There are seven main families of oral antidiabetic drugs: bigu-anides, sulfonylureas, meglitinides (glinides), thiazolidinediones (glitazones), alpha-glucosidase inhibitors, DPP-4 inhibitors (gliptins), and sodium-glucose co-transporter 2 (SGLT-2) inhibitors. These agents are approved for use in type 2 diabetes, but agents such as the SGLT-2 inhibitors are used off-label in combination with insulin for the treatment of type 1 diabetes—
with clinical studies in progress. In the past, the oral agents were used only after a program of diet modification and exercise had failed to yield sufficient glycemic control. Today, one oral agent—metformin—is usually started immediately after type 2 diabetes has been diagnosed.
CHAPTER 57 Drugs for Diabetes Mellitus
Class and Specific Agents Actions Major Adverse Effects
ORAL DRUGS Biguanide
Metformin [Fortamet, Glucophage,
Glumetza, Riomet] Decreases glucose production by the liver,
increases tissue response to insulin GI symptoms: decreased appetite, nausea, diarrhea
Lactic acidosis (rarely) Second-Generation Sulfonylureas
Glimepiride [Amaryl]
Glipizide [Glucotrol, Glucotrol XL]
Glyburidea [DiaBeta, Glynase PresTab]
Promote insulin secretion by the pancreas; may
also increase tissue response to insulin Hypoglycemia Weight gain Meglitinides (Glinides)
Nateglinide [Starlix]
Repaglinide [Prandin, GlucoNorm ] Promote insulin secretion by the pancreas Hypoglycemia Weight gain Thiazolidinediones (Glitazones)
Pioglitazone [Actos]
Rosiglitazone [Avandia] Decrease insulin resistance and thereby increase glucose uptake by muscle and adipose tissue, and decrease glucose production by the liver
Hypoglycemia, but only in the presence of excessive insulin
Heart failure Bladder cancer Fractures (in women)
Ovulation, and thus possible unintended pregnancy
Alpha-Glucosidase Inhibitors Acarbose [Precose, Glucobay ]
Miglitol [Glyset] Delay carbohydrate digestion and absorption, thereby decreasing the postprandial rise in blood glucose
GI symptoms: flatulence, cramps, abdominal distention, borborygmus DPP-4 Inhibitors (Gliptins)
Alogliptin [Nesina]
Linagliptin [Tradjenta]
Saxagliptin [Onglyza]
Sitagliptin [Januvia]
Enhance the activity of incretins (by inhibiting their breakdown by DPP-4), and thereby increase insulin release, reduce glucagon release, and decrease hepatic glucose production
Pancreatitis
Hypersensitivity reactions
Sodium-Glucose Co-Transporter 2 (SGLT-2) Inhibitors Canagliflozin [Invokana]
Dapagliflozin [Farxiga]
Empagliflozin [Jardiance]
Increase glucose excretion via the urine by inhibiting SGLT-2 in the kidney tubules, decreasing glucose levels, and inducing weight loss via caloric loss through the urine
Genital mycotic infections Orthostasis
Dopamine Agonist
Bromocriptine [Cycloset] Activates dopamine receptors in the CNS; how
it improves glycemic control is unknown Orthostatic hypotension Exacerbation of psychosis NON-INSULIN INJECTABLE DRUGS
Incretin Mimetics Exenatide [Byetta]
Exenatide extended-release [Bydureon]
Liraglutide [Victoza]
Lixisenatide [Adlyxin]
Albiglutide [Tanzeum]
Dulaglutide [Trulicity]
Lower blood glucose by slowing gastric emptying, stimulating glucose-dependent insulin release, suppressing postprandial glucagon release, and reducing appetite
Hypoglycemia
GI symptoms: nausea, vomiting, diarrhea Pancreatitis
Renal insufficiency
Thyroid cancer (?) (liraglutide, exenatide extended-release, albiglutide, and dulaglutide)
Amylin Mimetics
Pramlintide [Symlin] Delays gastric emptying and suppresses glucagon secretion, decreasing the postprandial rise in glucose
Hypoglycemia Nausea
Injection-site reactions TABLE 57.10 ■ Drugs for Type 2 Diabetes
aCommonly known as glibenclamide outside the United States.
3% to 5% of patients, GI side effects lead to discontinuation of treatment. Therefore, the dose of metformin must be titrated up to the target dose to minimize the severity of GI side effects.
Metformin decreases absorption of vitamin B12 and folic acid, and can thereby cause deficiencies of both. Deficiency of B12, in turn, can contribute to peripheral neuropathy, a common long-term consequence of diabetes. Based on recent evidence, the ADA states that long-term metformin use may be associated with vitamin B12 deficiency and recommends that periodic measurement of B12 levels be considered in metformin-treated patients. This is especially true in patients with anemia or symptoms of peripheral neuropathy. As discussed in Chapter 81, deficiency of folic acid during pregnancy can impair development of the CNS, resulting in neural tube defects, which manifest as anencephaly or spina bifida. Nonetheless, current evidence suggests that metformin is safe for use during pregnancy.
