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Efficacy and safety of Glucagon-like peptide-1 (GLP-1) analogs compared with other antidiabetics which are most common used.

Principal Investigator: Prof. Mohamed A. El-Moselhy

Co-investigators: Hadeel Alharbi, Maha Alzahrani, Razan Alshaikh

Introduction

Diabetes mellitus (DM) is a metabolic disorder that causes elevated blood sugar levels (hyperglycemia) (1), It happens because disorders in insulin secretion, insulin action, or both so the body cannot produce or use the insulin hormone properly. (2)

Insulin is a pancreatic protein hormone secreted by beta cells in the islets of Langerhans and is specifically important for the digestion of carbohydrates and for the regulation of blood glucose levels. Insulin is a hormone that transfers sugar from the blood to cells for stored or used for energy purposes. And diabetes mellitus may appear if abnormality happened in this mechanism. (3)

DM that causes serious complications over time (Skin complications and complications of the eyes (glaucoma, cataracts) Neuropathy, Foot complications, DKA (ketoacidosis), Kidney disease (nephropathy) Elevated blood pressure increases the risk of heart attack, stroke. (4)

There are three types of diabetes mellitus, they are type 1, type 2 and gestational diabetes mellitus. (5)

For individuals with type 1 diabetes, the immune system mistakes the body's own healthy cells for foreign invaders. The immune system targets and kills beta cells that produce insulin in the pancreas. Since these beta cells have been damaged, the body is unable to generate insulin.

Type 2 diabetes which accounts for 90–95% of those with diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Previously is referred to as non–insulin-dependent diabetes, type 2 diabetes, or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency At least initially, and often throughout their lifetime (7). When you develop type 2 diabetes, the pancreas will try to compensate for by releasing more insulin. Since your body is unable to use insulin properly, glucose can concentrate in your bloodstream. (6)

Gestational diabetes (GDM) is a form of diabetes that consists of elevated blood glucose levels during pregnancy and is associated with complications for both mothers and infants. GDM usually disappears after birth, but women and their children are at higher risk of developing type 2 diabetes later in life. (6)

Risk factor that develop type 2 diabetes are overweight or obese and obesity itself causes some degree of insulin resistance, age 45 or older, family history of diabetes, high blood pressure, dyslipidemia, or have a history of gestational diabetes, not physically active, have a history of heart disease or stroke, depression (8)

The most common is type 2 diabetes mellitus, usually in adults. About 422 million people worldwide have diabetes, and 1.6 million deaths are directly attributed to diabetes each year and Saudi Arabia is one of the 21 countries and territories of the intranational diabetes federation middle east and north Africa ( IDF MENA region) 55 million people in the MENA Region have diabetes in the world ,Total adult in Saudi Arabia population: 23,324,700 , Prevalence of diabetes in adults :  18.3% Total cases of diabetes in adults :  4,275,200 (9) what make the treatment of diabetes a big challenge for scientist and healthcare professionals, so that efforts are made every day to discover and develop new ways to treat DM depend on the patient situation and his health condition.

classification diabetes mellitus treatment.

1- nonpharmacologic:

lifestyle changes (weight loss, increasing physical activity, diet) and offered ongoing patient education. (10)

2-pharmacological

Insulin replacement therapy is the mainstay for patients with type 1 DM, Insulin is also important in type 2 DM when blood glucose levels cannot be controlled by diet, weight loss, exercise and oral medications. hypoglycemic agents (11).

