Endocrinology

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Chapter 14 Endocrinology

α-Glucosidase Inhibitors (AGIs)

Description

α-Glucosidase inhibitors (AGIs) are agents that reduce blood glucose by inhibiting the breakdown of carbohydrates to glucose in the gut.

Prototype and Common Drugs

image Prototype: acarbose
image Others: miglitol, voglibose

MOA (Mechanism of Action)

image Glucosidases (GSs) such as maltase, dextranase, sucrase, and glucoamylase aid in carbohydrate absorption by cleaving complex carbohydrates to yield glucose. Only monosaccharides such as glucose or fructose can be absorbed into the bloodstream (Figure 14-1).
image The AGIs are carbohydrate analogues that bind reversibly and with much greater affinity than carbohydrates to these GS enzymes.
image The competitive inhibition of these GSs delays the absorption of carbohydrates along the gastrointestinal (GI) tract. These agents are therefore useful in reducing the spike in blood sugar that occurs after a meal.
image The different AGIs differ slightly in the target enzymes they inhibit. Acarbose also has a small effect on α-amylase, whereas miglitol inhibits isomaltase and β-glucosidases. The β-glucosidases cleave β-linked sugars such as lactose.
image

Figure 14-1

Pharmacokinetics

image Acarbose is meant to act locally in the GI tract and therefore has minimal systemic bioavailability (approximately 2%).
image Metabolism occurs within the GI tract, by the action of intestinal bacteria and digestive enzymes.

Indications

image Diabetes mellitus (type 2), for:

image Predominantly postprandial hyperglycemia
image New-onset diabetes with mild hyperglycemia

Contraindications

image Irritable bowel syndrome (IBS), inflammatory bowel disease: The GI side effects associated with the use of AGIs (see later) may exacerbate the symptoms of IBS.

Side Effects

image GI (flatulence, bloating, abdominal discomfort, diarrhea): GI side effects are all caused by the actions of bacteria on undigested carbohydrates that reach the large intestine. The carbohydrate load that reaches the large intestine is a substrate for bacteria, which generate gas when they consume the carbohydrate. This side effect seems to be reduced with time, possibly because of an up-regulation of α-glucosidase enzymes in the distal small intestine.
image Hypoglycemia: Hypoglycemia is typically seen only with concomitant administration of sulfonylureas. The hypoglycemia should be managed with glucose and not sucrose, as the breakdown of sucrose might be inhibited by the actions of the α-glucosidase inhibition.

Rare

image Increased serum aminotransferases: Reversible elevations in aminotransferase levels (one of the liver enzymes) have been seen with these agents, although this is considered to be a rare phenomenon.

Important Notes

image The effects of AGIs are generally considered additive to those of other antidiabetics.
image Acarbose has been shown in some studies to have potential beneficial cardiovascular effects beyond that of simply lowering blood glucose.
image Because of their mechanism of action, namely reducing postprandial glucose levels, there has been considerable interest in the potential for AGIs to prevent onset of type 2 diabetes mellitus. Postprandial hyperglycemia is considered to be an early warning sign for development of type 2 diabetes. The STOP-NIDDM trial was a large (N = 1429 participants) double-blind randomized controlled trial that found that the number needed to treat (NNT) for preventing one new case of diabetes over 3 years was 11 for acarbose. Given that these results are from only one study, they should be interpreted with caution; however these findings do suggest further investigation is warranted.

Evidence

α-Glucosidase Inhibitors versus Placebo or Other Antidiabetics in Type 2 Diabetes Mellitus

image A 2005 Cochrane review (41 trials, N = 8130 patients) included studies largely 24 to 52 weeks in duration, with all the various AGIs. Few data on mortality, morbidity, or quality of life were available. The AGIs improved surrogate markers such as HbA1c (−0.8%), fasting blood glucose (−1.1 mmol/L), and postload blood glucose (−2.3 mmol/L) versus placebo.

FYI

image Lactase is a β-glucosidase that breaks down lactose, a disaccharide composed of glucose and galactose. Because acarbose is specific for α-glucosidases, the metabolism of lactose is unaffected.

Biguanides

Description

Biguanides reduce blood glucose without stimulating insulin secretion.

