Diabetes Handout 2024: Products Used in the Treatment of Diabetes Mellitus

Products Used in the Treatment of Diabetes Mellitus I. Insulin: Chemistry- Two polypeptide chains: an A chain, consisting of 21 amino acids, and a B chain, containing 30 amino acids. The two chains are connected by two disulfide bonds, and there is an additional disulfide linkage within the A chain....

Products Used in the Treatment of Diabetes Mellitus I. Insulin: Chemistry- Two polypeptide chains: an A chain, consisting of 21 amino acids, and a B chain, containing 30 amino acids. The two chains are connected by two disulfide bonds, and there is an additional disulfide linkage within the A chain. 1. Mechanism of Action Binds to specific high-affinity receptors located on the plasma membrane. The βsubunits of these insulin receptors have tyrosine kinase activity, while the αsubunits serve as the binding sites for insulin. The increase in glucose transport in muscle and adipose tissue is mediated by the recruitment of GLUT4 transport proteins, which are relocated from the cytoplasm and inserted into the plasma membrane. 2. Insulin Receptor. Is a glycoprotein consisting of two α-subunits and two β-subunits linked covalently by disulfide bonds. After insulin binds to the α-subunits on the extracellular surface of the plasma membrane, the tyrosine kinase activity of the transmembrane βsubunits are unmasked, which results in phosphorylation of tyrosine residues on the β-subunits themselves (autophosphorylation), as well as several critical tyrosine residues in the “insulin receptor substrates” (IRS-1, IRS-2, IRS-3, and IRS-4) Phosphorylated IRS’s then to bind and activate/initiate an incredibly complex array of kinases and second messenger pathways. Amongst all of these pathways it is worth mentioning two especially important ones, the phosphtidylinositol-3 kinase pathway (PIP3 kinase pathway) and the MAP kinase pathway. a. Via activation of the PIP3 kinase pathway, the phosphorylation of the GLUT 4 transporter and its subsequent translocation to the cell membrane is ultimately achieved (2-3 steps). Additionally this pathway leads to alterations in the phosphorylation state of key metabolic enzymes, resulting in enzyme activation or inactivation. For example, the transcription of several genes involved in glycogen and triglyceride storage, glucose catabolism, etc., is enhanced, whereas the transcription of other genes involved in gluconeogenesis or glycogen breakdown are inhibited. 1 b. Modulation of the rate of mRNA transcription by insulin is extremely important. It is important to remind students that insulin is a growth factor. Expression of genes involved in cell growth, proliferation, and survival is insulin-mediated partly by the ras signaling complex (a critical component of the MAP kinase pathway). Insulin-like growth factor (IGF) can also bind to and activate insulin receptors. 2 3 Insulin Plays a Major Role in a Complex Web of Cellular Signaling Pathways 4 B. Types of insulin 1. Recombinant human insulin 2. Recombinant, bioengineered derivatives of insulin 3. Neutral protamine Hagedorn (NPH) = “Isophane Insulin” 4. ALL insulin products contain zinc; the ratio of zinc to insulin determines both the rate of insulin release from the site of administration and the duration of action. 5. Insulin preparations are marketed primarily as 100 units/mL (U-100). patients demonstrating extreme insulin resistance, e.g. a daily insulin requirement of 200 or more units, a U-500 preparation is available. For 6. Insulin units used to be based on biological activity, but units can now be determined based on the weight of the recombinant insulin obtained from a recrystallized sample. C. The goal of insulin therapy: 1. To prevent the development of the metabolic abnormalities experienced by diabetics. For many diabetics, the goal can be realized only by supplemental or replacement insulin therapy. 2. No single insulin preparation or combination of preparations can successfully meet the demands of such a diverse group of patients as “diabetics.” Consequently, a large number of insulin preparations have been developed, each of which has certain advantages and disadvantages. 3. Although all of these preparations consist primarily of insulin and exhibit the biological effects of insulin, they do differ in their onset and duration of action. D. Addition of Protamine to Alter the Pharmacokinetics of Insulin 1. Protamine: Obtained from the semen of fish, protamine is a basic protein that bears a net positive charge, while insulin bears a net negative charge. The two can be combined to form a protamine-zinc-insulin complex, which is less soluble in extracellular fluids than insulin, and leaves the site of injection more slowly. This accounts for the delayed onset and prolonged duration of action. 