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A Review of Oral Antihyperglycemic Therapies for Type 2 Diabetes

An increased understanding of the deleterious effects of hyperglycemia on tissue repair, with or without the addition of medications, may help patients begin to make better lifestyle choices and become more positively engaged in their own care. This author focuses on what you need to know about the oral agents used to treat patients with elevation of blood glucose.

Despite the availability of many types of oral antihyperglycemic therapies, patients and prescribers should appreciate that lifestyle modification is the cornerstone of all strategies employed in treating patients with insulin resistance or type 2 diabetes (with or without wounds). While it is helpful to appreciate why glucose elevation is “bad,” it is equally important to understand the other variables which negatively affect wound healing: hyperlipidemia, smoking, and hypertension, for example.

Type 2 diabetes continues to play a major role in the development of and delay in healing acute and chronic wounds. Not uncommonly, patients present to clinics, emergency rooms, and hospitals with nonhealing wounds and are found to have prediabetes (insulin resistance) or are diagnosed with type 2 diabetes. Prediabetes is diagnosed by a single fasting blood glucose level of 100–125 mg/dL or a hemoglobin A1c of 5.7–6.4%. A diagnosis of type 2 diabetes can be made by two separate findings of fasting plasma glucose of ≥ 125 mg/dL or A1c of ≥ 6.5%. Because glucometers and devices that measure A1c are universally available, not only is it possible now to optimize the management of a patient’s wounds, but wound care providers who are licensed to prescribe antihyperglycemic medications can and should consider initiating treatment for either of these conditions.

Due to many factors, COVID-19 notwithstanding, patients may be unable to establish primary care otherwise in a timely manner. Therefore, the importance of initiating treatment for prediabetes or type 2 diabetes with the biguanide, glucophage, or an insulin secretagogue, when indicated, cannot be overstated.  

In humans, hemoglobin, found inside the red blood cell, is used to deliver oxygen to tissues. Hemoglobin is naturally bound to monosaccharide sugars (galactose, fructose, and glucose) through a process called glycation. The laboratory test we know as the A1c measures the amount of glycated hemoglobin in the blood. “Normal” levels of blood sugar produce a “normal” amount of glycated hemoglobin, which is 3.5–6% depending on the laboratory testing method utilized. Higher blood glucose levels predictably lead to higher levels of irreversibly glycated hemoglobin molecules within the red blood cell. Ultimately, a higher than normal A1c negatively affects a variety of downstream metabolic events, leading to proportionately impaired delivery of oxygen to the body’s tissues.

Thus, simply put, tissue repair and regeneration (wound healing) is negatively affected by elevations of A1c because of the impaired delivery of oxygen. The good news is that improved blood sugar control can begin to improve the A1c in as little as 20 days. Clinicians in wound management therefore have another opportunity, when indicated, to optimize wound healing by initiating antihyperglycemic medications sooner than later.

All oral antihyperglycemic medications lower blood glucose levels and ultimately lower the amount of glycated hemoglobin in the blood. Historically, lowering hepatic production of glucose was the pathway most of these medications targeted. More recently, novel medications have been developed that target newly identified sites within the pathways of insulin and glucose metabolism. These include: enhanced activity of the patient’s own insulin (increasing production of and decreasing insulin degradation); enhancing intracellular enzymatic processing of glucose utilization in skeletal muscle, adipose tissue, and enzymes within the gastrointestinal tract; and increasing the secretion and excretion of glucose through the kidneys.  

Biguanides

Metformin (Glucophage, Bristol-Myers Squibb). Metformin is the most widely used oral antihyperglycemic medication. It is the only one of its biguanide class that is still available for use. It works by decreasing the hepatic gluconeogenesis and glycogenolysis. Initiation of monotherapy with metformin is recommended for someone who is found to have insulin resistance or type 2 diabetes. At maximal dosing metformin can lower the A1c by 1–2%. Metformin has superior or equivalent efficacy of lower glucose concentrations compared to other oral agents. Not only has it been found to decrease microvascular complications of type 2 diabetes, but more limited data indicates it has a positive benefit on macrovascular disease as well.1  

Metformin is generally well tolerated when initiated but it can cause symptoms of diarrhea, gas, and nausea. However, starting with the low dose of 250–500 mg taken at night and/or administration with a meal decreases these potential occurrences. It rarely causes hypoglycemia, is inexpensive, is not associated with weight gain, and has a beneficial effect on low density lipoproteins (LDL). Although metformin works in the liver, it is excreted through the kidneys and is contraindicated in patients who have a glomerular filtration rate (GFR) less than 30 mL/min. For patients who are already taking metformin and whose GFR falls to within 30–45 mL/min, metformin can be continued but close monitoring and a dose reduction is advised. Metformin should be stopped prior to surgery or administration of contrast dye until post-event renal function can be assessed. It is contraindicated in patients who require renal replacement therapy (hemodialysis or peritoneal dialysis).

