Pharmacology_Katzung

Pharmacology_Katzung. 3. Insulin detemir—In this insulin the terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the B29 lysine. These modifications prolong the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. The affinity of insulin detemir is fourto fivefold lower than that of human soluble insulin and, therefore, the U100 formulation of insulin detemir has a concentration of 2400 nmol/mL compared with 600 nmol/mL for NPH. The duration of action for insulin detemir is about 17 hours at therapeutically relevant doses. It is recommended that the insulin be injected once or twice a day to achieve a stable basal coverage. This insulin has been reported to have lower within-subject pharmacodynamic variability compared with NPH insulin and insulin glargine. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Insulin Degludec—In this insulin analog, the threonine at position B30 has been removed and the lysine at position B29 is conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer. In the vial, in the presence of phenol and zinc, the insulin is in the form of dihexamers but, when injected subcutaneously, it self-associates into large multihexameric chains consisting of thousands of dihexamers. The chains slowly dissolve in the subcutaneous tissue, and insulin monomers are steadily released into the systemic circulation. The half-life of the insulin is 25 hours. Its onset of action is in 30–90 minutes, and its duration of action is more than 42 hours. It is recommended that the insulin be


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 41–5 Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase considerably when dosage is increased. injected once or twice a day to achieve a stable basal coverage. Insulin degludec is available in two concentrations, U100 and U200, and dispensed in pre-filled disposable pens. 5. Mixtures of insulins—Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in patients with diabetes usually requires supplements of rapidor short-acting insulin before meals. For convenience, these are often mixed together in the same syringe before injection. The regular insulin or rapidly acting insulin analog is withdrawn first, then the NPH insulin and then injected immediately.


Pharmacology_Katzung

Pharmacology_Katzung. Stable premixed insulins (70% NPH and 30% regular) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or insufficient manual dexterity. Premixed preparations of rapidly acting insulin analogs (lispro, aspart) and NPH are not stable because of exchange of the rapidly acting insulin analog for the human regular insulin in the protamine complex. Consequently, over time, the soluble component becomes a mixture of regular and rapidly acting insulin analog at varying ratios. To remedy this problem, intermediate insulins composed of isophane complexes of protamine with the rapidly acting insulin analogs were developed (neutral protamine lispro [NPL]; aspart protamine). Premixed combinations of NPL and insulin lispro are now available for clinical use (Humalog Mix 75/25 and Humalog Mix 50/50). These mixtures have a more rapid onset of glucose-lowering activity compared with 70% NPH/30% regular human insulin mixture and can be given within


Pharmacology_Katzung

Pharmacology_Katzung. use (Humalog Mix 75/25 and Humalog Mix 50/50). These mixtures have a more rapid onset of glucose-lowering activity compared with 70% NPH/30% regular human insulin mixture and can be given within 15 minutes before or after starting a meal. A similar 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is now available. The main advantages of these new mixtures are that (1) they can be given within 15 minutes of starting a meal and (2) they are superior in controlling the postprandial glucose rise after a carbohydrate-rich meal.


Pharmacology_Katzung

Pharmacology_Katzung. Insulin glargine or insulin detemir cannot be acutely mixed with either regular insulin or the rapid-acting insulin analogs. Insulin degludec, however, can be mixed and is available as 70% insulin degludec/30% insulin aspart and is injected once or twice a day. A. Insulin Syringes and Needles Disposable plastic syringes with needles attached are available in 1-mL (100 units), 0.5-mL (50 units), and 0.3-mL (30 units) sizes. The “low-dose” 0.3-mL syringes are popular because many patients with diabetes do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. They are also available in half-unit marking. Three lengths of needles are available; longer needles are preferable in obese patients to reduce variability of insulin absorption. If the skin is clean it is not necessary to use alcohol. Rotation of sites is recommended to avoid problems with absorption due to lipohypertrophy from overuse of injection sites.


Pharmacology_Katzung

Pharmacology_Katzung. B. Insulin Pens The pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro, insulin aspart, and insulin glargine are available for reusable pens (Lilly, Novo Nordisk, and Owen Mumford). Disposable prefilled pens are also available for regular insulin (U100, U500), insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine, insulin degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50% insulin lispro, 70% insulin aspart protamine/30% insulin aspart, and 70% insulin degludec/30% insulin aspart (Table 41–6). C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results.


Pharmacology_Katzung

Pharmacology_Katzung. Normally, the 24-hour background basal rates are preprogrammed and relatively constant from day to day, although temporarily altered rates can be superimposed to adjust for a short-term change in requirement. For example, the basal delivery rate might need to be decreased for several hours because of the increased insulin sensitivity associated with strenuous activity.


Pharmacology_Katzung

Pharmacology_Katzung. Boluses are used to correct high blood glucose levels and to cover mealtime insulin requirements based on the carbohydrate content of the food and concurrent activity. Bolus amounts are either dynamically programmed or use pre-programmed algorithms. When the boluses are dynamically programmed, the user calculates the dose based on the amount of carbohydrate consumed and the current blood glucose level. Alternatively, the meal or snack dose algorithm (grams of carbohydrate covered by a unit of insulin) and insulin sensitivity or blood glucose correction factor (fall in blood glucose level in response to a unit of insulin) can be preprogrammed into the pump. If the user enters the carbohydrate content of the food and current blood glucose value, the insulin pump will calculate the most appropriate dose of insulin. Advanced insulin pumps also have an “insulin on board” feature that adjusts a high blood glucose correction dose to correct for residual activity of previous bolus doses.


Pharmacology_Katzung

Pharmacology_Katzung. The traditional pump (by MiniMed, Animas, Roche, Sooil)— which contains an insulin reservoir, the program chip, the keypad, and the display screen—is about the size of a pager. It is usually placed on a belt or in a pocket, and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion set, although flanks and thighs are also used. The insulin reservoir, tubing, and infusion set need to be changed using sterile techniques every 2 or 3 days. Currently, only one pump does not require tubing (OmniPod, Insulet). In this model, the pump is attached directly to the infusion set (electronic patch pump). Programming is done through a hand-held unit that communicates wirelessly with the pump.


Pharmacology_Katzung

Pharmacology_Katzung. Optimal use of these devices requires responsible involvement and commitment by the patient. Insulin aspart, lispro, and glulisine all are specifically approved for pump use and are preferred pump insulins because their favorable pharmacokinetic attributes allow glycemic control without increasing the risk of hypoglycemia. A mechanical patch pump (V-Go, Valeritas) designed specifically for patients with type 2 diabetes is available on a basalplus-bolus insulin regimen. The device is preset to deliver one of three fixed and flat basal rates (20, 30, or 40 units) for 24 hours (at which point it must be replaced), and there is a button that delivers two units per press to help cover meals. D. Inhaled Insulin


Pharmacology_Katzung

Pharmacology_Katzung. A dry powder formulation of recombinant regular insulin (technosphere insulin, Afrezza) is now approved for use in adults with diabetes. It consists of 2to 2.5-μm crystals of the excipient, fumaryl diketopiperazine, that provide a large surface area for adsorption of proteins like insulin. After inhalation from the small, single-use device, pharmacokinetic studies show that peak levels are reached in 12–15 minutes and decline to baseline in 3 hours, significantly faster in onset and shorter in duration than subcutaneous insulin. Pharmacodynamic studies show that median time to maximum effect with inhaled insulin is approximately 1 hour and declines to baseline by about 3 hours. In contrast, the median time to maximum effect with subcutaneous insulin lispro is about 2 hours and declines to baseline by 4 hours. In trials, inhaled insulin combined with injected basal insulin was as effective in lowering glucose as injected rapid-acting insulin combined with basal insulin. It is


Pharmacology_Katzung

Pharmacology_Katzung. to baseline by 4 hours. In trials, inhaled insulin combined with injected basal insulin was as effective in lowering glucose as injected rapid-acting insulin combined with basal insulin. It is formulated as a single-use color coded cartridge delivering 4, 8 or 12 units immediately before the meal. The manufacturer provides a dose conversion table; patients injecting up to 4 units of rapid-acting insulin analog should use the 4-unit cartridge. Those injecting 5–8 units should use the 8-unit cartridge. If the dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit cartridge and one 8-unit cartridge or one 12-unit cartridge should be used. The inhaler is about the size of a referee’s whistle. The most common adverse effect of inhaled insulin was cough, affecting 27% of trial patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV1]) was seen in the first 3 months of use, which persisted over 2 years of follow-up. Inhaled insulin is


Pharmacology_Katzung

Pharmacology_Katzung. patients. A small decrease in pulmonary function (forced expiratory volume in 1 second [FEV1]) was seen in the first 3 months of use, which persisted over 2 years of follow-up. Inhaled insulin is contraindicated in smokers and patients with chronic lung disease, such as asthma and chronic obstructive pulmonary disease. Spirometry should be performed to identify potential lung disease prior to initiating therapy. During the clinical trials, there were two cases of lung cancer in patients who were taking inhaled insulin and none in the comparator-treated patients.


