There are eight classes of oral agents and they have different mechanisms of action. Three of the classes are secretagogues: first- and second-generation sulfonylureas, meglitinide, and D-phenylalanine. Two of the classes are insulin sensitizers: biguanides and thiazolidinediones. The α-glucosidase inhibitor class delays carbohydrate absorption from the gut. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the newest class of oral medications that work by reducing reabsorption of filtered glucose by the kidney and increasing urinary glucose excretion. Combination drug therapy can have additive effects.
All secretagogues allow the pancreas β-cells to secrete insulin in response to a glucose challenge. They are useful in patients with insulin deficiency.
Common side effects include hypoglycemia, weight gain, mild gastrointestinal complaints, and rarely skin reactions, photosensitivity, and cholestatic hepatitis. Most secretagogues are contraindicated in pregnancy. Secretagogues are used with caution in patients with liver disease. They also should be used with caution in renal disease (except for repaglinide and nateglinide which don’t have renal dosage requirements).
Each of the secretagogue classes works a little differently.
First- and Second-Generation Sulfonylureas
Sulfonylureas bind to sulfonylurea receptors on the β-cells, which stimulate insulin secretion or sensitize the β-cells to the presence of glucose. Second-generation sulfonylureas are more commonly prescribed than first-generation and have fewer side effects. A1C can decrease by as much as 1.25% with sulfonylureas (Sherifali et al, 2010). Most patients begin with a low dose of sulfonylurea and increase them at 1 – 2 week intervals depending on the self-monitored glucose readings and A1C results. Once daily preparations are available and are more convenient to patients.
As type 2 diabetes progresses, β-cells secrete less and less insulin and thus sulfonylureas will not be able to optimize glucose levels by themselves. Most clinicians do not discontinue them, but rather add insulin sensitizers.
Meglitinides are a class of rapid-acting, short duration insulin secretagogues. The only drug of this class approved in the United States is repaglinide. A1C lowering is typically less compared to sulfonylureas. Repaglinide is taken before each meal and with any bedtime snacks. This class allows patients the flexibility to skip a dose if they skip a meal thus preventing hypoglycemia. Unfortunately, the patient has to take it several times a day for effectiveness. It is not contraindicated in renal insufficiency.
D-Phenylalanine derivatives are faster acting and shorter duration secretagogues than the meglitinides (rapaglinide). Nateglinide is the only member of this class. It can also be used in patients with renal insufficiency. Both nateglinide and rapaglinide can be useful in patients who are found to have optimal fasting glucose levels but high post-prandial glucose levels. Again, patients have to take it several times a day which is a drawback.
The Insulin Sensitizers
Both classes of insulin sensitizers, biguanides and thiazolidinediones, are considered possible therapies to delay type 2 diabetes in patients with insulin resistance, glucose intolerance (prediabetes). These drugs are used in patients with polycystic ovarian syndrome which carries a component of insulin resistance.
Biguanides decrease gluconeogenesis from the liver, increase glucose uptake in muscle tissues, enhance the basal metabolic rate, and may lower food intake because of their gastrointestinal side effects. They do not stimulate insulin secretion from the pancreas. The exact mechanism of action is complex and not well understood, but the medication is often broadly referred to as an insulin sensitizer.
The only biguanide available in the United States is metformin. This is one of the diabetes drugs with which we have the most experience and is available in generic form at low cost. It can reduce the A1C by ~1% and fasting glucose levels by 60 mg/dL (Sherifali et al, 2010). Metformin can decrease or stabilize patient weight, can reduce cholesterol and triglyceride levels, and may reduce myocardial infarction risk.
Metformin should be titrated slowly because GI tolerability of the medication occurs over time. A 500 mg dose started at dinner is recommended and an additional dose can be added to breakfast after a week. There are higher dose tablets and extended release forms available. Current data shows that it is most clinically effective at a dose of 2000 mg/day.
Care must be used in those with liver disease, active pulmonary or cardiac disease. Guidelines suggest using metformin with caution when the estimated GFR dips below 60 mL/minute, and not at all when eGFR dips below 30. These guidelines are based on case reports of lactic acidosis, particularly in the context of acute kidney injury, hypoxemia, sepsis, alcohol abuse, liver failure, myocardial infarction, and shock. However, there is growing evidence that benefit outweighs the mostly theoretical risk of lactic acidosis with mild to moderate impaired renal function (eGFR 30-60mL/min; Ekstrom et al, 2012; Lipska et al, 2011; Lu et al, 2013; Rocha et al, 2013). There is also a growing recognition that the longstanding concern for lactic acidosis is based on a side effect of a medication in the same family that is no longer on the market (phenformin; Lalau, 2010). It should be withheld prior to any radiology study requiring contrast dye or if going to surgery, and restored once renal function has returned to normal. Metformin is a category B drug (no evidence of risk in humans) in pregnancy and breast feeding. Side effects can include flatulence, diarrhea, nausea, and a metallic taste. It may be associated with vitamin B12 deficiency.