Oral hypoglycemic agents include according to mechanism of action

* Sulfonylureas

Mechanism of action: Sulfonylureas promote insulin release by binding to a particular site on the β cell KATP channel complex (SUR) and inhibiting its function. Cell membrane depolarization and the cascade of events leading to insulin secretion are caused by KATP channel inhibition. Acute administration of sulfonylureas to type 2 diabetes patients improves the release of insulin from the pancreas. Circulating insulin levels decrease with chronic administration to those that existed before treatment, but decreased plasma glucose levels are retained despite this decrease in insulin levels. The absence of acute stimulatory effects of sulfonylurea during chronic therapy on the secretion of insulin is attributable to the downregulation of sulfonylurea cell surface receptors on the pancreatic β-cell. (12) Many side effects are found in Sulfonylureas, including comas, may cause hypoglycemic reactions. A common side effect of improving glycemic control with sulfonylurea treatment is weight gain

of 1–3 kg. Different mechanisms (decreased hepatic metabolism or renal excretion, displacement from protein-binding sites) can increase the hypoglycemic effect of sulfonylurea. Some medications (sulfonamides, clofibrate, and salicylate) displace protein-binding sulfonylureas, thus transiently raising free drug concentrations. The action of sulfonylureas may be enhanced by ethanol and cause hypoglycemia. Hypoglycemia in patients taking sulfonylurea in combination with one or more of the following agents may be more frequent: Anticoagulants, Androgens, antifungal azole, gemfibrozil, chloramphenicol, fenfluramine, fluconazole, salts of magnesium, methyldopa, MAOIs, probenecid, sulfinpyrazone, tricyclic antidepressants sulfonamides, and acidifiers of the urine, By increasing hepatic metabolism, increasing renal excretion, or inhibiting insulin secretion (β-blockers, Ca2 + channel blockers, cholestyramine, diazoxide, estrogens, hydantoins, isoniazid, nicotinic acid, phenothiazines, rifampin, sympathomimetics, thiazide diuretics, and urinary alkalinizers), these medicines may decrease the glucose-lowering effect of sulfonylureas. (12)

*Thiazolidinediones

Thiazolidinediones activate peroxisome proliferator-activated receptor-Y (PPARy) receptors, which are primarily expressed in lower-expression adipose tissue in cardiac, skeletal, and smooth muscle cells; ß islet cells; macrophages; and vascular endothelial cells. Small lipophilic molecules such as oxidized linoleic acid, arachidonic acid, and prostaglandin metabolite 15dPGJ2 comprise the endogenous ligands for PPARy. The main response to PPARy activation is dipocyte differentiation. Ligand binding to PPARy induces heterodimer formation with the retinoid X receptor and association with PPAR response elements on specific genes. That activity of PPARy also facilitates the absorption of fatty acids in fat cells and transfers lipid stores from extra-adipose sites to adipose tissue. (13) The most common adverse effects of the thiazolidinediones are weight gain and edema. For the first year of therapy, thiazolidinedione induces a rise in body adiposity and an overall weight gain of 2-4 kg. (14), in patients using both rosiglitazone and pioglitazone, macular edema has been reported, but this has not been a consistent finding in recent clinical trials. In clinical trials, exposure to these medications for many years was associated with an increased rate of heart failure of up to 2-fold. (15)

*Biguanides

Several mechanisms to clarify the central pharmacological action of metformin, the reduction of hepatic gluconeogenesis primarily by limiting gluconeogenesis. In mitochondrial respiration, metformin has unique actions that decrease intracellular ATP and increase AMP. Experimental evidence supports metformin activation of AMP-dependent protein kinase (AMPK), leading to hepatic fatty acid oxidation stimulation, glucose uptake, and metabolism of non-oxidative glucose and reduction of lipogenesis and gluconeogenesis. Metformin also inhibits the dehydrogenase of mitochondrial glycerol phosphate, thereby changing the cell's redox state. Other mechanisms, including blunting the effects of glucagon, inhibiting the conversion of lactate and glycerol to glucose, and moving the liver towards a negative lipid balance, are implicated in more recent proof. (16) The most common side effects of Biguanides (10 -25 %) are GI: nausea, indigestion, stomach cramps or bloating, diarrhea, or a combination of these. Metformin, including interference with the absorption of glucose and bile salts, and its direct effects on GI function. Metformin use is also related to (20 -30 %) lower vitamin B12 blood levels and these levels should be controlled. With continued use, most of the adverse GI effects of metformin decrease over time and can be minimized by starting at low doses and slowly titrating over several weeks to the target dose, as well as by having patients take the medicine with a meal. (17)