Prototype

image Metformin

MOA (Mechanism of Action)

image There are several proposed mechanisms behind the glucose-reducing effects of biguanides (Figure 14-2):

image Reduced gluconeogenesis

• Gluconeogenesis is the formation of glucose from noncarbohydrate precursors.
• Adenosine monophosphate (AMP) kinase is believed to mediate some of this effect by inhibiting enzymes involved in gluconeogenesis.
• AMP kinase plays a role in energy homeostasis and has become a focal point for research into new therapies for diabetes mellitus and other metabolic conditions.

image Increased action of insulin in muscle and fat

• This is also believed to occur through stimulation of the actions of AMP kinase.

image Delayed glucose absorption from GI tract
image Direct stimulation of glycolysis in tissue with increased glucose removal from blood

• Glycolysis is the breakdown of glucose.

image Reduced plasma glucagon

• Glucagon is a hormone that increases glucose levels by breaking down glycogen.

image

Figure 14-2

Pharmacokinetics

image Metformin is not metabolized and is excreted in urine unchanged. Renal clearance occurs mainly through tubular secretion.

Indication

image Type 2 diabetes mellitus

Contraindication

image Metabolic acidosis: See Side Effects.

Side Effects

image GI: Abdominal pain, nausea, diarrhea. Mechanism unknown.
image Reduced absorption of vitamin B12 and folate: Mechanism is unknown, but the risk of reduced vitamin B12 appears to increase with dose and duration of therapy.
image Hypoglycemia: There is a low risk of hypoglycemia.

Serious

image Lactic acidosis (rare): Typically not seen at recommended doses. Patients who have renal impairment are at higher risk. Metformin must be discontinued if this occurs.

Important Notes

image Because metformin does not stimulate the release of insulin, it is less likely to cause hypoglycemia than the oral hypoglycemics.
image Metformin is also used in the management of polycystic ovarian syndrome (PCOS). Hyperinsulinemia is believed to contribute to PCOS by stimulating excess testosterone production by the ovaries and decreasing synthesis of sex hormone binding globulin in the liver. Metformin reduces insulin levels, therefore inhibiting this process.
image Lactic acidosis was a major concern with this drug class, as an original member of this class (phenformin) was withdrawn from the market in the 1970s because of this potentially fatal side effect. The incidence of lactic acidosis with metformin is actually very low (less than one case per 1000 patient years). This risk can increase substantially if metformin is given with other agents that cause acidosis or in patients with renal impairment.

Advanced

image There is increasing evidence from animal and now human studies that metformin may have beneficial effects that extend beyond its known effects in reducing blood glucose. In particular, metformin may have beneficial cardiovascular effects, including a reduction in microvascular complications and improved endothelial function.

Evidence

Metformin Monotherapy in Type 2 Diabetes Mellitus

image A 2005 Cochrane review compared metformin with sulfonylureas (13 trials, N = 1167 participants), placebo (12 trials, N = 702), diet (three trials, N = 493), thiazolidinediones (TZDs) (three trials, N = 132), insulin (two trials, N = 439), meglitinides (two trials, N = 208), and glucosidase inhibitors (two trials, N = 111). Obese participants with type 2 diabetes who were treated with intensive metformin therapy had a reduced risk for any clinical endpoint related to type 2 diabetes, including all-cause mortality and stroke compared with intensive therapy with chlorpropamide, glibenclamide, or insulin. The authors described metformin as eliciting a strong benefit for HbA1c compared with placebo or diet.

FYI

image The biguanides originated from the French lilac plant, which had been used for centuries to treat symptoms of diabetes mellitus. Guanidine is believed to be a major active ingredient in the plant, and two molecules were joined together to form the biguanides.

Incretins

Description

Incretins are oral hypoglycemic agents.

Prototypes and Common Drugs

Dipeptidyl Peptidase (DPP)–4 Inhibitors (Also Known As the “Gliptins”)

image Prototype: sitagliptin
image Others: saxagliptin, vildagliptin

Incretin Mimetics

image Prototype: exenatide

MOA (Mechanism of Action)

image Patients with type 2 diabetes mellitus appear to have an impaired insulin response (insulin resistance) and an inappropriate increase in glucagon release compared with normal individuals. Glucagon is a hormone that does the opposite of insulin—it increases blood glucose.
image Incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) lower blood glucose. They accomplish this by a number of mechanisms:

image GLP-1 and GIP stimulate insulin release from pancreatic beta cells under conditions of normal or elevated blood glucose.
image GLP-1 also lowers glucagon secretion from alpha cells, reduces appetite, slows gastric emptying, and regulates beta-cell growth (Figure 14-3).

image The DPP-4 enzyme inactivates incretin hormones, and therefore agents that overcome the actions of this enzyme enhance the effects of incretins (see Figure 14-3).
image Two approaches have been taken to enhance incretin hormones. Incretin mimetics are GLP-1 analogues that are not degraded by DPP-4 and thus act as GLP-1 agonists. The gliptins work by inhibiting the DPP-4 enzyme, which prevents the breakdown of incretins, thus enhancing their actions.
image The net effects of incretins are an increase in insulin release and a decrease in glucagon.
image

Figure 14-3

Pharmacokinetics

image Exenatide is administered by subcutaneous injection. It has a circulating half-life of 60 to 90 minutes.
image Unlike exenatide, the gliptins are administered orally.

