[Music] hello guys welcome to another session of diabetes medius and in this session we will be discussing about the drugs that I use for the treatment of diabetes medius mainly anti-diabetic drugs we'll first see what are the learning objectives of this session at the end of the session the student should understand the mechanism of action of various anti-diabetic agents and he should understand the individual anti-diabetic drugs and also the treatment algorithm for type two diabetes meletus diabetes meletus is a condition in which there is reduced insulin secretion there is reduced action of insulin or there is a combination of both these things so normally what insulin does is that it will move glucose from plasma ma to tissues when insulin is reduced or when insulin is not acting properly this will result in increased glucose in plasma that is one of the important feature of diabetes meus so the agents used for the treatment of diabetes milus they will reduce the plasma glucose in one way or the other so the anti-diabetic drugs they can be broadly classified into four different classes depending upon their mechanism of action the most important mechanism of action of anti-diabetic agent is by increasing insulin secretion and there are certain agents that will increase insulin secretion and the second mechanism of action of antidiabetic agent is those agents that reduce insulin resistance insulin resistance is a condition in which insulin is present in the body but binding of insulin to receptors does not produce any response and the third mechanism of action of anti-diabetic agent is by reducing the glucose reabsorption from the kidneys and the fourth mechanism is those agents that reduce the absorption of glucose from the gastrointestinal tract so first we will discuss about the agents that will increase insulin secretion four groups of Agents increase insulin secretion the most commonly used agent among the Agents that increase insulin secretion are sulfan uas and an example is gide okay and the second group of Agents that increase insulin secretion is meglitinide analoges example is repaglinide and the third group of agent that increase insulin secretion is G dp1 Agonist example is exanti and the fourth group of Agents that increase insulin secretion is dipti peptidase 4 Inhibitors examl is cagin okay so first we will we will discuss about all these agents in detail and first we will discuss about sanile uas so three sanile uas are commonly used in clinical practice they are glyde iide and Glyburide how these sulfine uas increase the insulin secretion so normally in the beta cells of the pancreas there are potassium channels in the cell membrane and these potassium channels will move the potassium from the intracellular to the extracell and this will result in a state of hyperpolarization and this hyperpolarization will inhibit insulin secretion okay Inver movement of positively charged ions or inhibition of these potassium channels can result in depolarization and this will result in insulin secretion so what the sanile uas do is that they will inhibit these potassium channels and this will result in reduced outward movement of potassium so potassium accumulates inside the cell and this will result in development of a positive charge intracellularly and this will produce depolarization and depolarization will trigger the release of insulin there are other mechanisms of action of sanile uas as well sanile uas when they are administered for long duration of time it will increase the sensitivity of tissues to insulin so when the sensitivity of the tissues are increased this will result in increased action of insulin and that will result in increased movement of glucose from the plasma into tissues so the mechanism of action of sulan uas is by increasing the insulin secretion so when insulin secretion increases it can produce reduction in plasma glucose so this can produce hypoglycemia so one thing you have to remember about sanile Ura is that sanile uas will stimulate insulin secretion even when the plasma glucose is low so the stimulation of insulin secretion with sulin uas is not dependent upon the plasma levels of glucose so a person who is having low plasma glucose if he is taking sulon uas he will definitely develop hypoglycemia so that is one major drawback of the sulfan UA another disadvantage of sulfan Ura is that since insulin is an anabolic hormone and Insulin secretion is increased by suany uas this use of sulfan uas can produce weight gain sulfan uas reduce the hpy by 1 to 2 percentage so when you learning about anti-diabetic agents this is the most important thing that you should remember how much does the how much hbcy is reduced by each group of drugs so you will be able to understand how much efficacious each of the drug is one important advantage of sulfan Ura is that it is very cheap and it is available everywhere okay next group of Agents that increase in insulin secretion is meglitinide analoges two meglitinide analoges are available in the market they are repaglinide and nlite so you don't have to remember much about this megalan analoges because they are exactly similar to that of sanile uas only thing different is their chemical structure so if you learn sanile uas you'll be able to know meglitinide analoges so the next group of agent that in inre insulin secretion are glp1 agonis so they mimic the incretin hormone glucagen like peptide