Dipeptidyl peptidase-4 inhibitors (DPP4-I). This class of medications has really improved diabetes management. Not since the development of metformin has there been as much improvement in diabetes control with the addition of a single agent. DPP4-I medications exert their effect by ultimately increasing glucose-mediated insulin secretion and suppressing glucagon secretion. They also have a positive effect in lowering hemoglobin A1c levels up to 0.6–0.9%.

Listed below are the four drugs in this class that are currently available in the United States. They are all very well tolerated and have a few side effects. They can be used with other oral therapies and insulin but they should not be used with other agents that affect the same pathway. Linagliptin does not require dose reduction in patients with renal impairment.
Sitagliptin (Januvia, Merck) 25–100 mg po daily
Saxagliptin (Onglyza, AstraZeneca) 2.5–5 mg po daily
Linagliptin (Tradjenta, Boehringer Ingelheim) 5 mg po daily;  
Alogliptin (Nesina, Takeda) 6.35–25 mg po daily

Sulfonylureas

Sulfonylureas are insulin secretagogues and are often started as initial monotherapy when treatment is indicated. They increase the production of insulin through a mechanism that involves binding to potassium channels on the beta cells within the pancreas. They are universally available, usually well tolerated, rarely cause hypoglycemia, are inexpensive, and are also not associated with weight gain. Although the sulfonylurea medications are generally not associated with hypoglycemia, hypoglycemia has been observed to occur in elderly patients who have missed meals; used alcohol; had worsening renal or cardiac function; and had concurrent use of salicylates, sulfonamides, fibric acid derivatives, and warfarin.  

Glipizide (Glucotrol, Pfizer). Glipizide is a short-acting sulfonylurea. A typical starting dose of glipizide, especially for an elderly patient, is 2.5 mg taken 30 minutes prior to breakfast or their first meal of the day. In the non-geriatric population, dosages can be increased to 10–20 mg/day once or twice daily. A dose of 40 mg daily should be divided into AM and PM dosing times. For patients on higher dosages and who develop a glomerular filtration rate (GFR) less than 50%, the dose should be decreased by 50%. Glipizide use should be avoided in patients who require renal replacement therapy. For patients who have hepatic impairment, a starting dose of 2.5 mg daily is recommended.  

Glimepiride (Amaryl, Sanofi). The usual starting dose of glimepiride is 1 mg po daily and can be gradually increased every 2 weeks to a total of 8 mg as a daily dose. It can be given to patients requiring renal replacement therapy at a lower dose. Either is useful for initial and monotherapy in patients who are not candidates for metformin. Glimepiride is not recommended to be used during pregnancy or during breastfeeding.

Glyburide (DiaBeta, Sanofi). Glyburide is a long-acting sulfonylurea. It is not a good choice to start someone on if they have irregular meal patterns or are prone to skipping meals as geriatric patients are prone to do. Otherwise a daily starting dose of 2.5–5 mg daily, given with the first meal of the day is appropriate. Weekly increases of 1.25–2.5 mg dosing may be employed up to 10 mg/day. It can be used during pregnancy but is not recommended for use during breastfeeding.

Non-Sulfonylureas

As with sulfonylureas, this class of insulin secretagogues increases pancreatic beta cell insulin production through alteration of potassium channels. They are very short acting and useful for multiple pre-prandial dosing regimens. They are often displaced by other protein-bound medications such as beta-blockers and nonsteroidal anti-inflammatory drugs (NSAIDs); and medications such as itraconazole, trimethoprim, simvastatin, and clarithromycin can significantly alter its metabolism. These are generally more expensive than the sulfonylureas.

Repaglinide (Prandin, Novo Nordisk). Repaglinide can be used as initial oral therapy starting with 0.5 mg TID dosing if the A1c is less than 8% or if the GFR is 20–40 mL/min. The starting dose can be 1–2 mg prior to meals TID if the A1c is over 8%. The dose can be skipped if a meal is skipped. The maximum dose per day is 16 mg. Its use is discouraged during pregnancy or when breastfeeding.

Nateglinide (Starlix, Novartis). Nateglinide is used as monotherapy and in combination with other oral agents. The starting dose is usually 120 mg po TID 30 minutes prior to meals. If the A1c is close to goal, it can be started at 60 mg po tid prior to meals. If should be skipped if meals are skipped. Its cost usually precludes its use.

Thiazolidinediones

This class of antihyperglycemic medications works inside the cell nucleus of primarily adipose cells and to a lesser extent in cardiac, skeletal, and smooth muscle cells, islet beta cells, macrophages, and vascular endothelial cells. This intranuclear activity in adipose cells ultimately promotes uptake of circulating fatty acids and shifts lipid stores from extra-adipose sites to adipose tissue. Consequent to this action, there is 30%–50% increased insulin mediated glucose uptake (cells are more sensitive to insulin) in muscle and adipose tissues. Hence this class is often referred to as “insulin sensitizers.” There is also a positive benefit on lipid metabolism as triglyceride storage is shifted from non-adipose tissue to adipose tissues and from visceral to subcutaneous fat depots.