Pharmacology_Katzung

Pharmacology_Katzung. Immunopathology of Insulin Therapy At least five molecular classes of insulin antibodies may be produced in diabetics during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. There are two major types of immune disorders in these patients: 1. Insulin allergy—Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to non-insulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Immune insulin resistance—A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus. Injection of animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection. Since the development of human and analog insulin preparations of neutral pH, this type of immune complication is almost never seen. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours. Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoiding the specific injection site.


Pharmacology_Katzung

Pharmacology_Katzung. Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoiding the specific injection site. Several categories of glucose-lowering agents are available for patients with type 2 diabetes: (1) agents that bind to the sulfonylurea receptor and stimulate insulin secretion (sulfonylureas, meglitinides, d-phenylalanine derivatives); (2) agents that lower glucose levels by their actions on liver, muscle, and adipose tissue (biguanides, thiazolidinediones); (3) agents that principally slow the intestinal absorption of glucose (α-glucosidase inhibitors); agents that mimic incretin effect or prolong incretin action (GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors), (5) agents that inhibit the reabsorption of glucose in the kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and agents that act by other or ill-defined mechanisms (pramlintide, bromocriptine, colesevelam).


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action The major action of sulfonylureas is to increase insulin release from the pancreas (Table 41–7). They bind to a 140-kDa high-affinity sulfonylurea receptor that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel (Figure 41–2). Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. TABLE 41–7 Regulation of insulin release in humans. Stimulants of insulin release Humoral: Glucose, mannose, leucine, arginine, other amino acids, fatty acids (high concentrations) Hormonal: Glucagon, glucagon-like peptide 1 (7–37), glucose-dependent insulinotropic polypeptide, cholecystokinin, gastrin Neural: β-Adrenergic stimulation, vagal stimulation Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol, acetylcholine Inhibitors of insulin release


Pharmacology_Katzung

Pharmacology_Katzung. Neural: β-Adrenergic stimulation, vagal stimulation Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol, acetylcholine Inhibitors of insulin release Hormonal: Somatostatin, insulin, leptin Neural: α-Sympathomimetic effect of catecholamines Drugs: Diazoxide, phenytoin, vinblastine, colchicine Adapted, with permission, from Greenspan FS, Gardner DG [editors]: Basic & Clinical Endocrinology, 6th ed. McGraw-Hill, 2001. Copyright © The McGraw-Hill Companies, Inc. Efficacy & Safety of the Sulfonylureas


Pharmacology_Katzung

Pharmacology_Katzung. Efficacy & Safety of the Sulfonylureas Sulfonylureas are metabolized by the liver and, with the exception of acetohexamide, the metabolites are either weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of cases. The second-generation sulfonylureas have greater affinity for their receptor compared with the first-generation agents. The correspondingly lower effective doses and plasma levels of the second-generation drugs therefore lower the risk of drug-drug interactions based on competition for plasma binding sites or hepatic enzyme action.


Pharmacology_Katzung

Pharmacology_Katzung. In 1970, the University Group Diabetes Program (UGDP) in the United States reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide was excessive compared with either insulin-treated patients or those receiving placebos. Owing to design flaws, this study and its conclusions were not generally accepted. In the United Kingdom, the UKPDS did not find an untoward cardiovascular effect of sulfonylurea usage in their large, long-term study. The sulfonylureas continue to be widely prescribed, and six are available in the United States.


Pharmacology_Katzung

Pharmacology_Katzung. Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short (6–10 hours), with an elimination half-life of 4–5 hours, and it is best administered in divided doses (eg, 500 mg before each meal). Some patients only need one or two tablets daily. The maximum dosage is 3000 mg daily. Because of its short half-life and inactivation by the liver, it is relatively safe in the elderly and in patients with renal impairment. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These drugs inhibit the metabolism of tolbutamide in the liver and increase its circulating levels.


Pharmacology_Katzung

Pharmacology_Katzung. Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; approximately 20–30% is excreted unchanged in the urine. The average maintenance dosage is 250 mg daily, given as a single dose in the morning. Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group. Other adverse effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and hyponatremia due to its effect on vasopressin secretion and action. Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dosage should be divided and given twice daily.


Pharmacology_Katzung

Pharmacology_Katzung. Acetohexamide is no longer available in the United States. Its half-life is only about 1 hour but its more active metabolite, hydroxyhexamide, has a half-life of 4–6 hours; thus the drug duration of action is 8–24 hours. Where available, its dosage is 0.25–1.5 g/d as single dose or in two divided doses. Chlorpropamide, tolazamide, and acetohexamide are now rarely used in clinical practice. Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. They should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.


Pharmacology_Katzung

Pharmacology_Katzung. Glyburide is metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended. A formulation of “micronized” glyburide (Glynase PresTab) is available in a variety of tablet sizes. However, there is some question as to its bioequivalence with non-micronized formulations, and the FDA recommends careful monitoring to re-titrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs. Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion, and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Glipizide has the shortest half-life (2–4 hours) of the more potent agents. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast because absorption is delayed when the drug is taken with food. The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. When higher daily dosages are required, they should be divided and given before meals.


Pharmacology_Katzung

Pharmacology_Katzung. The maximum total daily dosage recommended by the manufacturer is 40 mg/d, although some studies indicate that the maximum therapeutic effect is achieved by 15–20 mg of the drug. An extended-release preparation (Glucotrol XL) provides 24-hour action after a once-daily morning dose (maximum of 20 mg/d). However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over the latter (which can be obtained as a generic drug). At least 90% of glipizide is metabolized in the liver to inactive products, and the remainder is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with significant hepatic impairment. Because of its lower potency and shorter duration for action, it is preferable to glyburide in the elderly and for those patients with renal impairment.


Pharmacology_Katzung

Pharmacology_Katzung. Glimepiride is approved for once-daily use as monotherapy or in combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dosage of any sulfonylurea compound. A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dosage is 8 mg. Glimepiride’s half-life under multidose conditions is 5–9 hours. It is completely metabolized by the liver to metabolites with weak or no activity. Gliclazide (not available in the United States) has a half-life of 10 hours. The recommended starting dosage is 40–80 mg daily with a maximum dosage of 320 mg daily. Higher dosages are usually divided and given twice a day. It is completely metabolized by the liver to inactive metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. Repaglinide is the first member of the meglitinide group of insulin secretagogues. These drugs modulate beta-cell insulin release by regulating potassium efflux through the potassium channels previously discussed. There is overlap with the sulfonylureas in their molecular sites of action because the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site.


Pharmacology_Katzung

Pharmacology_Katzung. Repaglinide has a fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion, but the duration of action is 4–7 hours. It is cleared by hepatic CYP3A4 with a plasma half-life of 1 hour. Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions. The drug should be taken just before each meal in doses of 0.25–4 mg (maximum 16 mg/d); hypoglycemia is a risk if the meal is delayed or skipped or contains inadequate carbohydrate. It can be used in patients with renal impairment and in the elderly. Repaglinide is approved as monotherapy or in combination with biguanides. There is no sulfur in its structure, so repaglinide may be used in type 2 diabetics with sulfur or sulfonylurea allergy.


Pharmacology_Katzung

Pharmacology_Katzung. Mitiglinide (not available in the United States) is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It has been approved for use in Japan.


Pharmacology_Katzung

Pharmacology_Katzung. Nateglinide, a d-phenylalanine derivative, stimulates rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K+ channel. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. The overall duration of action is about 4 hours. It is taken before the meal and reduces the postprandial rise in blood glucose levels. It is available as 60and 120-mg tablets. The lower dose is used in patients with mild elevations in HbA1c. Nateglinide is efficacious when given alone or in combination with non-secretagogue oral agents (such as metformin). Hypoglycemia is the main adverse effect. It can be used in patients with renal impairment and in the elderly. DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE


Pharmacology_Katzung

Pharmacology_Katzung. DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the United States because of its association with lactic acidosis. Metformin is the only biguanide currently available in the United States. Mechanisms of Action A full explanation of the mechanism of action of the biguanides remains elusive, but their primary effect is to activate the enzyme AMP-activated protein kinase (AMPK) and reduce hepatic glucose production. Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after administration of biguanides; however, hypoglycemia during biguanide therapy is rare. These agents are therefore more appropriately termed “euglycemic” agents.


Pharmacology_Katzung

Pharmacology_Katzung. Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin’s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, the biguanide accumulates and thereby increases the risk of lactic acidosis, which appears to be a dose-related complication. Metformin can be safely used in patients with estimated glomerular filtration rates (eGFR) between 60 and 45 mL/min per 1.73 m2. It can be used cautiously in patients with eGFR between 45 and 30 mL/min per 1.73 m2. It is contraindicated if the eGFR is less than 30 mL/min per 1.73 m2.


Pharmacology_Katzung

Pharmacology_Katzung. Biguanides are recommended as first-line therapy for type 2 diabetes. Because metformin is an insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such persons. The UKPDS reported that metformin therapy decreases the risk of macrovascular as well as microvascular disease; this is in contrast to the other therapies, which only modified microvascular morbidity. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. Metformin is useful in the prevention of type 2 diabetes; the landmark Diabetes Prevention Program concluded that metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner


Pharmacology_Katzung

Pharmacology_Katzung. the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner prediabetics.