one and four agents are available in the market now exanti liraglutide dulaglutide and lixisenatide okay so before we go into the mechanism of action of uh GP one ionus we should understand what these incret do in our body the beta cells of the pancreas contains receptors for incron okay so they have receptors for gp1 and also for Gip so binding of these incret to the beta cells of the pancreas will result in increased levels of intracellular cyclic amb and when the intracellular cyclic amb levels are increased this will result in blockade of the potassium channels which are present in the plasma membrane of the beta cells of the pancreas so this will reduce the outward movement of potassium so when potassium channels are blocked the intracellular positive charge will increase and this will result in depolarization and depolarization will trigger the release of insulin glp1 Agonist also have other actions other than increase in insulin secretion they reduce the peristalsis so food stays in the gastrointestinal tract for longer duration of time they also reduce the appetite so by reducing the gastrointestinal movements and also by reducing the appetite glp1 agonis produces weight loss so unlike sulfan Urias glp1 Agonist stimulate insulin secretion only when glucose is present in sufficient quantity in the plasma sanile uas will will stimulate insulin secretion even if the plasma glucose levels are low so that can produce hypoglycemia whereas this glp 1 nist they will stimulate insulin secretion only when the plasma glucose levels are sufficient so it does not produce any hypoglycemia at all so that is one advantage of this gp1 aonis compared to that of sulfan Urias the major disadvantage of glp1 Agonist is that they are given as injections subcutaneous injections so a person who is having diabetes melus he might need to take treatment for his lifespan so nobody would be very keen on getting injected every day with glp1 neon or any other injection glp1 Agonist reduce the glycated hemoglobin by 1% the major adverse de reactions of gp1 Agonist are one is nausea and vomiting the major adverse duug reactions are gastrointestinal it can produce nausea and vomiting it can also produce pancreatitis so these are the major adverse drug reactions of glp1 agonis another major disadvantage of glp1 Agonist is that they are expensive they are relatively new to the market so they are expensive the fourth group of Agents that increase insulin secretion is dpp4 Inhibitors many dpp4 Inhibitors are available in the market we will be discussing mainly about three agents one is sagon second one is wiag lipon and the third one is telpon so dpp4 is an enzyme that metabolizes incret so increased levels of incret will increase the action of incret in the beta cells of the pancreas and that will stimulate insulin release so the insulin release is increased by at least two fold and compared to sulfan uas this dpp4 Inhibitors do not stimulate insulin secretion even when the plasma glucose is low so this does not produce significant hypoglycemia dpp4 Inhibitors they reduce the glycated hemoglobin by .5 to8 per and the major adverse de reactions associated with with the pp4 Inhibitors is that it will produce joint pain and it also produces naso faringitis so that concludes the Agents that increase the insulin secretion the Agents that increase the insulin secretion are sulfon uas meglitinide analogs glp1 on and dpp4 Inhibitors so coming to the next mechanism of action of anti-diabetic drugs that is reducing insulin resistance two agents are available in the market that can reduce insulin resistance these agents are metformin and biosol so the synthesis of glucose from fats and amino acids is known as gluconeogenesis so this is a normal process that happens in our body when we are fasting or when we are deficient in energy so this process requires ATP and in the presence of ATP only this glucon neogenesis takes place so met forming what it does is that it will inhibit the ATP production thereby reducing gluconeogenesis gluconeogenesis is also inhibited by an enzyme called as kyes or ampk metformin will stimulate this amp kyese enzyme and that will reduce gluconeogenesis and Metformin also reduces the absorption of glucose from the gas as intestinal tract thereby reducing the glucose that reaches the plasma metformin also has an action of reducing the appetite and this action is achieved by increasing the levels of glp1 as you remember glp1 reduces the peristalsis and also reduces the appetite so because of this metformin can produce loss of appetite metformin also increases the sensitivity of tissues to insulin so when tissues are more sensitive to insulin more amount of glucose will enter inside the cell glucose will be moved from the plasma into the tissues that will result in reduction in plasma glucose when you are using Metformin it will reduce the complications associated with diabetes meletus so diabetes meletus is a disease which which has got many complications both microvascular complications and also macrovascular complications and using Metformin can reduce all these complications this is one important thing that you should remember about metformin metformin is the firstline drug for the treatment of diabetes melitus especially type two diabetes melus and this it is the drug of choice for treatment starting treatment of type 2 diabetes melus unless otherwise contraindicated and one