Indication

image Diabetes mellitus (type 2)

Contraindications

image None of major significance

Side Effects

image The incretins are generally well tolerated.
image Hypersensitivity reactions: DPP-4 contributes to the activation of T cells, so inhibition of the activity of this enzyme might affect immune function.
image Increased incidence of infection: This was observed with sitagliptin in clinical trials, but the mechanism has not been explained. Once again, there might be a connection with immune function.

Important Notes

image The first indication that incretins exist came from the observation that an oral glucose load is more effective at stimulating insulin secretion than glucose given intravenously. It was subsequently discovered that two hormones (GIP and GLP-1) that are released from the upper and lower bowel enhance glucose-dependent insulin release. This increased effect of oral glucose on insulin secretion is identified as the incretin effect.

Advanced

Pregnancy

image The safety of sitagliptin in pregnancy has not been established.

Evidence

DPP-4 Inhibitors versus Other Antidiabetics and Placebo in Type 2 Diabetes Mellitus

image A 2008 Cochrane review included studies of sitagliptin (11 trials, N = 6743 patients) and vildagliptin (14 trials, N = 6121 patients) from 12 to 52 weeks’ duration. No data were published for mortality, diabetic complications, or quality of life. Compared with placebo, absolute reductions in HbA1c were sitagliptin 0.7% and vildagliptin 0.6%. Compared with the effects of other agents, no improvements in metabolic control were detected.
image All-cause infections increased with sitagliptin and with vildagliptin, but the difference was statistically significant only with sitagliptin. Otherwise the agents were well tolerated.

FYI

image Exenatide is a synthetic analogue of exendin-4, a peptide found in the venom of the Gila monster, a large lizard.
image Original attempts to use GLP-1 therapeutically were thwarted by its rapid inactivation by DPP-4. The actions on GLP-1 lasted for only a few minutes; therefore it had to be administered by continuous infusion. Exenatide acts as an agonist at GLP-1 receptors but is not broken down to an appreciable extent by DPP-4; thus it represents the first clinically feasible incretin analogue.

Insulins

Description

Insulin is a naturally occurring hormone that reduces blood glucose.

Prototypes and Common Drugs

Short-Acting Insulin

image Prototype: insulin R (regular)
image Others: insulin aspart, insulin lispro, insulin glulisine

Intermediate-Acting Insulin

image Prototype: Neutral Protamine Hagedorn (NPH) insulin
image Others: insulin Lente

Long-Acting Insulin

image Prototype: insulin ultralente
image Others: insulin protamine zinc, insulin glargine, insulin detemir

MOA (Mechanism of Action)

image Insulin is a hormone secreted by beta cells of the islets of Langerhans in the pancreas. It has several functions, many of which serve to lower blood glucose (Figure 14-4):

image Controls the uptake, use, and storage of cellular nutrients:

• The most widely known function of insulin is to promote the uptake of glucose by cells. Insulin does this by mobilizing glucose transporters (GLUT-4) on the surface of muscle and adipose tissue.
• In the liver and in muscle, insulin leads to increased glycogen deposition by increasing its synthesis and inhibiting its degradation. Glycogen is the primary means for storing glucose in the body.
• In the liver, insulin inhibits the synthesis of glucose (gluconeogenesis).
• In muscle, insulin facilitates uptake of amino acids, promoting protein synthesis.
• In adipose, insulin promotes synthesis of triglycerides and inhibits lipolysis.

image Aside from its multiple metabolic effects, insulin also binds to the insulin-like growth factor receptor (IGF-1) and appears to have growth-promoting effects.
image

Figure 14-4

Pharmacokinetics

image As is the case with most peptides, insulin cannot be administered orally. It is most frequently delivered parenterally, typically subcutaneously.
image An inhaled formulation of insulin is now available in some jurisdictions.
image A wide variety of insulins is available, characterized by onset and duration of action, summarized in Table 14-1.
image There is considerable interindividual variability in the pharmacokinetics of insulin, thus creating variability and unpredictability in the time to peak hypoglycemic effect.
image The Lente insulins absorb more slowly because of their crystal size.