Pharmacology_Katzung

Pharmacology_Katzung. Although the recommended maximal dosage is 2.55 g daily, little benefit is seen above a total dosage of 2000 mg daily. Treatment is initiated at 500 mg with a meal and increased gradually in divided doses. Common schedules would be 500 mg once or twice daily increased to 1000 mg twice daily. The maximal dosage is 850 mg three times a day. Epidemiologic studies suggest that metformin use may reduce the risk of some cancers. These data are still preliminary, and the speculative mechanism of action is a decrease in insulin (which also functions as a growth factor) levels as well as direct cellular effects mediated by AMPK. Other studies suggest a reduction in cardiovascular deaths in humans and an increase in longevity in mice (see Chapter 60).


Pharmacology_Katzung

Pharmacology_Katzung. The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), occurring in up to 20% of patients. They are dose related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3–5% of patients because of persistent diarrhea. Metformin interferes with the calcium-dependent absorption of vitamin B12–intrinsic factor complex in the terminal ileum, and vitamin B12 deficiency can occur after many years of metformin use. Periodic screening for vitamin B12 deficiency should be considered, especially in patients with peripheral neuropathy or macrocytic anemia. Increased intake of calcium may prevent the metformin-induced B12 malabsorption.


Pharmacology_Katzung

Pharmacology_Katzung. Lactic acidosis can sometimes occur with metformin therapy. It is more likely to occur in conditions of tissue hypoxia when there is increased production of lactic acid and in renal failure when there is decreased clearance of metformin. Almost all reported cases have involved patients with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency; alcoholism). Acute kidney failure can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that renal function has not deteriorated. Renal function should be checked at least annually in patients on metformin therapy, and lower doses should be used in the elderly who may have limited renal reserve and in those with eGFR between 30 and 45 mL/min per 1.73 m2.


Pharmacology_Katzung

Pharmacology_Katzung. Thiazolidinediones act to decrease insulin resistance. They are ligands of peroxisome proliferator-activated receptor gamma (PPAR-f), part of the steroid and thyroid superfamily of nuclear receptors. These PPAR receptors are found in muscle, fat, and liver. PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. Observed effects of the thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, increased adiponectin and decreased release of resistin from adipocytes, and increased differentiation of preadipocytes to adipocytes. Thiazolidinediones have also been shown to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Two thiazolidinediones are currently available: pioglitazone and rosiglitazone.


Pharmacology_Katzung

Pharmacology_Katzung. levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Two thiazolidinediones are currently available: pioglitazone and rosiglitazone. Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. An earlier compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain.


Pharmacology_Katzung

Pharmacology_Katzung. Pioglitazone has some PPAR-α as well as PPAR-γ activity. It is absorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected. Absorption is decreased with concomitant use of bile acid sequestrants. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites. The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estrogen-containing oral contraceptives; additional methods of contraception are advised. Pioglitazone may be taken once daily; the usual starting dosage is 15–30 mg/d, and the maximum is 45 mg/d. Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.


Pharmacology_Katzung

Pharmacology_Katzung. Rosiglitazone is rapidly absorbed and highly protein bound. It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 2–8 mg is the usual total dosage. Rosiglitazone is approved for use in type 2 diabetes as monotherapy, in double combination therapy with a biguanide or sulfonylurea, or in quadruple combination with a biguanide, sulfonylurea, and insulin. The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. These drugs also have some additional effects apart from glucose lowering. Pioglitazone lowers triglycerides and increases high-density lipoprotein (HDL) cholesterol without affecting total cholesterol and low-density lipoprotein (LDL) cholesterol.


Pharmacology_Katzung

Pharmacology_Katzung. Rosiglitazone increases total cholesterol, HDL cholesterol, and LDL cholesterol but does not have significant effect on triglycerides. These drugs have been shown to improve the biochemical and histologic features of nonalcoholic fatty liver disease. They seem to have a positive effect on endothelial function: pioglitazone reduces neointimal proliferation after coronary stent placement, and rosiglitazone has been shown to reduce microalbuminuria.


Pharmacology_Katzung

Pharmacology_Katzung. Safety concerns and troublesome side effects have significantly reduced the use of this class of drugs. A meta-analysis of 42 randomized clinical trials with rosiglitazone suggested that this drug increased the risk of angina pectoris or myocardial infarction. As a result, its use was suspended in Europe and severely restricted in the United States. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the meta-analysis finding and so the United States restrictions have been lifted. The drug remains unavailable in Europe.


Pharmacology_Katzung

Pharmacology_Katzung. Fluid retention occurs in about 3–4 % patients on thiazolidinedione monotherapy and occurs more frequently (10–15%) in patients on concomitant insulin therapy. Heart failure can occur, and the drugs are contraindicated in patients with New York Heart Association class III and IV cardiac status (see Chapter 13). Macular edema is a rare adverse effect that improves when the drug is discontinued. Loss of bone mineral density and increased atypical extremity bone fractures in women are described for both compounds; this is postulated to be due to decreased osteoblast formation. Other adverse effects include anemia, which might be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when used in combination with a sulfonylurea or insulin. Some of the weight gain is fluid retention but there is also an increase in total fat mass. In preclinical trials, bladder tumors were observed in male rats on pioglitazone. Initial


Pharmacology_Katzung

Pharmacology_Katzung. or insulin. Some of the weight gain is fluid retention but there is also an increase in total fat mass. In preclinical trials, bladder tumors were observed in male rats on pioglitazone. Initial clinical reports indicated that this might also be true in humans. A 10-year observational cohort study of patients taking pioglitazone, however, failed to find an association with bladder cancer. A large multi-population pooled analysis (1.01 million persons over 5.9 million person-years) also failed to find an association between cumulative exposure of pioglitazone or rosiglitazone and incidence of bladder cancer. Another population based study generating 689,616 person-years of follow-up did find that pioglitazone but not rosiglitazone was associated with an increased risk of bladder cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Troglitazone, the first medication in this class, was withdrawn because of cases of fatal liver failure. Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the drugs are not recommended for use in patients with active liver disease or pretreatment elevation of alanine aminotransferase (ALT) 2.5 times greater than normal. Liver function tests should be performed prior to initiation of treatment and periodically thereafter. The `-glucosidase inhibitors competitively inhibit the intestinal α-glucosidase enzymes and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides. Acarbose and miglitol are available in the United States. Voglibose is available in Japan, Korea, and India. Acarbose and miglitol are potent inhibitors of glucoamylase, α-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase.


Pharmacology_Katzung

Pharmacology_Katzung. Acarbose has the molecular mass and structural features of a tet rasaccharide and very little is absorbed. In contrast, miglitol has structural similarity to glucose and is absorbed. Acarbose treatment is initiated at a dosage of 50 mg twice daily with gradual increase to 100 mg three times a day. It lowers post prandial glucose levels by 30–50%. Miglitol therapy is initiated at a dosage of 25 mg three times a day. The usual maintenance dosage is 50 mg three times a day, but some patients may need 100 mg three times a day. The drug is not metabolized and is cleared by the kidney. It should not be used in renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Prominent adverse effects of α-glucosidase inhibitors include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas. These adverse effects tend to diminish with ongoing use because chronic expo sure to carbohydrate induces the expression of α-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon. Although not a problem with monotherapy or combina tion therapy with a biguanide, hypoglycemia may occur with con current sulfonylurea treatment. Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked. An increase in hepatic aminotransferases has been noted in clinical trials with acarbose, especially with dosages greater than 300 mg/d. The abnormalities resolve on stopping the drug.


Pharmacology_Katzung

Pharmacology_Katzung. These drugs are infrequently prescribed in the United States because of their prominent gastrointestinal adverse effects and relatively modest glucose-lowering benefit.


Pharmacology_Katzung

Pharmacology_Katzung. An oral glucose load provokes a higher insulin response compared with an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones (“incretins”), principally GLP-1 and glucose-dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion. When GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin release and lowers glucose levels. The GLP-1 effect is glucose dependent in that the insulin release is more pronounced when glucose levels are elevated but less so when glucose levels are normal. For this reason, GLP-1 has a lower risk for hypoglycemia than the sulfonylureas. In addition to its insulin stimulatory effect, GLP-1 has a number of other biologic effects. It suppresses glucagon secretion, delays gastric emptying, and reduces apoptosis of human islets in culture. In animals, GLP-1 inhibits feeding by a central nervous system mechanism. Type 2 diabetes patients on GLP-1 therapy


Pharmacology_Katzung

Pharmacology_Katzung. delays gastric emptying, and reduces apoptosis of human islets in culture. In animals, GLP-1 inhibits feeding by a central nervous system mechanism. Type 2 diabetes patients on GLP-1 therapy are less hungry. It is unclear whether this is mainly related to the deceleration of gastric emptying or whether there is a central nervous system effect as well.