important advantage of Metformin is that we have been using Metformin for a long duration of time and Metformin is very cheap and since metformin does not increase insulin secretion it does not produce hypoglycemia and Metformin by increasing the levels of gp1 it reduces the appetite and that will result in weight loss so this is a suitable agent for patients who are obese and diabetic the usual dose of Metformin is5 to2 G per day beyond 2 GS metformin does not produce any considerable reduction in plasma glucose metformin is also used off label because it is not a approved indication for a condition known as polycystic ovarian syndrome okay polycystic ovarian syndrome is a condition that is that develops due to insulin resistance so metformin reduces this insulin resistance and thereby produces Improvement in polycystic OV IND disas the major adverse AG reactions of Metformin are very mild it produces gastrointestinal adverse de reactions like nausea and vomiting methin also produce blotting long-term use of Metformin can reduce the absorption of vitamin B12 and that can result in B12 deficiency metformin also increases the amount of lactic acid in the plasma that can result in lactic acidosis this is a very important adverse reaction of metformin and you should be very aware that metformin can produce lactic acidosis metformin reduces the glycated hemoglobin by 1 to 2 percentage the next agent that reduces insulin resistance is poog gltool adipose tissue skeletal muscles and liver contains a type of receptors known as PP gamma so this is an abbreviation for peroxisome proliferator activator receptor gamma so stimulation of these receptors will result in increased movement of glucose from the plasma into this tissues so plyto will stimulate these receptors thereby increasing the uptake of glucose by skeletal muscles adipose tissue and also liver and by increasing the uptake of glucose by these tissue bogason will reduce insulin resistance the synthesis of glucose from fats and amino acids is known as gluconeogenesis plyto inhibits this gluc neogenesis thereby reducing the plasma glucose plyto also has got a favorable effect on plasma lipids it will increase the plasma HDL level which is a good cholesterol plyto reduces the glycated hemoglobin by .5 to 1.4% biogon can produce weight gain this is by causing fluid retention fluid retention will result in increased accumulation of fluid inside the body and and that will result in increase in weight plyto can also precipitate cardiac failure especially in patients who are having pre-existing cardiac conditions long-term use of bogason is also associated with bone fractures so that's all about the agents that reduce insulin resistance two agents are available in the market one is metformin and the other one is biogon metformin is the first line agent for treatment of all the patients who are having type 2 diabetes melus unless contraindicated so third group of Agents uh that are used for the treatment of diabetes meletus these agents will reduce the glucose reabsorption from the kidneys normally the glucose present in plasma will be filtered by the glomus and they will go through the proximal convoluted tubule Loop of f distal convoluted tubule and collecting tubule so in the proximal convoluted tubule there are Transporters that will transport sodium and glucose into the cell and from there this will be reabsorb and this transporter is known as sodium glucose Co Transporter 2 or sglt2 so the agents that reduce glucose reabsorption will inhibit this transporter so this will reduce the reabsorption of sodium and also the reabsorption of glucose so this will result in increased excretion of glucose through urine so these agents they are called as sglt2 Inhibitors or sodium glucose Co Transporter 2 Inhibitors three agents are available in the market canag gphin empa gphin and dag gphin these three agents are used for the treatment of type 2 diabetes meitus these agents reduce the glycated hemoglobin by 7 to 1 per sglt2 Inhibitors can produce mild reduction in weight due to loss of fluid since it does not increase the secretion of insulin it does not produce hypoglycemia so the major drawback of this sglt2 Inhibitors is that more amount of glucose is excreted through the urinary tract so it can result in urinary tract infections when more amount of glucose is present in the urine that will be a very good medium for organisms to grow so that will result in urinary tract infection and since more amount of glucose is excreted through the urine this urine will obviously come into contact with the genital so it can result in genital tract infections as well long-term use of sglt2 Inhibitors can produce bone fractures the disadvantage of sglt2 inhibitors is that they are very expensive they are comparatively new to the market so they are expensive okay so that's about the agents that reduce reabsorption of glucose from the kidneys so three agents are available dagin osin and gagin they are expensive and they produce urinary tract infections and also genital tract infections so the last group of agents that are used for the treatment of diabetes meletus are the agents that reduce absorption of glucose from the gastrointestinal tract so the complex carbohydrates that are present in the diet will be broken down into simple carbohydrates by an enzyme called as Alpha glucosides so this enzyme breaks down the complex carbohydrates into simple