5 2. NPH insulin- Neutral Protamine Hagedorn- A complex of insulin, zinc, and protamine formulated in a phosphate buffer at neutral pH (pH=7) The protamine and zinc insulin crystals are in stoichiometric quantities. The term “isophane” was coined to reflect this. NPH is a cloudy solution with an onset of 2 hours (peak at 68 hours) and a duration of action of 10-16 hours. E. General Classification of Insulin Products The available insulin formulations can be broadly classified into four categories reflecting rates of onset and durations of action: Ultra-rapid onset with short duration of action (insulin lispro, insulin aspart, insulin glulisine) Rapid onset with short action (regular insulin) Intermediate in both onset and duration of action (NPH insulin) Intermediate onset with extended action (insulin glargine, insulin detemir, insulin degludec) F. Insulin Products 1. Ultra-rapid onset and short action: Insulin lispro (Humalog®) Insulin aspart (Novolog®) Insulin glulisine (Apidra®) Bioengineered recombinant insulins Dissolve more rapidly at site of administration Insulin lispro: Regular insulin exists as a hexamer. Absorption is delayed as the insulin dissociates from hexamers into dimers and monomers. Keep in mind that the active form of insulin is the monomer. While human insulin contains proline and lysine in the C-terminal portion of the beta chain at positions β28 and β29 respectively, the new insulin analog (Humalog® = insulin lispro) has lysine and proline at those two positions. By the simple inversion of these two amino acids in human insulin, the ability of insulin to dissociate into dimers and then 6 monomers is enhanced, with the result being the creation of a rapidly absorbed insulin. Insulin aspart: Proline at position β28 of the beta-chain of normal human insulin is replaced with aspartic acid. This substitution prevents aggregation of insulin aspart into hexamers and dimers, thus facilitating its absorption from subcutaneous injection sites. Insulin glulisine: The amino acid lysine at position β29 of regular insulin is replaced by glutamic acid, and the amino acid asparagine at position β3 of regular insulin is replaced by lysine. Insulin glulisine is stable only in normal saline if it is to be used IV. These derivatives enter circulation twice as fast as regular crystalline insulin Ultra-rapid in onset (approx. 15 minutes) for all three agents Duration of action: Insulin lispro – 2 to 4 hours Insulin aspart – 3 to 5 hours Insulin glulisine – 2 to 4 hours Clinical use: Suitable for use immediately prior to meals; can be dosed on a sliding scale (as can regular insulin) These are clear solutions that are administered s.c. Intermittent SC injections should be given within 15 minutes before to 20 minutes after starting a meal. These insulins can be administered via external SC infusion pump. 2. Rapid onset and short action: Regular (crystalline zinc) insulin (Regular Insulin, Humulin R®, Regular Iletin II®, Velosulin BR®) A short-acting, soluble crystalline zinc insulin 7 Onset: 30 min following s.c. injection Duration of action: 5 to 7 hours Recombinant human insulin preparations are available: Lilly – from E. coli Novo Nordisk – from Baker’s yeast Clinical uses Used IV in emergencies (ketoacidosis) Administered s.c. in ordinary maintenance regimens Alone or used in conjunction with an intermediate-acting (NPH) or long-acting preparations Required administration 30 – 60 min before each meal 3. Intermediate onset and duration of action: a. Neutral Protamine Hagedorn (NPH) (NPH Insulin, Humulin N®, NPH Iletin II®) Also known as “isophane insulin suspension” A suspension of crystalline zinc insulin combined with protamine at neutral pH in phosphate buffer Complex of insulin with protamine decreases solubility and delays absorption Onset: 2 to 4 hours Duration of action: 10 to 16 hours Administered by s.c. injection NOT suitable for IV use 8 Clinical use: Maintains fasting blood glucose level Administered by s.c. injection NOT suitable for IV use 4. Intermediate onset and extended action: a. Insulin glargine (Lantus®) Bioengineered long-acting preparation Glycine replaces arginine at position 21 on the alpha-chain (α21) of normal human insulin. In addition, two arginines are added at the end of the β-chain. The addition of the two positively-charged arginines to insulin changes the isoelectric point in comparison to normal human insulin Insulin glargine is soluble at acidic pH and less soluble at physiological pH. Injected as a clear solution buffered at pH = 4, it is neutralized in subcutaneous tissues where it forms microprecipitates, delaying its absorption from