Pharmacology_Katzung

Pharmacology_Katzung. GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and by other enzymes such as endopeptidase 24.11 and is also cleared by the kidney. The native peptide therefore cannot be used therapeutically. One approach to this problem has been to develop metabolically stable analogs or derivatives of GLP-1 that are not subject to the same enzymatic degradation or renal clearance. Four such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide, and dulaglutide are available for clinical use. The other approach has been to develop inhibitors of DPP-4 and prolong the action of endogenously released GLP-1 and GIP. Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States. An additional inhibitor, vildagliptin, is available in Europe.


Pharmacology_Katzung

Pharmacology_Katzung. Exenatide, a derivative of the exendin-4 peptide in Gila monster venom, has a 53% homology with native GLP-1 and a glycine substitution to reduce degradation by DPP-4. Exenatide is approved as an injectable, adjunctive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control.


Pharmacology_Katzung

Pharmacology_Katzung. Exenatide is dispensed as fixed-dose pens (5 mcg and 10 mcg). It is injected subcutaneously within 60 minutes before breakfast and dinner. It reaches a peak concentration in approximately 2 hours with a duration of action of up to 10 hours. Therapy is initiated at 5 mcg twice daily for the first month and if tolerated can be increased to 10 mcg twice daily. Exenatide LAR is a once-weekly preparation that is dispensed as a powder (2 mg). It is suspended in the provided diluent just prior to injection. When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. The major adverse effect is nausea (about 44% of users), which is dose dependent and declines with time. Exenatide mono-therapy and combination therapy results in HbA1c reductions of 0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contributes to the improvement of glucose control. In comparative trials the long-acting (LAR) preparation lowers


Pharmacology_Katzung

Pharmacology_Katzung. in HbA1c reductions of 0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contributes to the improvement of glucose control. In comparative trials the long-acting (LAR) preparation lowers the HbA1c level a little more than the twice-daily preparation. Exenatide undergoes glomerular filtration, and the drug is not approved for use in patients with estimated GFR of less than 30 mL/min.


Pharmacology_Katzung

Pharmacology_Katzung. High-titer antibodies against exenatide develop in about 6% of patients, and in half of these patients an attenuation of glycemic response has been seen. Liraglutide is a soluble fatty acid-acylated GLP-1 analog. The half-life is approximately 12 hours, permitting once-daily dosing. It is approved in patients with type 2 diabetes who achieve inadequate control with diet and exercise and are receiving concurrent treatment with metformin, sulfonylureas, or thiazolidinediones. Treatment is initiated at 0.6 mg and increased after 1 week to 1.2 mg daily. If needed the dosage can be increased to 1.8 mg daily. In clinical trials liraglutide results in a reduction of HbA1c of 0.8–1.5%; weight loss ranges from none to 3.2 kg. The most frequent adverse effects are nausea (28%) and vomiting (10%). Liraglutide at a dose of 3 mg daily has been approved for weight loss.


Pharmacology_Katzung

Pharmacology_Katzung. Liraglutide at a dose of 3 mg daily has been approved for weight loss. Albiglutide is a human GLP-1 dimer fused to human albumin. The half-life of albiglutide is about 5 days and a steady state is reached after 4–5 weeks of once weekly administration. The usual dose is 30 mg weekly by subcutaneous injection. The drug is supplied in a self-injection pen containing a powder that is reconstituted just prior to administration. Weight loss is much less common than with exenatide and liraglutide. The most frequent adverse effects were nausea and injection-site erythema. Dulaglutide consists of two GLP-1 analog molecules covalently linked to an Fc fragment of human IgG4. The GLP-1 molecule has amino acid substitutions that resist DPP-4 action. The half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg weekly by subcutaneous injection. The maximum recommended dose is 1.5 mg weekly. The most frequent adverse reactions were nausea, diarrhea, and vomiting.


Pharmacology_Katzung

Pharmacology_Katzung. All of the GLP-1 receptor agonists may increase the risk of pancreatitis. Patients on these drugs should be counseled to seek immediate medical care if they experience unexplained persistent severe abdominal pain. Cases of renal impairment and acute renal injury have been reported in patients taking exenatide. Some of these patients had preexisting kidney disease or other risk factors for renal injury. A number of them reported having nausea, vomiting, and diarrhea and it is possible that volume depletion contributed to the development of renal injury. Both exenatide and liraglutide stimulate thyroidal C-cell (parafollicular) tumors in rodents. Human thyroidal C cells express very few GLP-1 receptors, and the relevance to human therapy is unclear. The drugs, however, should not be used in persons with a past medical or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2.


Pharmacology_Katzung

Pharmacology_Katzung. Sitagliptin is given orally as 100 mg once daily, has an oral bioavailability of over 85%, achieves peak concentrations within 1–4 hours, and has a half-life of approximately 12 hours. It is primarily excreted in the urine, in part by active tubular secretion of the drug. Hepatic metabolism is limited and mediated largely by the cytochrome CYP3A4 isoform and, to a lesser degree, by CYP2C8. The metabolites have insignificant activity. Dosage should be reduced in patients with impaired renal function (50 mg if estimated GFR is 30–50 mL/min and 25 mg if <30 mL/min. Sitagliptin has been studied as monotherapy and in combination with metformin, sulfonylureas, and thiazolidinediones. Therapy with sitagliptin has resulted in HbA1c reductions of 0.5–1.0%.


Pharmacology_Katzung

Pharmacology_Katzung. Common adverse effects include nasopharyngitis, upper respiratory infections, and headaches. Hypoglycemia can occur when the drug is combined with insulin secretagogues or insulin. There have been postmarketing reports of acute pancreatitis (fatal and nonfatal) and severe allergic and hypersensitivity reactions. Sitagliptin should be immediately discontinued if pancreatitis or allergic and hypersensitivity reactions occur.


Pharmacology_Katzung

Pharmacology_Katzung. Saxagliptin is given orally as 2.5–5 mg daily. The drug reaches maximal concentrations within 2 hours (4 hours for its active metabolite). It is minimally protein bound and undergoes hepatic metabolism by CYP3A4/5. The major metabolite is active, and excretion is by both renal and hepatic pathways. The terminal plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for its active metabolite. Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial agents. It is approved as monotherapy and in combination with biguanides, sulfonylureas, and thiazolidinediones. During clinical trials, monoand combination therapy with saxagliptin resulted in an HbA1c reduction of 0.4–0.9%.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include an increased rate of infections (upper respiratory tract and urinary tract), headaches, and hypersensitivity reactions (urticaria, facial edema). The dosage of a concurrently administered insulin secretagogue or insulin may need to be lowered to prevent hypoglycemia. Saxagliptin may increase the risk of heart failure. In a postmarketing study of 16,492 type 2 diabetes patients, there were 289 cases of heart failure in the saxagliptin group (3.5%) and 228 cases in the placebo group (2.8%)—a hazard ratio of 1.27. Patients at the highest risk for failure were those who had a history of heart failure or had elevated levels of N-terminal of the prohormone brain natriuretic peptide (NTpBNP) or had renal impairment. Linagliptin lowers HbA1c by 0.4–0.6% when added to metformin, sulfonylurea, or pioglitazone. The dosage is 5 mg daily orally and, since it is primarily excreted via the bile, no dosage adjustment is needed in renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse reactions include nasopharyngitis and hypersensitivity reactions (urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity). The risk of pancreatitis may be increased. Alogliptin lowers HbA1c by about 0.5–0.6% when added to metformin, sulfonylurea, or pioglitazone. The usual dose is 25 mg orally daily. The 12.5-mg dose is used in patients with calculated creatinine clearance of 30 to 60 mL/min; the dose is 6.25 mg for clearance <30 mL/min. In clinical trials, pancreatitis occurred in 11 of 5902 patients on alogliptin (0.2%) and in 5 of 5183 patients receiving all comparators (<0.1%). There have been reports of hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome). Cases of hepatic failure have been reported, but it is unclear if alogliptin was the cause. The medication, however, should be discontinued in the event of liver failure.


Pharmacology_Katzung

Pharmacology_Katzung. Vildagliptin (not available in the United States) lowers HbA1c levels by 0.5–1% when added to the therapeutic regimen of patients with type 2 diabetes. The dosage is 50 mg orally once or twice daily. Adverse reactions include upper respiratory infections, nasopharyngitis, dizziness, and headache. Rarely, it can cause hepatitis, and liver function tests should be performed quarterly in the first year of use and periodically thereafter. In animal studies, high doses of DPP-4 inhibitors and GLP-1 agonists cause expansion of pancreatic ductal glands and generation of premalignant pancreatic intraepithelial (PanIN) lesions that have the potential to progress to pancreatic adenocarcinoma. The relevance to human therapy is unclear and currently there is no evidence that these drugs cause pancreatic cancer in humans.


