Q. There are so many medications to help lower blood sugars. Can you describe them each in detail?
A. The majority of people that are newly diagnosed with elevated blood sugars will be started with medications along with lifestyle modifications to bring the blood sugar down. Some may be able to attempt changes to diet choices and exercise alone but most will start with monotherapy (one single medication). Monotherapy can generally lower A1C by 0.5% to 1.5%. Not surprisingly, the higher your baseline A1C, the more of a reduction can be seen with each anti-diabetic medication. You will most likely see results quickly but it may take 3 to 6 months to see maximum blood sugar lowering effects from non-insulin monotherapy medications. If your A1C is at extreme high levels, your health care provider may start with dual therapy right off the bat. Let’s discuss the various single agent medications.
Biguanides: Metformin is the only medication in this class and is the most likely first-line medication prescribed to help lower your blood sugar. It works by decreasing the amount of glucose that is produced in your liver and then released into your bloodstream. It also makes your skeletal muscle tissue more sensitive to insulin thereby, more able to absorb the glucose to use as energy.
The most common side effects associated with metformin are nausea, diarrhea and stomach upset. To overcome this, we recommend taking metformin with food and starting on a lower dose (250mg to 500mg daily) and gradually, as tolerated, increase the dose to therapeutic effectiveness. Most people’s increase will require the maximum dose of 1000mg twice daily. Other common side effects are a metallic taste in mouth and vitamin B12 deficiency over time. For those people that also suffer from kidney or liver disease, there is a risk of lactic acidosis which is a condition caused by a build up of lactic acid in the bloodstream. This occurs when oxygen levels are quite low in specific areas where metabolism takes place or in the case of sympathetic overactivity due to exercise. This results in muscle aches, burning, breathing rapidly, nausea and abdominal discomfort. Metformin is not associated with any weight gain and has actually been known to modestly assist in weight loss. Due to the risk of lactic acidosis, metformin is contraindicated if you have any liver or severe kidney impairment or a previous lactic acidosis episode.
Alpha-glucosidase inhibitors: Acarbose (Prandase) is the sole medication in this class. It is not prescribed very much these days. As is the case with metformin, it is suggested to start low and increase the dose as tolerated. Flatulence (gas), diarrhea, nausea and abdominal discomfort are the most commonly reported side effects. It can help improve other anti-diabetic medications but has been known to reduce metformin. It is contraindicated in irritable bowel syndrome and inflammatory bowel disease.
Dipeptidyl Peptidase-4 Inhibitors (DDP4I): There are four medications within this class; alogliptin (Nesina), linagliptin (Trajenta), saxagliptin (Onglyza) and sitagliptin (Januvia). All of them may be taken with or without food and all have similar side effects including nasopharyngitis (inflammation of nasal passages and pharynx), hypersensitivity reactions, pancreatitis (rare) and severe joint pain (rare). Alogliptin and sitagliptin have low potential for drug interactions however both linagliptin and saxagliptin have the potential to have their clearance affected by other medications. Saxagliptin is the only one of this class that is contraindicated in people with heart failure.
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1): There are four medications within this class; dulaglutide (Trulicity), liraglutide (Victoza), lixisenatide (Adlyxine) and semaglutide (Ozempic, Rybelsus). Dulaglutide and liraglutide were commonly prescribed until Ozempic came along. All of these medications are given by injection subcutaneously (under the skin) with the exception of Rybelsus which is taken orally. Many are nervous about injections and would much prefer to take a medication orally but the oral version is not nearly as effective as the injectable counterparts. Sorry, but you are best to give yourself an injection if you are to be prescribed a GLP-1. You can do it!
All have the propensity to cause nausea, vomiting, diarrhea, skin reaction at injection site (except Rybelsus of course) and rarely acute pancreatitis. Weight loss is a welcome side effect associated with this class of medications which helped gain the popularity of Trulicity and Victoza. However, the improved effectiveness of weight reduction and the reduction of A1C seen with Ozempic has resulted in their reduced popularity. GLP-1’s stimulate insulin secretion and inhibits glucagon from entering the bloodstream. They also slow down stomach emptying which results in less glucose entering the bloodstream from your food. This action also may reduce the rate of absorption of some oral medications. All GLP-1’s should be used with caution in patients with heart rhythm disturbances and severe renal impairment. They are all contraindicated in pregnancy and also if you have a personal or a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.
Insulin secretagogues, sulfonylureas: This class includes gliclazide (Diamicron) and glyburide (Diabeta) and work by stimulating insulin secretion from the pancreas. Some people that have been living with diabetes for decades may be familiar with these medications. With the advent of much improved anti-diabetic medications, this class has fallen out of favour by prescribers. They have a tendency to cause prolonged low blood sugar (hypoglycemia) which can be aggravated by salicylates, sulfonamides and monoamine oxidase inhibitors. The hypoglycemic reaction may go unnoticed if you are also on a beta-blocker, a common heart medication. Hypoglycemia appears to be greater with glyburide, especially in the elderly or those individuals with renal impairment. These medications may also cause weight gain which is counterintuitive for most people living with diabetes.
Insulin Secretagogues, meglitinides: Regaglinide (GlucoNorm) is the sole medication in this class. It is similar to the sulfonylureas in that they stimulate insulin secretion from the pancreas and is also associated with weight gain. It too may cause hypoglycemia especially if it is taken on an empty stomach.
Sodium-Glucose Cotransporter 2 Inhibitors (SGLT): This class includes canagliflozin (Invokana), dapagliflozin (Forxiga) and empagliflozin (Jardiance) and work by reducing renal tubular glucose reabsorption which results in lower blood glucose. In other words, you rid of the excess glucose in your blood by excreting it through your urine. The higher concentration of sugar in the urine predisposes you to genitourinary infections and yeast infections. There is also an increased risk of hyptotension (low blood pressure) especially if you are on a loop diuretic such as furosemide, hyperkalemia (high potassium) and risk of diabetic ketoacidosis. All of the SGLT’s are less effective in moderate and ineffective in severe renal impairment.
Thiazolidinediones (TZDs): This class includes pioglitazone (Actos) and rosiglitazone (Avandia). These were widely prescribed anti-diabetic medications many years ago but with the evolving and more efficient choices available, the TZDs do not get much attention anymore. The side effects which likely led to its demise are weight gain, fluid retention, worsening heart failure, increased risk of fractures, macular degeneration and possible bladder cancer.
Hopefully, this explains the many choices that are available to add to your lifestyle choices to help get your blood sugars down to an appropriate level. In summary, treatment is usually started with a single agent (monotherapy) and given 3 to 6 months to reach maximum effect. If the blood sugars are extremely elevated, a second medication may be added sooner. Despite being on the market for several decades, metformin has remained highly effective and continues to be a first-line therapy unlike many others that have dwindled out of use. Because the various classes of medications have differing mechanisms of action, many can be added on to current treatment to further assist lowering the blood glucose. Stay tuned next week as we discuss combination therapy and insulins.
For more information on this or any other health topic, contact your pharmacist.