the injection site and prolonging its duration of action (note: the other long-acting insulin preparations are cloudy solutions). Onset of action is approximately 1.1 hours. Provides a peakless basal insulin level that lasts 24 hours Duration of action of insulin glargine is longer than NPH. Unlike NPH insulin, glargine has no peak concentration, so it mimics continuous infusion of rapid-acting regular insulin from a continuous infusion pump (i.e., nearly constant serum levels are achieved throughout). Thus, insulin glargine is administered once-a-day (every 24 hours). Dose at bedtime to achieve this effect) Never mix insulin glargine with any other insulin 9 b. Insulin detemir (Levemir®) Insulin detemir is a recombinant, soluble, long-acting insulin analog that is produced from a chemical modification of regular insulin: a 14-carbon fatty acid (myristic acid) is covalently bound to the amino acid lysine at position β29, and the amino acid threonine at position β30 is omitted. Fatty acid acylation enhances detemir’s affinity for albumin, which allows for a prolonged duration of action via delayed absorption due to albumin binding in subcutaneous adipose tissue and plasma. Unlike insulin glargine and NPH insulin, insulin detemir is soluble at neutral pH and therefore remains in solution following subcutaneous injection, increasing surface area and reducing variability in absorption. Administered once or twice daily by intermittent subcutaneous injection only Onset of action is approximately 2 hours. Duration of action is approximately 22 hours Similar to insulin glargine, insulin detemir is associated with a flatter time-action profile than other insulin products (i.e. lacks pronounced peak).. c. Insulin degludec (Tresiba®) Insulin degludec is an ultra-long acting insulin. The addition of hexadecanedioic acid to lysine at the β29 position allows for the formation of multi-hexamers in subcutaneous tissues. This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation. Longest half-life of all insulin products (approx.. 42 hours) May be mixed with rapid-acting insulins without altering the pharmacokinetics of the degludec or the rapid-acting insulin. (This is not true for glargine or detemir) 10 G. Side Effects of Insulin Products Hypoglycemia- Most serious of the side effects. Substantial overdose of any insulin product can be life-threatening. Hypoglycemia due to over-injection of long-acting insulins is harder to treat. Patients are advised to take their insulin injections on schedule and to eat at regularly scheduled intervals. Warning signs of hypoglycemia are nervousness, tachycardia, palpitations, tremor, diaphoresis (sweating), mental confusion or bizarre behavior, and coma. Remember that hypoglycemia is accompanied by activation of the sympathetic nervous system, the body’s attempt to overcome the hypoglycemia by effecting glycogenolysis in the liver (activation of α- and β2-adrenergic receptors), glucagon release (via β2, α2, α1 adrenergic receptors), and lipolysis in adipose tissue (activation of β3 adrenergic receptors). There is also increased release of epinephrine and cortisol from the adrenal gland and increased growth hormone (GH) release from the pituitary. Weight gain: Insulin promotes the conversion of fatty acids into triglycerides in adipose tissue, and increases the synthesis of lipoprotein lipase 11 Immunological toxic effects: due to the development of insulin antibodies Insulin resistance (IgG anti-insulin antibodies): neutralize insulin effect; most insulin-treated patients develop a low titer of IgG antibodies that very slightly neutralize the effect of insulin. Insulin allergies (IgE anti-insulin antibodies) o Immediate hypersensitivity reaction producing urticaria and anaphylaxis o Lipodystrophy: some patients experience hypertrophy of subcutaneous fat at the site of injection. This effect may be minimized by rotating (changing) the site of injection frequently. There has been a decreased incidence of lipoatrophy compared to the past because of the higher purity of most currently marketed insulin products. H. Drug Interactions Associated with the Use of Insulin Products 1. Ethanol- Increased risk of hypoglycemia because ethanol inhibits gluconeogenesis 2. β-blockers- Inhibit the protective effects of catecholamines on liver glycogenolysis and gluconeogenesis during hypoglycemia. In addition, βblockers will mask the warning signs of hypoglycemia (i.e. sympathetic activation such as tachycardia). I. Insulin delivery systems Standard mode of therapy: Subcutaneous injection with standard disposable needles and syringes. Other, more convenient means of administration are available or in clinical trials Portable pen-sized injectors are used to facilitate s.c. injection. Some contain replaceable cartridges, whereas others are disposable. Continuous s.c. insulin pumps prevent the requirement for numerous daily injections and afford flexibility in the arrangement of patients’ daily activities. Programmable pumps deliver a constant 24-hour basal rate, and manual modifications in the rate of delivery can accommodate changes in insulin requirements (e.g. before meals or exercise). 