Pharmacology_Katzung

Pharmacology_Katzung. Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by the action of sodium-glucose transporters (SGLTs). Sodium-glucose transporter 2 (SGLT2) accounts for 90% of glucose reabsorption, and its inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes. SGLT2 inhibitors lower glucose levels by changing the renal threshold and not by insulin action. The SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, all oral medications, are approved for clinical use. Canagliflozin reduces the threshold for glycosuria from a plasma glucose threshold of approximately 180 mg/dL to 70–90 mg/dL. It has been shown to reduce HbA1c by 0.6–1% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–5 kg. The usual dosage is 100 mg daily. Increasing the dosage to 300 mg daily in patients with normal renal function can lower the HbA1c by an additional 0.5%.


Pharmacology_Katzung

Pharmacology_Katzung. Dapagliflozin reduces HbA1c by 0.5–0.8% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of about 2–4 kg. The usual dosage is 10 mg daily, but 5 mg daily is recommended initially in patients with hepatic failure.


Pharmacology_Katzung

Pharmacology_Katzung. Empagliflozin reduces HbA1c by 0.5–0.7% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–3 kg. The usual dosage is 10 mg daily, but 25 mg/d may be used. In a postmarketing multinational study of 7020 type 2 patients with known cardiovascular disease, the addition of empagliflozin was associated with a lower primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio, 0.86; p = 0.04). The mechanisms regarding this benefit remain unclear. Weight loss, lower blood pressure, and diuresis may have played a role since there were fewer deaths from heart failure in the treated group whereas the rates of myocardial infarction were unaltered.


Pharmacology_Katzung

Pharmacology_Katzung. As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. Canagliflozin and empagliflozin are contraindicated in patients with estimated GFR less than 45 mL/min per 1.73 m2. Dapagliflozin is not recommended for use in patients with estimated GFR less than 60 mL/min per 1.73 m2. The main adverse effects are increased incidence of genital infections and urinary tract infections affecting about 8–9% of patients. The osmotic diuresis can also cause intravascular volume contraction and hypotension. Canagliflozin and empagliflozin caused a modest increase in LDL cholesterol levels (4–8%). In clinical trials patients taking dapagliflozin had higher rates of breast cancer (nine cases versus none in comparator arms) and bladder cancer (nine cases versus one in placebo arm). These cancer rates exceeded the expected rates in an age-matched reference diabetes population. Canagliflozin has been reported to cause a decrease in bone mineral density at the


Pharmacology_Katzung

Pharmacology_Katzung. one in placebo arm). These cancer rates exceeded the expected rates in an age-matched reference diabetes population. Canagliflozin has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip. In a pooled analysis of 8 clinical trial (mean duration 68 weeks), an increase in fractures by about 30% was observed in patients on canagliflozin. It is likely that the effect on the bones is a class effect and not restricted to canagliflozin. A modest increase in upper limb fractures was observed with canagliflozin therapy. It is not known if this is due to an effect on bone strength or related to falls due to hypotension. Interim analysis of the Canagliflozin Cardiovascular Assessment Study clinical trial reported an approximately doubled risk of leg and foot amputations in the trial group assigned to Canagliflozin; in 2017 the FDA issued a drug safety communication regarding the association. Cases of diabetic ketoacidosis have been reported with off-label use


Pharmacology_Katzung

Pharmacology_Katzung. in the trial group assigned to Canagliflozin; in 2017 the FDA issued a drug safety communication regarding the association. Cases of diabetic ketoacidosis have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1 patients are taught to give less insulin if their glucose levels are not elevated. Because type 1 patients on an SGLT2 inhibitor may have normal glucose levels, they may either withhold or reduce their insulin doses to such a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labelled as having type 2 diabetes but who are very insulin deficient and prone to ketosis.


Pharmacology_Katzung

Pharmacology_Katzung. Pramlintide is an islet amyloid polypeptide (IAPP, amylin) analog. IAPP is a 37-amino-acid peptide present in insulin secretory granules and secreted with insulin. It has approximately 46% homology with the calcitonin gene-related peptide (CGRP; see Chapter 17) and physiologically acts as a negative feedback on insulin secretion. At pharmacologic doses, IAPP reduces glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally decreases appetite. Pramlintide is an IAPP analog with substitutions of proline at positions 25, 28, and 29. These modifications make pramlintide soluble, non-selfaggregating, and suitable for pharmacologic use. Pramlintide is approved for use in insulin-treated type 1 and type 2 patients who are unable to achieve their target postprandial blood glucose levels. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. It is metabolized and excreted


Pharmacology_Katzung

Pharmacology_Katzung. blood glucose levels. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. It is metabolized and excreted by the kidney, but even at low creatinine clearance there is no significant change in bioavailability. It has not been evaluated in dialysis patients.


Pharmacology_Katzung

Pharmacology_Katzung. Pramlintide is injected immediately before eating; dosages range from 15 to 60 mcg subcutaneously for type 1 patients and from 60 to 120 mcg for type 2 patients. Therapy with this agent should be initiated at the lowest dosage and titrated upward. Because of the risk of hypoglycemia, concurrent rapid-or short-acting mealtime insulin dosages should be decreased by 50% or more. Pramlintide should always be injected by itself using a separate syringe; it cannot be mixed with insulin. The major adverse effects of pramlintide are hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia. Since the drug slows gastric emptying, recovery from hypoglycemia can be problematic because of the delay in absorption of fast-acting carbohydrates.


Pharmacology_Katzung

Pharmacology_Katzung. Selected patients with type 1 diabetes who have problems with postprandial hyperglycemia can use pramlintide effectively to control the glucose rise especially in the setting of a high-carbohydrate meal. The drug is not very useful in type 2 patients who can instead use the GLP-1 receptor agonists.


Pharmacology_Katzung

Pharmacology_Katzung. Colesevelam hydrochloride, the bile acid sequestrant and cholesterol-lowering drug, is approved as an antihyperglycemic therapy for persons with type 2 diabetes who are taking other medications or have not achieved adequate control with diet and exercise. The exact mechanism of action is unknown but presumed to involve an interruption of the enterohepatic circulation and a decrease in farnesoid X receptor (FXR) activation. FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism. Bile acids are natural ligands of the FXR. Additionally, the drug may impair glucose absorption. In clinical trials, it lowered the HbA1c concentration 0.3–0.5%. Adverse effects include gastrointestinal complaints (constipation, indigestion, flatulence). It can also exacerbate the hypertriglyceridemia that commonly occurs in people with type 2 diabetes.


Pharmacology_Katzung

Pharmacology_Katzung. Bromocriptine, the dopamine agonist, in randomized placebo-controlled studies lowered HbA1c by 0–0.2% compared with baseline and by 0.4–0.5% compared with placebo. The mechanism by which it lowers glucose levels is not known. The main adverse events are nausea, fatigue, dizziness, vomiting, and headache. Colesevelam and bromocriptine have very modest efficacy in lowering glucose levels, and their use for this purpose is questionable.


Pharmacology_Katzung

Pharmacology_Katzung. A well-balanced, nutritious diet remains a fundamental element of therapy for diabetes. It is recommended that the macronutrient proportions (carbohydrate, protein, and fat) be individualized based on the patient’s eating patterns, preferences, and goals. Generally most patients with diabetes consume about 45% of their calories as carbohydrates; 25–35% fats; and 10–35% proteins. Limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. A Mediterranean-style eating pattern (a diet supplemented with walnuts, almonds, hazelnuts, and olive oil) has been shown to improve glycemic control and lower combined endpoints for cardiovascular events and stroke. Caloric restriction and weight loss is an important goal for the obese patient with type 2 diabetes.


Pharmacology_Katzung

Pharmacology_Katzung. Education of the patient and family is a critical component of care. The patient should be informed about the kind of diabetes he or she has and the rationale for controlling the glucose levels (see Box: Benefits of Tight Glycemic Control in Diabetes). Self-monitoring of glucose levels should be emphasized, especially if the patient is on insulin or oral secretagogues that can cause hypoglycemia. The patient on insulin therapy should understand the action profile of the insulins. He or she should know how to determine if the basal insulin dose is correct and how to adjust the rapidly acting insulin dose for carbohydrate content of meals. Insulin adjustments for exercise and infections should be discussed. The patient and family members also should be informed about the signs and symptoms of hypoglycemia.