TABLE 14-1 Insulin Formulations

image

Indication

image Diabetes mellitus (type 1 and type 2)

Contraindications

image None of major significance

Side Effects

image Hypoglycemia: seen with overdose or a missed meal; signs and symptoms include:

image Sweating
image Tachycardia
image Tremor
image Weakness
image Hunger
image Blurred vision
image Confusion
image Convulsions
image Coma

image Most of these signs and symptoms are secondary to the release of counterregulatory hormones such as epinephrine, glucagon, growth hormone (GH), cortisol, and norepinephrine, with epinephrine and glucagon playing the most important roles.
image Mild hypoglycemia is typically managed by patients with intake of sugar, preferably glucose. More severe cases can be managed with intravenous glucose, or with glucagon, a hormone with actions opposite to those of insulin.
image Lipodystrophy: Insulin injections can lead to localized atrophy of subcutaneous fat (lipoatrophy) or enlargement of fat deposits (lipohypertrophy). Lipoatrophy may be caused by an immune response, whereas lipohypertrophy may be caused by generation of fat cells.
image Edema: Edema is attributed to Na+ retention.

Important Notes

image Recombinant human insulin was a very early example of the use of biotechnology in drug development. Insulins were originally derived from beef (bovine) or pork (porcine) sources, and these forms of insulin are still used in some areas of the world. As they were not of human origin, bovine and porcine insulins elicited immune responses that either made their administration unpredictable or in some cases led to hypersensitivity reactions. Porcine insulin differs from human by one amino acid, and bovine by three amino acids; therefore bovine insulin is more prone to cause immunogenic reactions.
image The beta cells of the pancreas actually secrete a 110–amino acid polypeptide called preproinsulin, which is cleaved to proinsulin in the endoplasmic reticulum and then to insulin in the Golgi and secretory granules. Insulin is composed of two polypeptide chains: an A chain of 21 amino acids and a B chain of 30 amino acids. Modification of these chains has yielded several different analogues of insulin with different onset times and duration.

Advanced

image The use of units for insulin dosages dates back to the time when insulin had to be standardized because of the use of impure hormone. One unit of insulin was the amount required to lower blood glucose in a fasting rabbit to 2.5 mM (45 mg/dL).
image Homogeneous preparations of human insulin contain 25 to 30 units/mg, and most insulin preparations are supplied in concentrations of 100 units/mL, or about 3.6 mg/mL.

Evidence

Short-Acting Analogues versus Regular Insulin

image A 2006 Cochrane review (49 trials, N = 8274 participants) assessed the effects of short-acting insulin analogues versus regular human insulin. There were minimal differences in efficacy. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was −0.1% in favor of short-acting insulin analogues versus insulin, and in patients with type 2 diabetes there was no difference. In type 1 diabetes the incidence of severe hypoglycemia was lower for insulin analogues versus insulin (median 22 versus 46 episodes per 100 person-years). In type 2 diabetes there were also fewer severe hypoglycemia events with analogues versus insulin (median 0.3 versus 1.4 per 100 person-years).

Gestational Diabetes Mellitus

image A 2009 Cochrane review (eight trials, N = 1418 women) compared the effects of various treatment policies with one another or with routine antenatal care for gestational diabetes mellitus (GDM) on both maternal and infant outcomes. Intensive management (including dietary advice and insulin) reduced the risk of preeclampsia compared with results of routine antenatal care (relative risk [RR] 0.65), based on one trial of 1000 participants. The risk of the composite outcome of perinatal morbidity (death, shoulder dystocia, bone fracture, and nerve palsy) was also reduced for those on intensive therapy for mild GDM versus routine antenatal care (RR 0.32), based on one trial of 1030 infants. Note that gestational diabetes leads to large babies, which can then experience complications in the birthing process because of their size.

FYI

image Lente means slow in Italian.
image Banting and Best are credited with the discovery of insulin in the 1920s. In essence, they were the first to isolate and identify insulin and to use this “pancreatic extract” in patients. This built on work that had begun in the late 1880s, when the pancreas had been identified as playing a role in diabetes, and work at the turn of the century that had first used pancreatic extracts to treat diabetic animals and (unsuccessfully) patients.
image The islets of Langerhans have other specialized cells that are responsible for the secretion of glucagon (alpha cells) and somatostatin (delta cells).
image NPH insulin is created by treating regular insulin with protamine and zinc at a neutral pH (7.2). This results in a fine precipitate of protamine zinc insulin that provides for slow and even absorption when administered subcutaneously. Hagedorn (the H in NPH) was the name of the scientist who created the formulation.
image In an attempt to create a long-acting heparin injection, protamine was also originally added to heparin. However, the two chemicals formed a precipitate, and it was this discovery that led to the use of protamine as a reversal agent for heparin.
image Protamine is manufactured from salmon sperm.

Meglitinides

Description

Meglitinides are oral agents that lower blood glucose by increasing insulin secretion.