*Sodium-glucose Transporter 2 Inhibitors

SGLT2 is a Sodium-glucose cotransporter found almost exclusively in the proximal portion of the renal tubule. SGLT2 is a high-affinity, low capacity transporter that moves glucose against a concentration gradient from the tubular lumen using energy produced from Sodium flux through the epithelial cells In non-diabetic individuals, renal glucose retention is almost complete, and SGLT2 accounts for 80% - 90% of this reclamation; the remainder is more distally recovered in the tubule by SGLT1. Early studies in diabetic animals showed that hyperglycemia could be nearly ameliorated by the naturally occurring compound phlorizin, an SGLT inhibitor. Drugs that are particular inhibitors of SGLT2 were developed to treat diabetes on the basis of this proof of concept. (18) By promoting urinary loss, these agents block glucose transport in the proximal tubule and lower blood glucose. SGLT2 inhibitors decrease the glucose reclamation rate in the proximal tubule and change the glucose excretion renal threshold from approximately 180 to 50 mg / dL (10 to 2.8 mM). (19), From their mechanism of action, the side effects of SGLT2 inhibitors are predictable. There is a minor (1-2%) rise in lower urinary tract infections and an increase in genital mycotic infections of (3-5%) (20)

*Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase IV is a serine protease expressed as an ectoenzyme on vascular endothelial cells, on the surface of T lymphocytes, and in a circulating form that is widely distributed throughout the body. DPP-4 cleaves the two peptide N-terminal amino acids with proline or alanine in the second position. (21) And the inactivation of GLP-1 and GIP seems to be particularly important. As activated by food ingestion, DPP-4 inhibitors increase the AUC of GLP-1 and GIP. Several agents provide

DPP-4 with almost complete and long-lasting inhibition, raising the proportion of active GLP-1 from 10% to 20 % of the overall circulating immunoreactivity of GLP-1 to almost 100%. Competitive inhibitors of DPP-4 are allogliptin, linagliptin, and sitagliptin; vildagliptin and saxagliptin bind covalently to the enzyme. All five medicines can be administered at doses that lower the detectable activity of DPP-4 by more than 95% over 12 hours. This causes plasma concentrations of active GIP and GLP-1 to increase more than 2-fold and is associated with increased insulin secretion, decreased glucagon levels and improvement in both fasting and postprandial hyperglycemia. Inhibition of DPP-4 does not seem to have a direct effect on insulin sensitivity, gastric motility or satiety; body weight is also not affected by prolonged treatment with a DPP-4 inhibitor. (22) also, many side effects are found in DPP-4 There are no consistent adverse effects for any of the DPP-4 inhibitors that have been noted in clinical trials. Broad studies of cardio-vascular safety on alogliptin, saxagliptin, and sitagliptin have been published. The frequency of cardiovascular events in diabetic patients was not affected by these medications, while patients treated with saxagliptin had an increased hospitalization rate for heart failure. The FDA has issued a warning that severe joint pain is seldom associated with this class of drugs. DPP-4 is expressed on lymphocytes, and the enzyme is referred to as CD26 in the immunology literature. Effects on immune function deserve investigation as these drugs are used to treat more patients. (23)

*GLP-1 Receptor Agonists

Exenatide. Exendin-4, with a 53% sequence homology to GLP-1, is a naturally occurring 39-amino acid reptilian peptide. This peptide is a potent GLP-1RA that shares many of the physiological and pharmacological effects of GLP-1. It is not metabolized by DPP-4 and thus has prolonged post-injection activity. Exenatide, synthetic exendin-4, is approved for use as monotherapy and as an adjunctive therapy in patients with type 2 diabetes who do not meet glycemic goals with other medicines. Exenatide, alone or in combination with metformin, sulfonylurea, or thiazolidinedione, was associated with improved glycemic control in clinical trials, as demonstrated in an approximately 1 % decrease in Alc and weight loss of 2.5-4 kg on average. Data from clinical trials has shown that exenatide can also be used with basal insulin in combination. An extended-release form of exenatide is given once a week by subcutaneous injection, with greater efficacy than twice-daily treatment.