Pharmacology_Katzung

Pharmacology_Katzung. The American Diabetes Association criteria for acceptable control include an HbA1c of less than 7% (53 mmol/mol) and pre-meal glucose levels of 90–130 mg/dL (5–7.2 mmol/L) and less than 180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3 mmol/L) two hours after meals. While the HbA1c target is appropriate for individuals treated with lifestyle interventions and euglycemic therapy, it may need to be modified for individuals treated with insulin or insulin secretagogues due to their increased risk of hypoglycemia. Less stringent blood glucose control also is appropriate for children as well as patients with a history of severe hypoglycemia, limited life expectancy, and significant microvascular and macrovascular disease. For the elderly frail patient an HbA1c greater than 8% may be appropriate. Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. A. Type 1 Diabetes


Pharmacology_Katzung

Pharmacology_Katzung. Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. A. Type 1 Diabetes For most type 1 patients, at least 3 or 4 insulin injections a day are necessary for safe and effective control of glucose levels. A combination of rapidly acting insulin analogs and long-acting insulin analogs allow for more physiologic insulin replacement. Generally, for an adult with type 1 diabetes, the total daily insulin requirement in units is equal to the weight in pounds divided by four, or 0.55 times the person’s weight in kilograms. Approximately 40% of the total daily insulin dosage covers the background or basal insulin requirements, and the remainder covers meal and snack requirement and high blood sugar corrections. This is an approximate calculation and should be individualized. Examples of


Pharmacology_Katzung

Pharmacology_Katzung. A long-term randomized prospective study involving 1441 type 1 patients in 29 medical centers reported in 1993 that “near normalization” of blood glucose resulted in a delay in onset and a major slowing of progression of microvascular and neu-ropathic complications of diabetes during follow-up periods of up to 10 years (Diabetes Control and Complications Trial [DCCT] Research Group, 1993). In the intensively treated group, mean glycated hemoglobin (HbA1c) of 7.2% (normal <6%) and mean blood glucose of 155 mg/dL were achieved, whereas in the conventionally treated group, HbA1c averaged 8.9% with mean blood glucose of 225 mg/dL. Over the study period, which aver-aged 7 years, a reduction of approximately 60% in risk of diabetic retinopathy, nephropathy, and neuropathy was noted in the tight control group compared with the standard control group. The DCCT study, in addition, introduced the concept of glycemic memory, which comprises the long-term benefits of any significant period of


Pharmacology_Katzung

Pharmacology_Katzung. control group compared with the standard control group. The DCCT study, in addition, introduced the concept of glycemic memory, which comprises the long-term benefits of any significant period of glycemic control. During a 6-year follow-up period, both the intensively and conventionally treated groups had similar levels of glycemic control, and both had progression of carotid intimal-medial thickness. However, the intensively treated cohort had significantly less progression of intimal thickness. The United Kingdom Prospective Diabetes Study (UKPDS) was a very large randomized prospective study carried out to study the effects of intensive glycemic control with several types of therapies and the effects of blood pressure control in type 2 diabetic patients. A total of 3867 newly diagnosed type 2 diabetic patients were studied over 10 years. A significant frac-tion of these were overweight and hypertensive. Patients were given dietary treatment alone or intensive therapy with insulin,


Pharmacology_Katzung

Pharmacology_Katzung. type 2 diabetic patients were studied over 10 years. A significant frac-tion of these were overweight and hypertensive. Patients were given dietary treatment alone or intensive therapy with insulin, chlorpropamide, glyburide, or glipizide. Metformin was an option for patients with inadequate response to other therapies. Tight control of blood pressure was added as a variable, with an angio-tensin-converting enzyme inhibitor, a β blocker, or in some cases, a calcium channel blocker available for this purpose. Tight control of diabetes, with reduction of HbA1c from 9.1% to 7%, was shown to reduce the risk of microvascular complica-tions overall compared with that achieved with conventional therapy (mostly diet alone, which decreased HbA1c to 7.9%). Cardiovascular complications were not noted for any particular therapy; metformin treatment alone reduced the risk of macro-vascular disease (myocardial infarction, stroke). Epidemiologic analysis of the study suggested that every 1% decrease


Pharmacology_Katzung

Pharmacology_Katzung. for any particular therapy; metformin treatment alone reduced the risk of macro-vascular disease (myocardial infarction, stroke). Epidemiologic analysis of the study suggested that every 1% decrease in the HbA1c achieved an estimated risk reduction of 37% for micro-vascular complications, 21% for any diabetes-related end point and death related to diabetes, and 14% for myocardial infarction. Tight control of hypertension also had a surprisingly sig-nificant effect on microvascular disease (as well as more conven-tional hypertension-related sequelae) in these diabetic patients. Epidemiologic analysis of the results suggested that every 10-mmHg decrease in the systolic pressure achieved an esti-mated risk reduction of 13% for diabetic microvascular complica-tions, 12% for any diabetes-related complication, 15% for death related to diabetes, and 11% for myocardial infarction. Post-study monitoring showed that 5 years after the closure of the UKPDS, the benefits of intensive management on


Pharmacology_Katzung

Pharmacology_Katzung. complication, 15% for death related to diabetes, and 11% for myocardial infarction. Post-study monitoring showed that 5 years after the closure of the UKPDS, the benefits of intensive management on diabetic end points were maintained and the risk reduction for a myo-cardial infarction became significant. The benefits of metformin therapy were maintained. These studies show that tight glycemic control benefits both type 1 and type 2 patients.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 41–8 Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and NPH, or insulin detemir, glargine, or degludec in a 70-kg man with type 1 diabetes.1–3 1Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner. 2The dose of rapid-acting insulin analogs can be raised by 1 or 2 U if extra carbohydrate (15–30 g) is ingested or if premeal blood glucose is >170 mg/dL. The rapid-acting insulin analogs can be mixed in the same syringe with NPH insulin. 3Insulin glargine or insulin detemir must be given as a separate injection.


Pharmacology_Katzung

Pharmacology_Katzung. reduced insulin requirement include newly diagnosed persons and those with ongoing endogenous insulin production, long-standing diabetes with insulin sensitivity, significant renal insufficiency, or other endocrine deficiencies. Increased insulin requirements typically occur with obesity, during adolescence, and during the latter trimesters of pregnancy. Table 41–8 illustrates regimens of rapidly acting insulin analogs and basal analogs that might be appropriate for a 70-kg person with type 1 diabetes. If the patient is on an insulin pump, he or she may require about a basal infusion rate of 0.6 units per hour throughout the 24 hours with the exception of 4:00 am to 8:00 am, when 0.7 units per hour might be appropriate (dawn phenomenon). The ratios might be one unit for 12 grams carbohydrate plus one unit for 50 mg/dL (2.8 mmol/L) of blood glucose above a target value of 120 mg/dL (6.7 mmol/L). B. Type 2 Diabetes


Pharmacology_Katzung

Pharmacology_Katzung. B. Type 2 Diabetes Normalization of glucose levels can occur with weight loss and improved insulin sensitivity in the obese patient with type 2 diabetes. A combination of caloric restriction and increased exercise is necessary if a weight reduction program is to be successful. Understanding the long-term consequences of poorly controlled diabetes may motivate some patients to lose weight. For selected patients, medical or surgical options should be considered. Orlistat, phentermine/ topiramate, lorcaserin, naltrexone plus extended release bupropion, and high-dose liraglutide are approved weight loss medications for use in combination with diet and exercise. Bariatric surgery (Roux-en-Y, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically result in significant weight loss and can result in remission of the diabetes.


Pharmacology_Katzung

Pharmacology_Katzung. Nonobese patients with type 2 diabetes frequently have increased visceral adiposity—the so-called metabolically obese normal weight patient. There is less emphasis on weight loss in such patients, but exercise is important.


Pharmacology_Katzung

Pharmacology_Katzung. Multiple medications may be required to achieve glycemic control (Figure 41–6) in patients with type 2 diabetes. Unless there is a contraindication, medical therapy should be initiated with intensive lifestyle interventions (diet and exercise), diabetes self-management education, and metformin. If clinical failure occurs with metformin monotherapy, a second agent is added. Options include sulfonylureas, repaglinide or nateglinide, pioglitazone, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, and insulin. In the choice of the second agent, consideration should be given to efficacy of the agent, hypoglycemic risk, effect on weight, adverse effects, and cost. In patients who experience * Step taken if needed to reach individualized HbA1c target after ~ 3 months.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 41–6 Suggested algorithm for the treatment of type 2 diabetes. The seven main classes of agents are metformin, sulfonylureas (includes nateglinide, repaglinide), pioglitazone, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, insulins. (α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocriptine not included because of limited efficacy and significant adverse reactions). (Data from the consensus panel of the American Diabetes Association/ European Association for the Study of Diabetes, as described in Inzucchi SE et al: Diabetes Care 2012;35:1364.) hyperglycemia after a carbohydrate-rich meal (such as dinner), a short-acting secretagogue before that meal may suffice to control the glucose levels. Patients with severe insulin resistance may be candidates for pioglitazone. Patients who are very concerned about weight gain may benefit from a trial of a GLP-1 receptor agonist, a DPP-4 inhibitor, or an SGLT2 inhibitor, although the average weight loss with these


Pharmacology_Katzung

Pharmacology_Katzung. Patients who are very concerned about weight gain may benefit from a trial of a GLP-1 receptor agonist, a DPP-4 inhibitor, or an SGLT2 inhibitor, although the average weight loss with these medication is not great. If two agents are inadequate a third agent is added, although data regarding efficacy of such combined therapy are limited.