12 A rapid-acting inhaled formulation of insulin is now available (Afrezza®). This form is effective and convenient for covering mealtime insulin requirements. It is administered at the beginning of a meal. Side effects include cough and bronchospasm as well as hypoglycemia. Contraindicated in lung disease. J. Insulin Therapy: Standard therapy vs. Intensive treatment Standard therapy: Two s.c. insulin injections per day producing average blood glucose concentrations between 225 and 275 mg/dL. Blood glucose levels in a normal individual average 110 mg/dL. Intensive treatment: Tight glycemic control (no longer recommended due to an increased risk of hypoglycemic episodes) Stabilize blood glucose levels by more frequent insulin injections or the use of insulin pumps in conjunction with blood glucose monitoring: o Average blood glucose concentrations of 150 mg/dL can be attained o 60% decrease in long-term diabetic complications o Increased frequency (3X) of hypoglycemic episode 13 Insulin Preparation Onset (hrs) Peak (hrs) Duration (hrs) Insulin lispro 0.25 0.5 1.5 2-4 Insulin aspart 0.25 1-3 3-5 0.25 0.5 1.5 2-4 0.5 - 1 2-3 4-6 4 - 10 10 - 16 --------- 20 - 24 22 - 24 Rapid-Acting Insulin glulisine Short-Acting Regular Intermediate-Acting Isophane insulin susp. (NPH) 2-4 Long-Acting Insulin detemir Insulin glargine 1-2 4-5 14 Hemoglobin A1c (HbA1c) Hemoglobin A1c (HbA1c) is normal hemoglobin (HbA) that has been non-enzymatically glycosylated by serum glucose. ( The open-ring aldehyde form of glucose reacts with the N-terminus amino group (R-NH2) of hemoglobin to form an unstable intermediate, a Schiff base. Rearrangement of this Schiff base via the “Amadori reaction” (see below) forms a stable irreversible covalent bond between glucose and hemoglobin (“glycosylated hemoglobin”) HbA1c is a minor hemoglobin component (4-6%) in normal individuals, but increases in the presence of chronic hyperglycemia. The value is correlated with the average blood glucose concentration, and therefore can be used both diagnostically, or to estimate how effective therapy has been in controlling blood glucose over a 2-3 month period in a Type 1 or Type 2 diabetic. The goal of therapy in diabetics is to reduce HbA1c levels to < 6.5%. Mean Glucose Levels for Specified HbA1c Levels Mean Plasma-Glucose Concentration HbA1c % mg/dL mmol/L 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5 15 Human Insulin and Bioengineered Insulins: Illustration source: Katzung PHARMACOLOGY, 9th edition Section VII. Endocrine Drugs Chapter 41. Pancreatic Hormones & Antidiabetic Drugs 16 Oral Agents Used to Treat Type 2 Diabetes: A. Sulfonylureas History: In the early 1940’s, some patients died who were being treated for typhoid fever with a sulfa drug. These deaths were attributed to acute and prolonged hypoglycemia, caused by stimulation of pancreatic insulin release. Relatively little attention was paid to the potential significance of these drugs in the treatment of diabetes until several years later when clinical studies were reported. They have similar actions, thus their pharmacokinetic properties are their most distinctive characteristics. These drugs are POTENT hypoglycemic agents. Mechanism of Action: o Major mechanism: Stimulation of insulin release from pancreatic β-cells. Sulfonylureas bind to a receptor associated with KATP channels in the pancreatic β-cell membrane. Binding inhibits K+ efflux through the channel and results instead in depolarization of the β-cell. Depolarization opens a voltage-gated Ca2+ channel. The resulting influx of Ca2+ results in the release of insulin. Release of insulin in response to glucose is enhanced. o Reduction of serum glucagon levels: chronic administration of sulfonylureas in Type 2 diabetes reduces serum glucagon levels. The mechanism appears to involve indirect inhibition due to the enhanced release of insulin and somatostatin, both of which inhibit pancreatic β-cell secretion of glucagon. o Potentiation of insulin effects in target tissue: increased binding of insulin to tissue receptors does occur in Type 2 patients receiving sulfonylureas. This appears to be an effect secondary to the reduction of hyperglycemia and fatty acid levels produced by the increased release of insulin. Adverse effects: o Hypoglycemia- start