liraglutide peptide is a long-acting form of GLP-1 resistant to DPP-4, but with Lys34Arg replacement and a-glutamic acid spacer addition coupled to the C16 fatty acyl group at Lys26. The side chain of fatty acids enables binding to albumin and other plasma proteins and accounts for an extended t, which enables once-daily administration; the fatty acid also appears to provide some defense against N-terminal cleavage by DPP-4. Liraglutide's pharmacodynamic profile imitates GLP-1 and exenatide. Liraglutide caused both an increase in glycemic control and weight loss in clinical trials. Liraglutide lowered Alc by around 30% more than exenatide in a single comparative study, in patients who fail to maintain glycemic regulation with oral agents, liraglutide is indicated for adjunctive therapy. Oral agents or basal insulin may be added to liraglutide. In a recent study, in patients with type 2 diabetes and proven cardiovascular disease, liraglutide decreased the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Similar positive effects on cardiovascular risk were also seen in a semaglutide trial, A compound with similarities to liraglutide in growth. In the studies performed to date, other GLP-1 receptor agonists (exenatide and lixisenatide) are neutral with regard to cardiovascular risk.

Albiglutide is a fusion protein that includes two sequential GLP-1 moieties linked to human albumin; the GLP-1 sequences are changed to avoid cleavage of DPP-4. In patients with type 2 diabetes with suboptimal glucose regulation, albiglutide is also suggested and can be used in combination with oral agents and basal insulin.

Dulaglutide is a fusion protein composed of two linked molecules that have a modified version of GLP-1 related to the human immunoglobulin's Fc portion; the GLP-1 sequences are modified to defend against DPP-4 action. The pharmacodynamics are similar to other GLP-1RAs, and other antidiabetic agents can be used with the medication.

Lixisenatide has similar pharmacodynamics and is a slightly longer version of exendin-4. Data from a recent clinical trial of diabetic subjects with a previous history of cardiovascular disease indicated no impact of lixisenatide on recurrent events.

While all GLP-1RAs have been shown to be effective as monotherapy, none is regarded as a first-line agent. Although several clinical trials specifically comparing different GLP-1RAs are available, there are generally small differences in efficacy compared to the overall effect of the drugs, and definitive differences await more comprehensive studies

All GLP-1RAs share a similar mechanism, GLP-1 receptor activation a member of glucagon receptor family of GPCRs (class B GPCRs). GLP-1 receptors are expressed by ß cells, cells in the peripheral and central nervous systems, the heart and vasculature, kidney, lung, and GI mucosa. The CAMP-PKA pathway and several GEFs are activated by the binding of agonists to the GLP-1 receptor. (24)

Current guidelines recommend a patient‐centered approach when choosing appropriate glucose‐lowering treatments, with the primary goal of achieving individualized glycemic targets whilst minimizing adverse effects, particularly weight gain and hypoglycemia. (25) Glucagon Like peptide-1 Adverse Effects; subcutaneous or Intravenous administration of GLP-1 may cause nausea and vomiting (26)

GLP-1 analogs have less significant side effects than other drugs used to treat DMM.

And GLP-1 analogues have many advantages which have been reported to include weight loss in type 2 diabetes patients, and not causing hypoglycemia. There is some evidence by animal studies that GLP-1 analogues increase the beta-cell mass of the pancreatic islet and decrease the apoptosis of beta cells. If GLP-1 analogues boost the survival of beta cells and promote the growth of beta cells in people with type 2 diabetes, they can provide the easiest way to maintain or restore the functional mass of beta cells. This could be the most major advance. (27)

The dilemma in Previous studies that not sufficient because most of studies compared GLP-1 with Placebo or basal insulin.

Diabetes mellitus is widespread disease and the studies in the disease are constantly renewed, and these studies differ across countries according to different numbers and factors causing this disease.

That’s why This study designed to evaluate and compare the efficacy and safety of GLP-I analogs with other antidiabetic drugs which are most common used in Saudi Arabia

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