Prototype and Common Drugs

image Prototype: repaglinide
image Others: nateglinide

MOA (Mechanism of Action)

image The meglitinides are insulin secretagogues, stimulating the release of insulin from pancreatic beta cells in a manner similar to that of the sulfonylureas (Figure 14-5).
image They bind to a beta cell sulfonylurea receptor (SUR-1) that is associated with an inward rectifier adenosine triphosphate (ATP)–sensitive potassium channel. Binding leads to depolarization, which then opens a voltage-gated calcium channel, leading to calcium influx and insulin release.
image Meglitinides therefore rely on functioning beta cells in order to achieve their pharmacologic effect. They are thus not useful in type 1 diabetes mellitus.
image

Figure 14-5

Pharmacokinetics

image The meglitinides are rapidly and completely absorbed, achieving peak plasma concentrations in less than 1 hour after oral administration.
image They are metabolized in the liver, and have a short elimination half-life of 1 to 2 hours. Dose adjustments should be considered in patients with impaired liver function.
image Nateglinide acts more quickly than repaglinide and also has a shorter duration of action. Because both of these agents have a rapid onset and offset, they are typically administered just before meals for the management of postprandial hyperglycemia.
image Food increases the absorption of nateglinide but has minimal impact on repaglinide absorption.

Indication

image Diabetes mellitus (type 2)

Contraindication

image Concomitant gemfibrozil and repaglinide: Gemfibrozil (a fibrate) significantly reduces the metabolism of repaglinide, leading to as much as an eightfold increase in repaglinide levels. In some cases this has lead to severe episodes of hypoglycemia. Gemfibrozil is used to lower cholesterol; multiple risk-reduction strategies are frequently used in patients with multiple risk factors for atherosclerosis and thus there is a risk that these two drugs can be co-administered.

Side Effects

image Hypoglycemia: Although less common than with the sulfonylureas, hypoglycemia still occurs in approximately 1% of patients. This side effect is treated in the same manner as hypoglycemia seen with other insulin secretagogues.

Important Notes

image The rapid onset of action of the meglitinides, particularly nateglinide, makes them useful agents in the management of postprandial hyperglycemia. Patients can take these agents just before eating, allowing them flexibility in choosing the timing of their meals. The sulfonylureas do not allow for this much flexibility.

Evidence

Meglitinides versus One Another, Metformin, and Placebo

image A 2007 Cochrane review (15 trials, N = 3781 patients) did not find any studies that reported on morbidity or mortality. Compared with the effects of placebo, HbA1c was reduced by both repaglinide (0.1% to 2.1%) and nateglinide (0.2% to 0.6%). In trials comparing the two agents, repaglinide performed better than nateglinide with respect to reducing HbA1c. Repaglinide had similar reductions in HbA1c to metformin (three studies, N = 248 patients), whereas nateglinide had similar or slightly less of an effect on HbA1c compared to metformin (one study, N = 355 patients).
image Weight gain was generally greater with meglitinides versus metformin; diarrhea occurred less frequently and hypoglycemia more frequently with meglitinides versus metformin.

FYI

image The meglitinides were approved 40 years after the approval of the first sulfonylurea, tolbutamide.

Sulfonylureas

Description

Sulfonylureas are oral agents that lower blood glucose by increasing insulin secretion.

Prototypes and Common Drugs

First-Generation Agents

image Prototype: Tolbutamide
image Others: Chlorpropamide, tolazamide, acetohexamide

Second-Generation Agents

image Prototype: Glyburide
image Others: Glipizide, gliclazide, glimepiride

MOA (Mechanism of Action)

image Patients with type 2 diabetes mellitus appear to have an impaired insulin response (insulin resistance) and an inappropriate increase in glucagon release compared with normal individuals. Glucagon is a hormone that does the opposite of insulin—it increases blood glucose.
image The sulfonylureas are insulin secretagogues, meaning that they stimulate insulin release from the beta cells of the pancreas.
image They bind to a beta-cell sulfonylurea receptor (SUR-1) that is associated with an inward rectifier ATP-sensitive potassium channel. Binding leads to depolarization, which then opens a voltage-gated calcium channel, leading to calcium influx and insulin release (Figure 14-6).
image Sulfonylureas also reduce serum glucagon levels. Although the mechanism behind this has not been definitively established, sulfonylureas enhance the release of insulin and somatostatin, and it is believed that one or both of these effects may in turn lead to a reduction in glucagon release from pancreatic alpha cells.
image

Figure 14-6

Pharmacokinetics

image The elimination half-lives of first-generation agents vary considerably, whereas the half-lives of second-generation agents are typically short (3 to 5 hours). However, the biologic half-lives, the amount of time for which they are effective, is longer than their elimination half-lives would suggest, for reasons that are still unknown.
image All sulfonylureas are metabolized by the liver and excreted in urine. Because of the risk of hypoglycemia, dose adjustments must be considered in patients with hepatic impairment. A small proportion is also excreted unchanged in urine, therefore caution should also be exercised in patients with renal impairment.