Pharmacology_Katzung

Pharmacology_Katzung. When the combination of oral agents and injectable GLP-1 receptor agonists fails to adequately control glucose levels, insulin therapy should be instituted. Various insulin regimens may be effective. Simply adding nighttime intermediateor long-acting insulin to the oral regimen may lead to improved fasting glucose levels and adequate control during the day. If daytime glucose levels are problematic, premixed insulins before breakfast and dinner may help. If such a regimen does not achieve adequate control or leads to unacceptable rates of hypoglycemia, a more intensive basal bolus insulin regimen (long-acting basal insulin) combined with rapid-acting analog before meals can be instituted. Metformin has been shown to be effective when combined with insulin therapy and should be continued. Pioglitazone can be used with insulin, but this combination is associated with more weight gain and peripheral and macular edema. Continuing with sulfonylureas, GLP-1 receptor agonists, DPP-4


Pharmacology_Katzung

Pharmacology_Katzung. Pioglitazone can be used with insulin, but this combination is associated with more weight gain and peripheral and macular edema. Continuing with sulfonylureas, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors can be of benefit in selected patients. Cost, complexity, and risk for adverse events should be considered when deciding which drugs to continue once the patient starts on insulin therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Acute Complications of Diabetes A. Hypoglycemia Hypoglycemic reactions are the most common complication of insulin therapy. It can also occur in any patient taking oral agents that stimulate insulin secretion (eg, sulfonylureas, meglitinide, d-phenylalanine analogs), particularly if the patient is elderly, has renal or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, warfarin). It occurs more frequently with the use of long-acting sulfonylureas. Rapid development of hypoglycemia in persons with intact hypoglycemic awareness causes signs of autonomic hyperactivity— both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)—and may progress to convulsions and coma if untreated.


Pharmacology_Katzung

Pharmacology_Katzung. In persons exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. This dangerous acquired condition is termed hypoglycemic unawareness. When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop— confusion, weakness, bizarre behavior, coma, seizures—at which point they may not be able to procure or safely swallow glucose-containing foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes. An identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every dia betic person who is receiving hypoglycemic drug therapy.


Pharmacology_Katzung

Pharmacology_Katzung. All the manifestations of hypoglycemia are relieved by glu cose administration. To expedite absorption, simple sugar or glucose should be given, preferably in liquid form. To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given. If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is 1 mg of glucagon injected either subcutaneously or intramuscularly. This may restore consciousness within 15 minutes to permit ingestion of sugar. Emergency medical services should be called in the event of loss of consciousness. The emergency personnel can restore consciousness by giving 20–50 mL of 50% glucose solution by intravenous bolus over a period of 2–3 minutes.


Pharmacology_Katzung

Pharmacology_Katzung. B. Diabetic Coma 1. Diabetic ketoacidosis—Diabetic ketoacidosis (DKA) is a life-threatening medical emergency caused by inadequate or absent insulin replacement, which occurs in people with type 1 diabetes and infrequently in those with type 2 diabetes. It typically occurs in newly diagnosed type 1 patients or in those who have experienced interrupted insulin replacement, and rarely in people with type 2 diabetes who have concurrent unusually stressful conditions such as sepsis or pancreatitis or are on high-dose steroid therapy. DKA occurs more frequently in patients on insulin pumps. Poor compliance—either for psychological reasons or because of inadequate education—is one of the most common causes of DKA, particularly when episodes are recurrent.


Pharmacology_Katzung

Pharmacology_Katzung. Signs and symptoms include nausea, vomiting, abdominal pain, deep slow (Kussmaul) breathing, change in mental status (including coma), elevated blood and urinary ketones and glucose, an arterial blood pH lower than 7.3, and low bicarbonate (15 mmol/L). The fundamental treatment for DKA includes aggressive intravenous hydration and insulin therapy and maintenance of potassium and other electrolyte levels. Fluid and insulin therapy is based on the patient’s individual needs and requires frequent reevaluation and modification. Close attention must be given to hydration and renal status, sodium and potassium levels, and the rate of correction of plasma glucose and plasma osmolality. Fluid therapy generally begins with normal saline. Regular human insulin should be used for intravenous therapy with a usual starting dosage of about 0.1 U/kg/h.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Hyperosmolar hyperglycemic syndrome—Hyperosmolar hyperglycemic syndrome (HHS) is diagnosed in persons with type 2 diabetes and is characterized by profound hyperglycemia and dehydration. It is associated with inadequate oral hydration, especially in elderly patients; with other illnesses; with the use of medication that elevates the blood sugar or causes dehydration, such as phenytoin, steroids, diuretics, and calcium channel blockers; and with peritoneal dialysis and hemodialysis. The diagnostic hallmarks are declining mental status and even seizures, a plasma glucose >600 mg/dL, and a calculated serum osmolality >320 mmol/L. Persons with HHS are not acidotic unless DKA is also present. The treatment of HHS centers around aggressive rehydration and restoration of glucose and electrolyte homeostasis; the rate of correction of these variables must be monitored closely. Low-dose insulin therapy may be required. Chronic Complications of Diabetes


Pharmacology_Katzung

Pharmacology_Katzung. Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the lens of the eye. These lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state subsequent to the onset of puberty and glycemic control. In type 1 diabetes, end-stage chronic kidney disease develops in up to 40% of patients, compared with less than 20% of patients with type 2 diabetes. Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years’ duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2


Pharmacology_Katzung

Pharmacology_Katzung. in type 1 patients (25% after 15 years’ duration). In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death, whereas patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death. Cigarette use adds significantly to the risk of both microvascular and macrovascular complications in diabetic patients.


Pharmacology_Katzung

Pharmacology_Katzung. •Glipizide•Glyburide•Glimepiride•Gliclazide1 Insulin secretagogues: Close K+ channels in betacells•increaseinsulin release Reduce circulating glucose in patients with functioning beta cells Type 2 diabetes Orallyactive•duration10–24h•Toxicity: Hypoglycemia, weight gain •Tolazamide, tolbutamide, chlorpropamide, acetohexamide: Older sulfonylureas, lower potency, greater toxicity; rarely used •ColesevelamhydrochlorideBile acid binder: Lowers glucose through unknown mechanisms Reduces glucose levels Type 2 diabetes Oral•24-hdurationofaction•Toxicity: Constipation, indigestion, flatulence 1Not available in United States.


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS SULFONYLUREAS Acetohexamide‡ Generic, Dymelor Chlorpropamide Generic, Diabinese Gliclazide‡ Generic, Diamicron Glimepiride Generic, Amaryl Glipizide Generic, Glucotrol, Glucotrol XL Glyburide Generic, Diaβeta, Micronase, Glynase PresTab Tolazamide Generic, Tolinase Tolbutamide Generic, Orinase MEGLITINIDES Repaglinide Generic, Prandin Mitiglinide‡ DPHENYLALANINE DERIVATIVE Nateglinide Generic, Starlix BIGUANIDE Metformin Generic, Glucophage, Glucophage XR METFORMIN COMBINATIONS† Glipizide plus metformin Generic, Metaglip Glyburide plus metformin Generic, Glucovance Pioglitazone plus metformin ACTOplus Met Repaglinide plus metformin Prandi-Met Rosiglitazone plus metformin Avandamet Saxagliptin plus metformin Kombiglyze Sitagliptin plus metformin Janumet Linagliptin plus metformin Jentadueto Alogliptin plus metformin Kazano Dapagliflozin plus metformin Xigduo Canagliflozin plus metformin Invokamet Empagliflozin plus metformin Synjardy THIAZOLIDINEDIONE


Pharmacology_Katzung

Pharmacology_Katzung. plus metformin Jentadueto Alogliptin plus metformin Kazano Dapagliflozin plus metformin Xigduo Canagliflozin plus metformin Invokamet Empagliflozin plus metformin Synjardy THIAZOLIDINEDIONE DERIVATIVES Pioglitazone Generic, Actos Rosiglitazone Avandia ALPHA-GLUCOSIDASE INHIBITORS Acarbose Generic, Precose GENERIC NAME AVAILABLE AS THIAZOLIDINEDIONE COMBINATION Pioglitazone plus glimepiride Duetact Alogliptin plus pioglitazone Oseni Rosiglitazone plus glimepiride Avandaryl Miglitol Glyset Voglibose‡ GLUCAGON-LIKE POLYPEPTIDE-1 RECEPTOR AGONISTS Exenatide Byetta Liraglutide Victoza Albiglutide Tanzeum, Eperzan Dulaglutide Trulicity DIPEPTIDYL PEPTIDASE-4 INHIBITORS Linagliptin Tradjenta Saxagliptin Onglyza Sitagliptin Januvia Alogliptin Nesina Vildagliptin‡ SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS Canagliflozin Invokana Dapagliflozin Farxiga Empagliflozin Jardiance SODIUM GLUCOSE CO-TRANSPORTER INHIBITORS COMBINATION Empagliflozin plus linagliptin Glyxambi ISMISCELLANEOUS DRUGSLET


Pharmacology_Katzung

Pharmacology_Katzung. 2 INHIBITORS Canagliflozin Invokana Dapagliflozin Farxiga Empagliflozin Jardiance SODIUM GLUCOSE CO-TRANSPORTER INHIBITORS COMBINATION Empagliflozin plus linagliptin Glyxambi ISMISCELLANEOUS DRUGSLET AMYLOID POLYPEPTIDE ANALOG Pramlintide Symlin BILE ACID SEQUESTRANT Colesevelam hydrochloride Welchol DOPAMINE RECEPTOR AGONIST Bromocriptine Generic, Parlodel, Cycloset GLUCAGON Glucagon Generic *See Table 41–5 for insulin preparations.