carbohydrates so that it can be absorbed into the systemic circulation so the agents that reduce gastrointestinal absorption of glucose will inhibit this enzyme Alpha glucoses thereby reducing the gastrointestinal absorption of carbohydrates three Alpha glucos Ras Inhibitors are available in the market they are acaros miglitol and vogos so this is the basic mechanism of action of alpha glucose race Inhibitors alpha glucose Ras Inhibitors also increase the levels of glp1 which is the incret glucagon like peptide 1 normally glucagon like peptide 1 will stimulate insulin secretion so increased levels of glp1 will increase the insulin secretion that is another mechanism of action of this Alpha glucosidase Inhibitors since alpha glucose race Inhibitors inhibit the absorption of complex carb carbohydrate this will be acted upon by the gut microflora and that can result in flatulence and due to the buildup of gas in the gastrointestinal tract it can also produce blotting okay Alpha glucos rase Inhibitors reduce the glycated hemoglobin by5 to8 per they are not used regularly for the treatment of type 2 diabetes mels they are mainly used for the control of postprandial hyperglycemia Okay so the agents that reduce gastrointestinal absorption of carbohydrates or glucose they inhibit the enzyme that breaks down complex carbohydrates into simple carbohydrates so three agents are available acaros miglitol and vlos all these agents will inhibit the alpha glucose R enzyme since this complex carbohydrates are not broken down this will be acted upon the by the intestinal micro microflora and that will result in development of flatulence and blotting so these are the anti-diabetic agents that are used for the treatment of type two diabetes melus so now we will see how to manage a patient who is newly detected with type 2 diabetes melus so a person who is coming with type two diabetes meus the assessment of his glycemic control should be based on HBA A1C so if he is detected to have diabetes meletus what all things you should should be doing first you should give an education regarding diabetes melus you should also make him understand what is the importance of nutrition and you should also make him understand what is the importance of physical activity and at the same time you should also screen for complications diabetes has got large number of complications micro and macrovascular complications the major complications are retinopathy nephropathy and neuropathy so you will have to do retinal examination and you have to check renal failure by checking the levels of albumin in urine you have to check for neuropathy and you have to check for also cardiovascular evaluation check for other comorbidities which are associated with type two diabetes Ms like dyslipidemia hypertension obesity and cardiovascular disease if these diseases are present you have to treat them as well and you have to start the person on Metformin since he is having type 2 diabetes melitus and Metformin is the first line agent for the treatment of di type two diabetes melus you have to start him on Metformin after you start treatment with metformin you'll have to reassess the hbcy after 3 months or six 6 months to see whether the person is responding to metformin if the person is not responding to metformin then you will have to add a second AG agent and there is no consensus statement which agent you should start it should be according to your discretion it should also be dependent upon the patient's financial status if the patient is having good glycemic control with metformin then you should continue metform and after adding the second agent you have to reassess for hba1c and if the person is not attaining adequate glycemic control with metformin and a second agent you have two options you can add another agent along with metformin and the second agent or you can switch to insulin along with metformin and after making this treatment choice you have to reassess the patient so our goal of treating a patient with type two diabetes melus is to keep the HBC less than 7 so patients who are having an bmnc less than 7 will be having less complications associated with type 2 diabetes melus so to summarize anti-diabetic agents they are the agents that are used for the treatment of type two diabetes milus and Metformin is the first Lan agent for the treatment of type two diabetes Ms unless contraindicated another commonly used agent is sulfan Uria it increases insulin secretion thereby reducing plasma glucose but the problem with sanile Ura is that it will increase insulin secretion invariable of the plasma glucose level so it can produce hypoglycemia and you should also remember the newer agents that are used for the treatment of type 2 diabetes Ms one is glp1 agonis which increase act on The glp1 receptors in the beta cells of the pancreas thereby increasing insulin secretion then there are dpp4 Inhibitors which will reduce the breakdown of incretin thereby insulin secretion and also agents that reduce the reabsorption of glucose from the kidneys that is sglt2 Inhibitors so I hope uh this session was very useful for you and this is very important because India has the second largest population of diabetics and if you will come across diabetics on an everyday basis so remember all these things while you are treating the patient and also remember all these things when you are going to write the exam also thank you [Music]