLP-1 agonists. To test this hypothesis, we used various genetic mouse models lacking GLP-1Rs subjected to an oral gavage of Exendin-4, a GLP-1RA. We found that vagal GLP-1Rs are necessary for the glucose-lowering effects of orally administered Exendin-4. These findings will ultimately facilitate the development of more efficacious tailored compounds for the treatment of T2D and enhance our knowledge of GLP-1 biology. Presentation: 6/1/2024

25-year-old female presented to the endocrine clinic suffering from uncontrolled blood sugar and irregular period, she was diagnosed with type 1 diabetes since she was 15 and treated with premixed insulin, on the other hand she was diagnosed with polycystic ovary syndrome and treated with oral contraceptive pills, on examination; there is acanthosis nigricans in the axilla and forearm, android lean body habitus and acromegalic face, hirsutism and prominent veins. Labs revealed high triglyceride (more than 1000 mg/dL), high fasting insulin, high total testosterone 0.9 ng/mL, HbA1c 14,5%, high ALT, albuminuria, she is using very high doses of insulin yet uncontrolled, we diagnosed her as generalized lipodystrophy, the drug of choice is metroleptin which is not available, so I started pioglitazone 45 mg with semaglutide 1mg, gradually weaned off insulin. After 3 months of treatment her HbA1c declined to 7 without insulin, triglyceride to 422 mg/dL, proteinuria declined but was not normalized. We postulate the hypothesis that the insulin sensitizing properties of GLP1 agonist in the treatment of insulin resistance syndromes can be implemented particularly in countries with middle and low socioeconomic status that don't have access to the expensive drugs. Figure 1. Patient footage oral consent taken. Table 1.Results of biochemical parameters before and after treatment.

Background. Glucagon-like peptide 1 (GLP-1) is an incretin hormone whose mechanism of action also includes a slight delay in gastric emptying (GE). Due to the prevalence of type 2 diabetes mellitus and obesity, GLP-1drugs are prescribed to many patients, including women of reproductive age who are also taking COCs. For oral contraceptives, malabsorption may result in ineffective pregnancy prevention.The purpose of this literature review was to review data from studies on the effect of GLP-1 agonists on oral hormonal contraceptives (COCs) and to analyze data on the safety of concomitant use of COCs and GLP-1 agonists.Methods. PubMed and ClinicalTrials.gov were searched for publications using keywords. A total of 3 clinical studies were selected for inclusion in the literature review.Results. Studies involving GLP-1 have not revealed a statistically or clinically significant difference in drug-drug interactions with COC drugs.Conclusion. This review compared the effects of currently available GLP-1 on COCs in three clinical studies. Due to the prevalence of type 2 diabetes and obesity, GLP-1 is likely to be prescribed to many patients, including women of reproductive age who are also taking COCs. These drugs may affect the pharmacokinetics of COCs. Changes in the area under the curve, maximum concentration, and time to maximum plasma concentration of oral drugs can be avoided by taking these drugs 1 hour after GLP-1.

Medical treatment and comorbidity in polycystic ovary syndrome: An updated review

Additive Effect of Oral Insulin and an Oral GLP-1 Agonist on Postprandial Glucose Excursions in a Porcine Model