low and titrate up every 1 to 2 weeks 17 o Nausea/vomiting, dyspepsia o Weight gain (via enhanced insulin release) o Allergic reactions: pruritis, rash o Hematological reactions (blood dyscresias) Earliest products: The “first generation sulfonylureas” *** Note: The 1st generation agents listed here are FYI. They are seldom, if ever, used anymore. They will NOT appear on any test or quiz in this course *** Tolbutamide (Orinase®) o Shortest acting sulfonylurea o Hepatically metabolized (95%) to inactive metabolite, which is renally excreted 95% bound to plasma proteins o Usual dose: 500 mg tid ac; tid dosing is a bid disadvantage 18 Chlorpropamide (Diabinese®) o Half-life of 36 hours overdose is more difficult to manage o 80% metabolized in liver to weakly active metabolite; other 20% is excreted by the kidney unchanged o 100 to 250 mg daily, up to 500 mg daily. Do not exceed 750 mg Disulfiram-like reaction with ethanol. o Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (SIADH): Chlorpropamide increases the sensitivity of the renal tubules to the actions ADH and also mildly stimulates the release of ADH. Tolazamide (Tolinase®) o Several mildly active metabolites, thus it is o 100 to 250 mg once a day o Seldom used Acetohexamide (Dymelor®) o Reduced in liver to potent active metabolite which is renally excreted. This strongly active metabolite is 2.5 times more active then the parent drug itself. o Uricosuric action o 250 to 500 mg once a day o Seldom used because the strongly active drug metabolite complicates dosing Newer agents: The “second generation sulfonylureas” These agents are similar in action to the 1st generation ones except that 2nd generation agents have longer durations of action (many can be used once daily) and have approximately 100 times more potent hypoglycemic activity. Overdose can be more troublesome with the 2nd generation agents because of their lengthy durations of action. Glyburide (Micronase® and Diabeta®) aka “glibenclamide” in UK o Liver metabolism to weakly active metabolites o 1.25 to 2.5 to 5 mg once a day to bid. Micronized formulation- Glynase Prestabs®: 1.5 to 3 to 6 mg once a day to bid o The metabolites of glyburide are weakly active, and this weak level of activity does not contribute substantially to the overall HbA1c lowering effects in most patients with diabetes. However, because these metabolites are cleared renally, patients with reduced kidney function will experience accumulation, which can lead to increased therapeutic effects and increase the risk of hypoglycemia. o Plasma half-life = 10 hours, but 4 hours for micronized formulation 19 Glipizide (Glucotrol®) o 5 to 10 mg bid (30 minutes before food) o Liver metabolism to inactive metabolites o Glucotrol XL = “extended length” of action: 5 or 10 mg once a day Glimepiride (Amaryl®) o 1 mg, 2 mg, or 4 mg once a day o Has an active metabolite with 33% of the activity of glimepiride Pharmacokinetics of the Sulfonylureas 20 B. Meglitinides Repaglinide (Prandin®) and Nateglinide (Starlix®) Pharmacology: o Non-sulfonylurea hypoglycemic agents o Rapid-acting and short duration of actions o Used in the management of post-prandial glucose levels in type 2 diabetics o Lower blood glucose levels by stimulating the release of insulin from the pancreas. Nateglinide, unlike repaglinide, has a greater effect on insulin secretion when plasma glucose levels are rising and therefore produces little stimulation of insulin secretion in the fasting state. o Mechanism of action for both agents is similar to that of the sulfonylureas, i.e. they bind to and close ATP-dependent K+ channels leading to depolarization of the β-cell, with subsequent calcium channel opening and the release of insulin. These agents are able to displace sulfonylureas from their binding sites on the β-cell membrane. Indications: o Administered shortly before a meal to reduce post-prandial glucose levels in type 2 diabetic patients inadequately controlled with diet and exercise. o In combination with metformin Pharmacokinetics: o Rapidly absorbed from the GI tract; Cmax within one hour o Plasma half life: 1 hour for repaglinide; 3 hours for nateglinide o Repaglinide is eliminated in the feces (90%). It is extensively metabolized in the liver by CYP2C8, 3A4, and UGT. It can be used in patients with chronic kidney disease o Nateglinide is hepatically metabolized (primarily by CYPC29 and to a lesser extent CYP3A4) with renal excretion of active metabolites 21 Adverse effects of meglitinides o Hypoglycemia and Weight gain (slightly less than sulfonylureas) o GI upset/ Headache o Severe hypoglycemia has been reported when repaglinide has been used in patients also taking the lipid-lowering drug gemfibrozil. Contraindicated. C. Biguanides: