Chapter 14 Endocrinology
α-Glucosidase Inhibitors (AGIs)
MOA (Mechanism of Action)
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).
The AGIs are carbohydrate analogues that bind reversibly and with much greater affinity than carbohydrates to these GS enzymes.
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.
Pharmacokinetics
Side Effects
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.
Important Notes
Acarbose has been shown in some studies to have potential beneficial cardiovascular effects beyond that of simply lowering blood glucose.
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
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.
Biguanides
MOA (Mechanism of Action)
There are several proposed mechanisms behind the glucose-reducing effects of biguanides (Figure 14-2):
Reduced gluconeogenesis
Side Effects
Important Notes
Because metformin does not stimulate the release of insulin, it is less likely to cause hypoglycemia than the oral hypoglycemics.
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.
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
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
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.
Incretins
MOA (Mechanism of Action)
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.
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:
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).
Pharmacokinetics
Side Effects
Important Notes
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.
Evidence
DPP-4 Inhibitors versus Other Antidiabetics and Placebo in Type 2 Diabetes Mellitus
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.
FYI
Exenatide is a synthetic analogue of exendin-4, a peptide found in the venom of the Gila monster, a large lizard.
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
MOA (Mechanism of Action)
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):
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.
Pharmacokinetics
As is the case with most peptides, insulin cannot be administered orally. It is most frequently delivered parenterally, typically subcutaneously.
A wide variety of insulins is available, characterized by onset and duration of action, summarized in Table 14-1.
There is considerable interindividual variability in the pharmacokinetics of insulin, thus creating variability and unpredictability in the time to peak hypoglycemic effect.
Side Effects
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.
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.
Important Notes
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.
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.
Evidence
Short-Acting Analogues versus Regular Insulin
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
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
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.
The islets of Langerhans have other specialized cells that are responsible for the secretion of glucagon (alpha cells) and somatostatin (delta cells).
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.
Meglitinides
MOA (Mechanism of Action)
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).
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.
Pharmacokinetics
The meglitinides are rapidly and completely absorbed, achieving peak plasma concentrations in less than 1 hour after oral administration.
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.
Contraindication
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.
Important Notes
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
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).
Sulfonylureas
MOA (Mechanism of Action)
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.
The sulfonylureas are insulin secretagogues, meaning that they stimulate insulin release from the beta cells of the pancreas.
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).
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.
Pharmacokinetics
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.
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.
Side Effects
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.
Flushing: Flushing occurs when these drugs are taken with alcohol and is more common with older agents like chlorpropamide.
Important Notes
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.
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.
Evidence
Glyburide for Hypoglycemic Events and Cardiovascular Risk
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
The sulfonylureas were the first oral agents for type 2 diabetes and have been in use for over 50 years.
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
MOA (Mechanism Of Action)
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).
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.
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.
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.
Pharmacokinetics
Side Effects
Weight gain: Weight gain is caused by redistribution of adipocytes from visceral to subcutaneous regions.
Edema: TZDs promote retention of sodium and water by up-regulating tubular transporters for sodium and reducing glomerular filtration rate (GFR).
Important Notes
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.
Evidence
Rosiglitazone versus Oral Antidiabetics or Placebo in Type 2 Diabetes Mellitus
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
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
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.
Glucagon
MOA (Mechanism of Action)
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.
Glucagon secretion is under the control of the sympathetic system and is regulated by the following:
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):
Because glucagon acts to increase blood sugar, it works against insulin, which acts to lower blood sugar.
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.
Important Notes
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.
Glucagon decreases hepatic glycogen but does not decrease skeletal muscle glycogen because there are no glucagon receptors on skeletal muscle.
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
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
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
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
MOA (Mechanism of Action)
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.
Contraindications
Hypercoagulable states: Estrogen is a procoagulant, and estrogen administration is a risk factor for pathologic thromboses (deep vein thrombosis [DVT] and pulmonary embolus [PE]).
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