Pharmacology_Katzung

Pharmacology_Katzung. †Other combinations are available. ‡Not available in the United States. Action to Control Cardiovascular Risks in Diabetes Study Group: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545. Adler AI et al: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. Br Med J 2000;321:412. ADVANCE Collaborative Group: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560. Ahmadian M et al: PPARγ signaling and metabolism: The good, the bad and the future. Nat Med 2013;19:557. American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36(Suppl 1):S67. Andrianesis V, Doupis J: The role of kidney in glucose homeostasis—SGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol 2013;6:519.


Pharmacology_Katzung

Pharmacology_Katzung. Andrianesis V, Doupis J: The role of kidney in glucose homeostasis—SGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol 2013;6:519. Bennett WL et al: Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602. Erratum in: Ann Intern Med 2011;155:67. Butler PC et al: A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013;36:2118. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26(Suppl 1):S5. Gaede P et al: Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580.


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Pharmacology_Katzung. Gaede P et al: Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580. Guo S: Insulin signaling, resistance, and the metabolic syndrome: Insights from mouse models to disease mechanisms. J Endocrinol 2014;220:T1. Inzucchi SE et al: Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015;58:429. Karagiannis T et al: Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: Systematic review and meta-analysis. BMJ 2012;344:e1369. Kitabchi A et al: Thirty years of personal experience in hyperglycemic crises: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab 2008;93:1541. Lefebvre P et al: Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147.


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Pharmacology_Katzung. Lefebvre P et al: Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147. Levin D et al: Pioglitazone and bladder cancer risk: A multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493. Miyazaki Y, DeFronzo RA: Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab 2008;10:1204. Nauck M: Incretin therapies: Highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016;18:203. Nwose OM, Jones MR: Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. Clin Med Insights Endocrinol Diabetes 2013;6:75.


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Pharmacology_Katzung. Nwose OM, Jones MR: Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. Clin Med Insights Endocrinol Diabetes 2013;6:75. Ratner RE et al: Amylin replacement with pramlintide as an adjunct to insulin therapy improves long term glycemic and weight control in type 1 diabetes mellitus: A 1-year randomized controlled trial. Diabetic Med 2004; 21:1204. Reitman ML et al: Pharmacogenetics of metformin response: A step in the path toward personalized medicine. J Clin Invest 2007;117:1226. Rizzo M et al: Non-glycemic effects of pioglitazone and incretin-based therapies. Expert Opin Ther Targets 2013;17:739. Rosenstock J, Ferrannini E: Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638. Standl E, Schnell O: Alpha-glucosidase inhibitors 2012—cardiovascular considerations and trial evaluation. Diab Vasc Dis Res 2012;9:163.


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Pharmacology_Katzung. Standl E, Schnell O: Alpha-glucosidase inhibitors 2012—cardiovascular considerations and trial evaluation. Diab Vasc Dis Res 2012;9:163. Switzer SM et al: Intensive insulin therapy in patients with type 1 diabetes mellitus. Endocrinol Metab Clin North Am 2012;41:89. Tuccori M et al: Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541. United Kingdom Prospective Diabetes Study (UKPDS) Group: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies: UKPDS 49. JAMA 1999;281:2005. United Kingdom Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703.


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Pharmacology_Katzung. This patient had significant insulin resistance, taking about 125 units of insulin daily (approximately 1 unit per kilogram). He had had limited instruction on how to manage his dia-betes. He had peripheral neuropathy, proteinuria, low HDL cholesterol levels, and hypertension. The patient underwent multifactorial intervention targeting his weight, glucose levels, and blood pressure. He was advised to stop smoking. He attended structured diabetes classes and received indi-vidualized instruction from a diabetes educator and a dieti-tian. Metformin therapy was reinitiated and his insulin doses were reduced. The patient was then given the GLP1 receptor agonist, exenatide. The patient lost about 8 kg in weight over the next 3 years and was able to stop his insulin. He had excellent control with an HbA1c of 6.5 % on a combination of metformin, exenatide, and glimepiride. His antihyperten-sive therapy was optimized and his urine albumin excretion declined to 1569 mg/g creatinine. This case


Pharmacology_Katzung

Pharmacology_Katzung. an HbA1c of 6.5 % on a combination of metformin, exenatide, and glimepiride. His antihyperten-sive therapy was optimized and his urine albumin excretion declined to 1569 mg/g creatinine. This case illustrates the importance of weight loss in controlling glucose levels in the obese patient with type 2 diabetes. It also shows that simply increasing the insulin dose is not always effective. Combin-ing metformin with other oral agents and non-insulin inject-ables may be a better option.


Pharmacology_Katzung

Daniel D. Bikle, MD, PhD

Pharmacology_Katzung. Daniel D. Bikle, MD, PhD


Pharmacology_Katzung

Pharmacology_Katzung. A 65-year-old man is referred to you from his primary care physician (PCP) for evaluation and management of pos-sible osteoporosis. He saw his PCP for evaluation of low back pain. X-rays of the spine showed some degenerative changes in the lumbar spine plus several wedge deformities in the thoracic spine. The patient is a long-time smoker (up to two packs per day) and has two to four glasses of wine with dinner, more on the weekends. He has chronic bronchitis, presumably from smoking, and has been treated on numerous occasions with oral prednisone for exacerba-tions of bronchitis. He is currently on 10 mg/d prednisone. Examination shows kyphosis of the thoracic spine, with some tenderness to fist percussion over the thoracic spine. The dual-energy x-ray absorptiometry (DEXA) measure-ment of the lumbar spine is “within the normal limits,” but the radiologist noted that the reading may be misleading because of degenerative changes. The hip measurement shows a T score (number of standard


Pharmacology_Katzung

Pharmacology_Katzung. the lumbar spine is “within the normal limits,” but the radiologist noted that the reading may be misleading because of degenerative changes. The hip measurement shows a T score (number of standard deviations by which the patient’s measured bone density differs from that of a normal young adult) in the femoral neck of –2.2. What further workup should be considered, and what therapy should be initiated?


Pharmacology_Katzung

Pharmacology_Katzung. Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function. Accordingly, the body has evolved complex mechanisms to carefully maintain calcium and phosphate homeostasis (Figure 42–1). Approximately 98% of the 1–2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone, the principal reservoir for these minerals. This reservoir is dynamic, with constant remodeling of bone and ready exchange of bone mineral with that in the extracellular fluid. Bone also serves as the principal structural support for the body and provides the space for hematopoiesis. This relationship is more than fortuitous, as elements of the bone marrow affect skeletal processes just as skeletal elements affect hematopoietic processes. During aging and in nutritional diseases such as anorexia nervosa and obesity, fat accumulates in the marrow, suggesting a dynamic interaction between marrow fat and bone.


Pharmacology_Katzung

Pharmacology_Katzung. hematopoietic processes. During aging and in nutritional diseases such as anorexia nervosa and obesity, fat accumulates in the marrow, suggesting a dynamic interaction between marrow fat and bone. Furthermore, bone has been implicated as an endocrine tissue with release of osteocalcin, which in its uncarboxylated form stimulates insulin secretion and testicular function. Abnormalities in bone mineral homeostasis can lead to a wide variety of cellular dysfunctions (eg, tetany, coma, muscle weakness), disturbances in structural support of the body (eg, osteoporosis with fractures), and loss of hematopoietic capacity (eg, infantile osteopetrosis).


Pharmacology_Katzung

Pharmacology_Katzung. Calcium and phosphate enter the body from the intestine. The average American diet provides 600–1000 mg of calcium per day, of which approximately 100–250 mg is absorbed. This amount represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The quantity of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. In general, more than 98% of filtered calcium and 85% of Ca, P D(+), PTH (+) D(+), PTH (+) CT(–) Serum Ca, P Gut Ca, P D(–)D(–) PTH(+)PTH(–) CT(+) CT(+) FGF23(+)


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 42–1 Mechanisms contributing to bone mineral homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations are controlled principally by three hormones, 1,25-dihydroxyvitamin D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on renal excretion. PTH and 1,25(OH)2D increase the input of calcium and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D also increases calcium and phosphate absorption from the gut. In the kidney, 1,25(OH)2D decreases excretion of both calcium and phosphorus, whereas PTH reduces calcium but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical regulator of calcium homeostasis, but in pharmacologic concentrations can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example,


Pharmacology_Katzung

Pharmacology_Katzung. but in pharmacologic concentrations can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, 1,25(OH)2D increases urinary calcium excretion indirectly through increased calcium absorption from the gut and inhibition of PTH secretion and may increase urinary phosphate excretion because of increased phosphate absorption from the gut and stimulation of FGF23 production.