Metformin (Glucophage®) Original biguanide was phenformin which was discontinued due to a high incidence of lactic acidosis associated with the use of the product. Metformin, the only biguanide agent now available, is the most widely prescribed of all of the oral agents used to treat Type 2 diabetes Mechanisms of action: Major mechanism: Decreases hepatic glucose production by inhibiting gluconeogenesis Metformin indirectly activates AMP-dependent kinase (AMPK) which is normally activated when cellular energy ATP/AMP ratio is low (i.e., decreased energy reserves). Activated AMPK phosphorylates transcription factors which in turn INHIBIT the expression of hepatic gluconeogenic genes. The ability of metformin to indirectly activate AMPK may result from its ability to inhibit Complex I of the mitochondrial oxidative phosphorylation process thereby decreasing the ATP/AMP ratio. Increases insulin binding to peripheral receptors (increases insulin sensitivity) Decreases intestinal glucose absorption Does NOT stimulate insulin secretion (“insulin-sparing”) Does NOT produce hypoglycemia as do the insulins, sulfonylureas, and meglitinides Other actions: Decreases triglycerides, total cholesterol, increases high density lipoproteins (HDL), it may? produce a modest weight loss, which is beneficial when the patient is obese (however most clinicians consider metformin “weight neutral”) Metformin is referred to an “anti-hyperglycemic” agent NOT a “hypoglycemic” agent Efficacy – comparable to the oral sulfonylureas with respect to effects on fasting plasma glucose concentration and HbA1c levels 22 Figure. Metformin acts primarily to suppress glucose production in the liver. While metformin's mechanism(s) of action remain controversial, current evidence indicates that metformin's most important effect in treating diabetes is to lower the hepatic production of glucose (as summarized in the top left box). Current evidence suggests that results from a combination of intracellular effects in the liver. When metformin is taken orally, it is absorbed into hepatocytes from the portal vein through plasma membrane transporters, including the organic cation transporter 1 (OCT1). Inside the cell metformin inhibits mitochondrial respiratory-chain complex 1, resulting in reduced ATP levels and increased AMP. Increased AMP levels activate Adenosine MonophosphateActivated Protein Kinase (AMPK), which contributes to lowering of glucose production by at least 2 pathways: i) increased AMPK phosphorylates CBP & CRTC2 transcription factors, which inhibits genes involved in the production of glucose (“gluconeogenic genes”); ii) increased AMPK also inhibits mitochondrial glycerol-3phosphate dehydrogenase (mGPD), leading to an increase in cytosolic NADH, which both stimulates the conversion of pyruvate to lactate, and simultaneously decreases gluconeogenesis. An accumulation of lactate to dangerous levels (lactic acidosis) can occur when metformin is taken by patients with other conditions resulting metabolic acidosis (liver disease, heart failure, sepsis, alcohol abuse), or kidney disease (as indicated by elevated creatinine levels) because metformin is eliminated by renal excretion 23 Indications: Management of Type 2 diabetes as monotherapy In combinations with sulfonylureas, meglitinides , SGLT2 inhibitors, TZD’s, insulin Elimination: Metformin is not metabolized and is excreted in the urine unchanged with a halflife of approx. 5 hours. Active tubular secretion in the kidney is the primary route of metformin elimination Adverse effects associated with metformin o Potential for lactic acidosis (rare): Warning-Avoid in patients with renal insufficiency, liver disease, hypoxemic pulmonary disease, heart failure, or shock as such patients are predisposed to lactic acidosis because of reduced drug elimination, or reduced tissue oxygenation. Contraindicated in pregnancy. o Commonest side effects are GI disturbances (anorexia, diarrhea, nausea usually, but not always, transient) o Advice to the patient: Expect some diarrhea at first (up to 30% of patients), which may go away in a few weeks (metformin increases 5-HT in the gut). o Taste disturbances (metallic) o Long-term use may interfere with absorption of vitamin B12 FYI: The principal substrates for gluconeogenesis are amino acids (alanine and glutamine) derived from muscle protein, glycerol derived from the triglycerides stored in adipocytes, and lactate from muscle. 24 D. Alpha glucosidase inhibitors: Acarbose (Precose®) and Miglitol (Glyset®) Oral alpha-glucosidase inhibitors these agents have approx. 