In contrast with sulfonylureas (see later), metformin does not cause weight gain. In fact, patients maintain or possibly lose weight with metformin therapy. As a result, metfor-min is considered a “weight-neutral” antidiabetic drug, in contrast with several other antidiabetic drugs that tend to increase weight (“weight-positive”). Appetite suppression and weight loss in response to metformin can occur both in the presence and absence of nausea, indicating that reduced food intake because of metformin-induced nausea is not the only reason for weight loss in those patients who lose weight.
Toxicity: Lactic Acidosis
Metformin inhibits mitochondrial oxidation of lactic acid and can thereby cause lactic acidosis. This condition is a medical emergency and has a mortality rate of about 50%. Fortunately, lactic acidosis is rare (about 3 cases/100,000 patient-years) when metformin is used at recommended doses in patients with good renal function. However, in patients with renal insufficiency, metformin can rapidly accumulate to toxic levels. Accordingly, the drug must never be used by these people. Specifically, metformin is considered contraindicated in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/
minute/1.73 m2. Cautious use is additionally recommended in those with an eGFR of less than 45 mL/minute/1.73 m2. In addition, metformin must be avoided in patients who are prone to increased lactic acid production. Among these are patients with liver disease, severe infection, or a history of lactic acidosis; patients who consume alcohol to excess; and patients with shock and other conditions that can result in hypoxemia.
All patients taking metformin should be informed about early signs of lactic acidosis—hyperventilation, myalgia, malaise, and unusual somnolence—and instructed to report these to the prescriber. Metformin should be withdrawn until lactic acidosis has been ruled out. If lactic acidosis is diagnosed, hemodialysis can correct the condition and remove accumulated metformin.
Because heart failure (HF) can predispose to lactic acidosis, metformin is contraindicated for people with failing hearts.
However, in one study, patients with HF who took the drug were less likely to die than those who took a sulfonylurea.
These data suggest that use of metformin in HF is much safer than previously believed.
Metformin is well suited for patients who tend to skip meals.
When meals are skipped, blood glucose can drop below a level that is healthy. Because metformin does not lower blood glucose any further, it won’t make the situation any worse. In contrast, drugs that actively lower blood glucose, such as the sulfonyl-ureas, can drop a normal or slightly low blood glucose into clinically significant hypoglycemia.
Prevention of Type 2 Diabetes. Data from the Diabetes Prevention Program (DPP), a large study sponsored by the National Institutes of Health, indicate that metformin can delay development of type 2 diabetes in high-risk individuals. The DPP enrolled 3234 people ages 25 to 85. All participants had impaired glucose tolerance (as determined by an OGTT), and all were severely overweight. Participants were randomly assigned to one of three protocols: (1) intensive lifestyle changes with the aim of reducing body weight by 7% through moderate exercise (e.g., vigorous walking 30 minutes a day 5 days a week) combined with a low-fat diet, (2) treatment with met-formin (850 mg twice daily), or (3) treatment with placebo.
The results? Metformin reduced the risk of developing type 2 diabetes by 31%. However, benefits were limited primarily to younger patients and to those who were most overweight;
the drug was relatively ineffective in older patients and those less overweight. It must be stressed, however, that metformin is not a substitute for diet and exercise. In fact, the DPP showed that lifestyle changes are even more effective than metformin:
The combination of moderate exercise plus weight loss (5%
to 7% of initial weight) reduced the average risk of type 2 diabetes by 58%. Benefits were greatest (71%) for people older than 60 years.
Gestational Diabetes. For decades, insulin was considered the preferred, if not the only, antidiabetic drug for managing diabetes during pregnancy, whether the mother had type 1 or type 2 diabetes. Recent clinical studies have compared met-formin with insulin in pregnant women with type 2 diabetes.
Multiple outcomes were assessed, including glycemic control in the mother and blood glucose and Apgar scores in the neonate.
The result? Outcomes with metformin were essentially the same as those with insulin, the traditional agent for managing gestational diabetes—suggesting that metformin may become an acceptable alternative for many women. (Note: The data obtained with metformin do not apply to other classes of oral agents, such as the sulfonylureas and glitazones.) That said, the ADA currently states that pregnant women using metformin should be informed that although no adverse effects on the fetus have been thus far demonstrated, long-term studies are currently lacking.
Polycystic Ovary Syndrome (PCOS). PCOS is a combined endocrine/metabolic disorder characterized by androgen excess and insulin resistance. It affects about 5% to 10% of women of reproductive age. Symptoms include irregular periods, anovulation, infertility, acne, and hirsutism. Although not approved for PCOS, metformin can be very helpful. Metformin treatment increases insulin sensitivity and decreases insulin levels, which, through an indirect mechanism, lowers androgen levels. The net result is improved glucose tolerance, improved ovulation, and increased pregnancy rates. PCOS and its manage-ment are discussed further in Chapter 63.
Side Effects
The most common side effects are decreased appetite, nausea, and diarrhea. These generally subside over time. However, in
CHAPTER 57 Drugs for Diabetes Mellitus
already taking metformin, the total daily dosage remains the same; it’s simply taken all at once. The maximum daily dosage is 2000 mg (or 2500 mg using Fortamet).