Thiazolidinediones have an insulin sensitizing effect on the peroxisome proliferator-activated nuclear receptors in liver cells, adipose tissue, and muscle. The reduction of insulin resistance also reduces blood glucose levels. Two thiazolidinediones, pioglitazone and rosiglitazone (until recently, limited access), are approved for use in the United States.
Side effects include mild anemia, weight gain, or mild edema due to volume expansion. They can be used in patients with renal insufficiency. Liver function monitoring is recommended periodically while using these drugs, and they are contraindicated in people with liver disease who have an ALT > 2.5 times the upper limit of normal. They are contraindicated in pregnancy and may stimulate ovulation in insulin resistant anovulatory women. There may be increased fracture risk with this medication, so use with caution in patients with osteoporosis. Thiazolidinediones are contraindicated in patients with Class III or IV New York Heart Association functional status. There is a concern for a small but significant increased risk for bladder cancer in patients using pioglitazone.
From 2010 to 2014, Rosiglitazone was only available by mail order through specialty certified pharmacies participating in the Avandia-Rosiglitazone Medicines Access Program because of an increased risk of heart attacks seen in studies. Patients who are taking rosiglitazone, especially those who are known to have underlying heart disease or who are at high risk of heart attack, should talk to their primary care physician about this information as they evaluate the available treatment options for their type 2 diabetes. You are likely to find very few patients on your rotation who are using this medication at the present time. (Click here to see the original FDA warning and the November 2013 FDA update.)
The Incretin Enhancers
Dipeptidyl-4 (DPP-4) inhibitors
Dipeptidyl-4 (DPP-4) inhibitors inhibit the degradation of endogenous incretins which increases insulin secretion and decreases glucose-dependent glucagon secretion. There are four drugs approved in the United States in this class, all dosed once daily, which include alogliptin, linagliptin, saxagliptin, and sitagliptin. A1c lowering is ~0.75% with DPP-4 inhibitors (Sherifali et al, 2010). They are indicated for patients with insulin resistance.
DPP-4 inhibitors are well tolerated but associated with rare reports of pancreatitis. They are weight neutral and associated with a low risk of hypoglycemia. Renal dosing adjustments are required for medications in this class except linagliptin.
Carbohydrate Absorption Delay Agents
Alpha-glucosidase inhibitors delay disaccharide and complex carbohydrate absorption in the small intestine and allow it to occur instead in the large intestine and colon. This mechanism allows improvement of glucose control. It does not have the same delay effect on lactose.
This class is excellent for patients with high 2-hour post meal hyperglycemia, and can be used in people with both insulin resistance and deficiency. They must be used with each meal to be effective. They reduce A1C by ~1% (Sherifali et al, 2010). Two α-glucosidase drugs are approved for use in the United States: acarbose and miglitol.
The side effects include diarrhea and flatulence. The drug should be titrated slowly to prevent these side effects. Alpha-glucosidase inhibitors may cause reversible liver enzyme elevation. It is contraindicated in patients with liver disease, renal insufficiency and inflammatory bowel disease. It does not cause hypoglycemia by itself, but if hypoglycemia develops in conjunction with sulfonylureas or insulin, the patient may use milk to raise the glucose level.
Sodium-glucose Co-transporter 2 (SGLT2) Inhibitors
These agents inhibit sodium-glucose co-transporter 2 (SGLT2) in the kidneys, leading to decreased reabsorption of glucose, and increased excretion of glucose in urine. Estimated A1C lowering ranges from 0.7% – 1%. There are currently two approved drugs in this class: canagliflozosin and dapafliflozin. They are indicated for patients with insulin resistance.
The first agent in this class was approved in 2013, so safety data is limited. This class may cause slight weight loss but may increase LDL. Clinical trials have noted increased risk of genital fungal infections, increased urinary tract infections, and hypotension. There may be an association with an increased risk of bladder cancer (dapagliflozin) and increased risk of stroke (canagliflozin). Renal dosing adjustments are required. SGLT2 inhibitors can be used as part of dual or triple therapy after other second-line therapies are tried; however, more information is needed on the adverse effect profile of this class of medications.
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