Indication

image Diabetes mellitus (type 2)

Contraindications

None of major significance.

Side Effects

image Hypoglycemia: Hypoglycemia is caused by oversecretion of insulin and occurs more frequently with glyburide. Glyburide may impair the body’s ability to prevent endogenous insulin secretion during hypoglycemia.
image Flushing: Flushing occurs when these drugs are taken with alcohol and is more common with older agents like chlorpropamide.
image Weight gain: Weight gain is caused by increased insulin activity in adipose. It occurs less frequently with the second-generation sulfonylureas.

Rare, Serious

image Hematologic toxicities: Anemias and thrombocytopenias occur and are mainly seen with chlorpropamide.

Important Notes

image Because of concerns over hypoglycemia, the sulfonylureas, particularly glyburide, should be initiated at a low dose, and patients should be observed carefully for changes in blood glucose over the first few weeks of therapy. Patients with irregular diets or who drink ethanol to excess are at increased risk for hypoglycemia.
image The hypoglycemic effects of the sulfonylureas tend to diminish with time. The most likely explanation for this reduced response is progressive loss of beta cells from diabetes.
image Patients with type 1 diabetes mellitus are unable to secrete appreciable amounts of insulin; therefore a drug that promotes insulin secretion will not work in these patients.

Advanced

Pregnancy

image Patients with gestational diabetes should not be treated with sulfonylureas, but should instead be treated with insulin.

Evidence

Glyburide for Hypoglycemic Events and Cardiovascular Risk

image A 2007 systematic review (21 trials, N = 7047 patients) compared glyburide with other insulin secretagogues and insulin for hypoglycemic and cardiovascular events. The authors found that glyburide was associated with a greater risk of experiencing a hypoglycemic event compared with other secretagogues (RR 1.52) or other sulfonylureas (1.83). Glyburide was not associated with an increased risk of cardiovascular events, death, or end-of-trial weight gain compared with other secretagogues.

FYI

image The sulfonylureas were the first oral agents for type 2 diabetes and have been in use for over 50 years.
image After a large study conducted in the 1970s found increased cardiovascular mortality with sulfonylureas, for many years there was an association drawn between this class and elevated cardiovascular risk. Subsequent studies have not found this association, although this class is still believed in some circles to carry this risk.

Thiazolidinediones

Description

The thiazolidinediones (TZDs) are oral agents that lower blood glucose by increasing the sensitivity of cells to insulin.

Prototype And Common Drugs

image Prototype: rosiglitazone
image Others: pioglitazone

MOA (Mechanism Of Action)

image The TZDs are peroxisome proliferator–activated receptor–gamma (PPAR-γ) agonists.
image The PPAR-γ receptors are a complex family of receptors found in the cell nucleus in muscle, fat, and liver. Among other roles, they regulate expression of genes responsible for lipid and protein metabolism, insulin signal transduction, and adipocyte and other tissue differentiation. It is through a combination of these effects that they are thought to decrease insulin resistance, although the relative importance of each has not been established (Figure 14-7).
image The TZDs are thought to exert their effects at PPAR-γ receptors in adipose tissue by promoting uptake and storage of free fatty acids (FFAs) in adipose tissue. They accomplish this by increasing the number of small adipocytes that store FFAs while decreasing the number of large adipocytes that release FFAs. Through a variety of poorly understood mechanisms, high concentrations of FFAs are thought to promote insulin resistance.
image The TZDs also promote the expression and translocation of glucose transporters in muscle and adipose tissue. This increases glucose uptake into muscle and adipose tissue. The TZDs also may reduce hepatic production of glucose, although the mechanism by which this is accomplished is unclear.
image Activation of the PPAR-γ receptor also has several other effects, including inhibition of proinflammatory genes and cytokine production, as well as increased adiponectin production. Adiponectin is thought to play several protective roles in the body, stimulating glucose uptake in muscle, protecting against atherosclerosis and endothelial cell apoptosis, and stabilizing plaques.
image

Figure 14-7

Pharmacokinetics

image Rosiglitazone peak plasma levels are seen 1 hour after administration, and absorption is not significantly affected by food.
image Pioglitazone reaches its peak in 2 hours. It has two active metabolites (M-III and M-IV).
image Both rosiglitazone and pioglitazone are metabolized by hepatic CYP450 enzymes. They do not appear to induce or inhibit any CYP450 isozymes.

Indication

image Diabetes mellitus (type 2)

Contraindication

image Heart failure: See Side Effects.