1000 times more affinity for the enzyme than natural carbohydrates Acarbose is a complex oligosaccharide, while miglitol is a simple imino-sugar. Both agents delay digestion of ingested carbohydrates, thereby resulting in delayed (not inhibition of) glucose absorption, and hence a smaller rise in blood glucose concentration following meals. The primary action is produced by a competitive, reversible inhibition of membrane ebound intestinal alpha-glucosidases which hydrolyze complex sugars to glucose. Acarbose inhibits inhibit pancreatic alpha-amylase, which hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine Taken three times daily with the first bite of each meal Acarbose is not absorbed from the GI tract. Small amounts of miglitol may be absorbed from the GI tract, but if so, the drug is rapidly eliminated, unchanged in the urine Do not affect the absorption of glucose, lactose, or fructose, which are not dependent on alpha-glucosidases for absorption. These agents prevent the breakdown of table sugar (sucrose), only glucose, or dextrose should be used to treat symptoms of hypoglycemia that may arise in patients who are taking one of these inhibitors along with an insulin or sulfonylurea. The therapeutic action is modest (in the range of a 30-60 mg/dL reduction in blood glucose levels). These drugs are usually not first-line ones. HbA1C is typically reduced 0.5 – 1.0% median = 0.8% Adverse effects Poorly tolerated due to GI symptoms: abdominal pain, diarrhea and flatulence (gas) → due to the presence of undigested carbohydrate in the lower GI tract. Most of the adverse effects occur at high doses. Contraindicated in irritable bowel disease and obstruction. 25 E. Thiazolidinediones (TZDs) – the “glitazones” Rosiglitzone (Avandia®) and Pioglitazone (Actos®) The “TZD agents by enhancing the expression of the genes for GLUT4, LPL, and certain factors involved in lipogenesis/adipogenesis can be thought of as sensitizers of cells to the actions of insulin, and therefore their effectiveness is ultimately dependent on a measure of circulating insulin being present. They do NOT increase the release of insulin from the pancreas (i.e., they are “insulin-sparing”); hence, they do not produce hypoglycemia when used as monotherapy. Overall, they enhance the uptake of fatty acids and glucose from plasma into adipocytes or muscle, and they mildly inhibit gluconeogenesis These agents bind to receptors that regulate the transcription of a number of insulin responsive genes that are critical for the control of glucose and lipid metabolism: A key action of these thiazolidinedione agents is to activate the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-χ). 26 This receptor, which is expressed in high levels in mammalian adipose tissue, and at moderate levels in muscle and liver, regulates the transcription of several key genes involved in adiptocyte differentiation and insulin-mediated glucose uptake into muscle and adipose tissue. The endogenous ligands for PPAR- χ are free fatty acids (FFAs) and eicosanoids. In the liver, TZDs inhibit glucose production. They also promote adipose tissue differentiation. They reduce expression of leptin (a signaling factor which regulates appetite, bodyweight, and energy balance), while increasing expression of enzymes involved in lipogenesis, including lipoprotein lipase (LPL), fatty acid transport protein, adipocyte lipid-binding protein (aP2), and the GLUT-4 transporter (which plays a key role in the facilitated transport of glucose into adipocytes and skeletal muscle). The major outcome of TZD-mediated effects on gene expression is an increase in the storage of fatty acids as triglycerides in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of glucose, in order to yield energy for cellular processes. Troglitazone (Rezulin®), the original TZD agent, was introduced with great fanfare in 1998, but several cases of severe hepatotoxicity, and in some cases death, resulted in its removal from the market. Subsequently, two new TZD agents, rosiglitazone (Avandia®) and pioglitazone (Actos®) were introduced in 1999. The serious hepatotoxicity associated with troglitazone was not encountered during clinical trials with these two newer agents, nonetheless their hepatotoxicity risks (if any) are unknown, and caution should be advised when using these agents. Accordingly, periodic liver function tests are required when treating a patient with these agents monitor LFT’s every 2-3 months for the first year. Indications: Monotherapy for Type 2 diabetes In combination with a sulfonylurea, metformin, or insulin (pioglitazone) Pharmacokinetics: Both agents are rapidly and nearly completely absorbed, with time to peak plasma concentration of less than 2 hours. Both are highly (>99%) bound to plasma proteins, both are subjected to hepatic metabolism, and both have a short (