Side Effects

image Weight gain: Weight gain is caused by redistribution of adipocytes from visceral to subcutaneous regions.
image Edema: TZDs promote retention of sodium and water by up-regulating tubular transporters for sodium and reducing glomerular filtration rate (GFR).
image Cardiovascular: Heart failure is likely caused by the edema described previously, observed with rosiglitazone in a large clinical trial. Myocardial ischemia has also been reported with rosiglitazone.
image Fractures: TZDs appear to impair osteoblasts, and higher fracture rates (upper arm, hand, or foot) in female subjects were observed in a large clinical trial.

Important Notes

image The PPAR-γ receptor has an extensive list of biologic actions, making it difficult to sort out the actions of agonists such as the TZDs. The most difficult effects to sort out are the cardiovascular effects. The TZDs initially appeared to have beneficial cardiovascular effects, but recently adverse cardiovascular effects, specifically heart failure, have emerged.

Advanced

image The TZDs appear to have variable effects on triglycerides and LDL, although they consistently raise HDL. Pioglitazone appears to have greater beneficial effects on lipid profiles compared with rosiglitazone.

Pregnancy

image Oral antidiabetics are generally not recommended. Insulin is the recommended treatment for diabetes during pregnancy.

Lactation

image Pioglitazone is secreted in breast milk in rats, and although human studies have not been performed, the TZDs are not recommended for breastfeeding women.

Drug Interactions

image Rosiglitazone is extensively metabolized by CYP2C8, with a minor contribution from CYP2C9.
image Pioglitazone is extensively metabolized by CYP2C8 and CYP3A4.

Evidence

Rosiglitazone versus Oral Antidiabetics or Placebo in Type 2 Diabetes Mellitus

image A 2007 Cochrane review (18 trials, N = 3888 patients) found no improvement in mortality, morbidity, adverse effects, and quality of life in trials with a follow-up of at least 24 weeks. HbA1c was not improved by rosiglitazone compared with other oral antidiabetic agents. Edema occurred significantly more frequently in rosiglitazone-treated patients, and the ADOPT study identified an increased risk of cardiovascular events with rosiglitazone. Data from ADOPT and another trial, PROactive, suggest increased risk of fractures in women treated with rosiglitazone.

Pioglitazone versus Oral Antidiabetics or Placebo in Type 2 Diabetes Mellitus

image A 2006 Cochrane review (22 trials, N = 6200 patients) did not find convincing evidence of improvement in mortality, morbidity, adverse effects, and health-related quality of life. Improvements in HbA1c were similar with pioglitazone compared with other oral antidiabetics. Edema occurred significantly more frequently with pioglitazone.

FYI

image The PPAR-γ receptor is very large and has several different distinct ligands, including warfarin, monounsaturated and polyunsaturated fats, some nonsteroidal antiinflammatory drugs (NSAIDs), and the angiotensin receptor blocker (ARB) telmisartan.
image The first marketed TZD, troglitazone, was removed from the market because of concerns over hepatotoxicity.
image Dual PPAR-α and PPAR-γ agonists are being developed in order to maximize the benefits of PPAR agonism on both lipids and glucose. PPAR-α agonists (fibrates) are used to treat hypercholesterolemia.

Glucagon

Description

Glucagon is an endogenous hormone that generally opposes the actions of insulin.

Prototype

image Glucagon

MOA (Mechanism of Action)

image Glucagon is a 29–amino acid protein secreted from the alpha cells in the pancreas and has significant homology with secretin, vasoactive intestinal peptide (VIP), and GI inhibitory polypeptide.
image Glucagon secretion is under the control of the sympathetic system and is regulated by the following:

image Dietary amino acids, glucose, and fatty acids (stimulation)
image Hypoglycemia
image Ketones (inhibition)

image The main effects of glucagon are on the liver, mediated by G protein–linked glucagon receptors and increased intracellular cyclic adenosine monophosphate (cAMP). The important specific actions include the following (Figure 14-8):

image Increased glycogenolysis via cAMP-stimulated phosphorylation
image Decreased glycogen synthesis via phosphorylation of glycogen synthase, which inactivates the enzyme
image Increased glycolysis via reduction in levels of fructose-2,6-bisphosphate, which is an important regulator in the rate-limiting step for glycolysis
image Increased ketogenesis
image Because glucagon acts to increase blood sugar, it works against insulin, which acts to lower blood sugar.
image In cardiac tissue glucagon binds a glucagon receptor and raises cAMP, resulting in a positive inotropic (contractility) and chronotropic (heart rate) effect on the heart. This is the mechanism by which it is therapeutic in β-blocker and calcium channel blocker overdoses; importantly, its action is independent of β receptors or calcium channels.
image Secretion of different pancreatic hormones influences other hormones:

image Glucagon stimulates endogenous insulin secretion.
image Insulin and somatostatin both inhibit glucagon secretion (see also the section on somatostatin analogs in this chapter).

image

Figure 14-8

Pharmacokinetics

image As a peptide, glucagon cannot be given orally because it will be digested into amino acids.
image Glucagon has a short half-life of 3 to 6 minutes. It is usually given as an intravenous infusion.

Indications

image Refractory hypoglycemia (not corrected by glucose administration)

image Oral hypoglycemia overdose
image Hyperinsulin states

• Insulin overdose
• Insulinoma (islet cell tumor that secretes insulin)

image Drug overdoses

image β-Blockers
image Calcium channel blockers

image Intestinal relaxation

image To facilitate some radiologic investigations of the GI tract

Contraindication

image Pheochromocytomas: These are rare catecholamine-secreting tumors and are sensitive to glucagon, which promotes catecholamine secretion from these tumors.

Side Effects

image Hyperglycemia
image Hypokalemia
image Nausea and vomiting, caused by delaying gastric emptying and hypotonicity

Important Notes

image Intravenous or oral glucose is the first-line treatment for hypoglycemia. Glucagon is the second-line treatment. Insulin overdoses are usually not treated with glucagon unless hypoglycemia is refractory to glucose administration.
image Glucagon decreases hepatic glycogen but does not decrease skeletal muscle glycogen because there are no glucagon receptors on skeletal muscle.
image Although some drugs that treat acute heart failure result in an increase in cAMP (β agonists and phosphodiesterase inhibitors), glucagon is not used for treating heart failure despite its similar action on cAMP.

Advanced

image Proglucagon is the precursor to glucagon and if cleaved at different locations also gives rise to glucagon-like peptides (GLP-1 and GLP-2), called incretins. Incretins are themselves a class of drugs used for diabetes management. GLP-1 and GLP-2 are secreted from intestinal cells and are involved with insulin and glucagon secretion, gastric emptying, intestinal blood flow, and permeability and appetite satiety.

Evidence

image There are no human controlled studies of glucagon use in β-blocker or calcium channel blocker therapy. However, “the available animal data, human clinical experience, and minimal adverse effect profile support the use of glucagon early in the course of both β-blocker and calcium channel blocker toxicity.”

FYI

image With the discovery that propranolol did not prevent the positive inotropic action of glucagon in cats and dogs, it was suggested that there was the possibility that glucagon may be useful in the treatment of heart failure induced by β-blockers; subsequently the logic was extended to the treatment of calcium channel blocker overdose.

Estrogens

Description

Estrogen is one of the endogenous female sex hormones. See also the discussions of progestins and hormone contraception.

Common Drugs

image Bioidentical estrogens: estrone sulfate (E1), estropipate (E1), 17β-estradiol (E2), estriol (E3)
image Esterified estrogens: ethinyl estradiol, mestranol, quinestrol, equilin
image Conjugated equine estrogens (CEEs): dienestrol

MOA (Mechanism of Action)

image Estrogens are transcription factors; they modify messenger RNA (mRNA) synthesis directly.
image Estrogens enter the cell passively (no receptor required) and bind to estrogen receptors in the nucleus, which then dimerize and bind DNA directly to regions called estrogen-responsive elements (EREs) and influence gene transcription.
image Important effects of estrogen include the following (Figure 14-9):

image Reproductive:

• Female sexual maturation (neonatal and pubescent)
• Endometrial growth stimulation
• Breast tissue stimulation

image Hematologic:

• Increased tendency for clotting via increased circulating levels of factors II, VII, IX, and X (vitamin K–dependant factors) and decreased antithrombin III

image Skin and mucosa:

• Increased pigmentation (melasma)
• Increased skin collagen content and skin thickness
• Maintenance of skin moisture by increasing acid mucopolysaccharides and hyaluronic acid

image Metabolic:

• Decreased bone resorption via antagonism of parathyroid hormone and interleukin-6 (IL-6)
• Increased high-density lipoprotein (HDL); decreased low-density lipoprotein (LDL); increased triglycerides

image

Figure 14-9

Pharmacokinetics

image Estrogen preparations include oral tablets, creams, and patches.

Indications

image Prevention of pregnancy (contraception)
image Menopausal hormone replacement therapy (HRT)
image Endometriosis
image Dysfunctional uterine bleeding (DUB)
image Urogenital atrophy: thinning and drying of vaginal mucosa
image Anti-androgen therapy: acne, hirsutism
image Infertility
image Polycystic ovarian syndrome (PCOS)

Contraindications

image Hypercoagulable states: Estrogen is a procoagulant, and estrogen administration is a risk factor for pathologic thromboses (deep vein thrombosis [DVT] and pulmonary embolus [PE]).
image Cancers that could demonstrate increased growth in response to estrogen: breast, ovarian, uterine, endometrial.
image Strong risk factors for atherosclerosis: hypertension (HTN), diabetes, high cholesterol, family history.

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