However, thiazolidinediones can cause or exacerbate congestive heart failure (CHF), cause rapid weight gain, and cause edema. Thiazolidinediones are contraindicated in patients with New York Heart Association (NYHA) Class III–IV CHF and not recommended for any symptomatic CHF. Currently there are 2 medications in this class available in the United States. They are used in combination with other oral antihyperglycemic agents and they are expensive.
Piaglitazone (Actos, Takeda). This reduces plasma triglycerides by 10–15%, raises high density lipoprotein (HDL) cholesterol levels and increases LDL cholesterol.

Rosiglitazone (Avandia, GlaxoSmithKline). This does not have the same effect on triglycerides and HDL but does increase LDL cholesterol. Patients who have reproductive potential should use effective contraception if pregnancy is not desired due to possible ovulation induction.

Alpha Glucosidase Inhibitors  

This class of medications reduces the intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of alpha glucosidase, an enzyme found within the lining of the intestines. Alpha glucosidase inhibitors also increase the secretion of other regulatory hormones from within the digestive tract, which may contribute to their antihyperglycemic effect.  

Acarbose (Precose, Bayer) and Miglitol (Glyset, Pfizer). Each of these medications works similarly, is available in the same strengths of 25, 50, and 100 mg, and is taken prior to meals. Understandably, the most common side effects are GI related and include excessive gas; bloating and diarrhea. Acarbose and miglitol can cause mild elevations of hepatic enzymes but are rarely associated with any liver injury. Cutaneous hypersensitivity reactions have been described but are also rare. They can interfere with absorption of other medications such as propranolol and digoxin; therefore, caution is advised. They are contraindicated in stage 4 renal insufficiency because they are cleared through the kidneys.

Sodium-Glucose Transporter 2 (SGLT2) Inhibitors

This class of medication exerts its effect of lowering serum glucose levels by increasing the glucose excretion in the kidneys. Normally any glucose contained in the urine filtrate is completely removed by and reclaimed by enzymes within the renal tubules. The SGLT2 enzyme complex accounts for 80–90% of this recovery. Inhibition of this process increases renal excretion of glucose. SGLT2 inhibitors can be used as initial once daily monotherapy and as such do not cause hypoglycemia. They are maximally effective 2 hours after dosing and are not affected if taken with food. They are frequently used in combination with other antihyperglycemic agents, which does increase the risk of the development of hypoglycemia.  

While the beneficial effects of these medications include A1c reduction by up to 1%, weight loss, and decreased blood pressure, there have been concerns about other possible negative effects. Because of their mechanism of action, there is an increased risk of development of urinary tract infections. Additionally, the elevation of glucose in the urine can stimulate a mild diuresis, which may cause hypotension; thus, caution is advised when used in elderly patients or those on other medications for hypotension. There is preliminary evidence that suggests mineral balance may be negatively affected through the vitamin D parathyroid hormone pathway, but at this time the evidence is inconclusive. Additionally, there have been rare cases of diabetic ketoacidosis associated with SGLT2 use. In phase 3 trials there was no evidence that these drugs had adverse effects on cardiovascular disease and data from other controlled trials found reduction in major cardiovascular events.1 Listed below are the three available drugs in this class, available dosage strengths, and individual drug considerations.  

Dapagliflozin (Farxiga, AstraZeneca). This is available in 5 and 10 mg.

Canagliflozin (Invokana, Janssen Pharmaceutica). This is available in 100 and 300 mg and associated with major cardiovascular event risk reduction. Although counterintuitive, canagliflozin has been associated with an increased risk of lower extremity amputations.

Empagliflozin (Jardiance, Boehringer Ingelheim/Lilly). This is available in 10 and 25 mg and is associated with major cardiovascular event risk reduction.

In Summary

There are numerous oral antihyperglycemic first line agents that have favorable benefit/risk ratios. Several of those reviewed do require that patients are monitored biochemically with a basic metabolic or complete metabolic panel at least every 3 months. If you are a provider, able to initiate basic antihyperglycemic medications and decide to do so, establishing that the patient can tolerate the new medication is fundamental. Beginning with 250–500 mg metformin po daily with food or at night is a very reasonable starting place. It can be titrated weekly up to 1,000 mg bid if needed. Patients should monitor fasting glucose levels for a goal of less than 100–115 mg/dL or an A1c less than 6%. The addition of other medications such as the DPP4 inhibitors is safe, reasonable and usually well tolerated.

Due to many factors, COVID-19 notwithstanding, patients may otherwise be unable to establish primary care in a timely manner. Clinicians in wound management have yet another opportunity, when indicated, to optimize wound healing by initiating antihyperglycemic medications sooner than later. The importance of initiating treatment for prediabetes or type 2 diabetes with one of the first line oral therapies, when indicated, cannot be overstated. Getting patients on the right track with diabetes control will jumpstart their ability to heal wounds.

Harriet Jones, MD, FACP, practices at the Internal Medicine Group of St. Dominic’s Hospital in Jackson, MS.    


 

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Harriet Jones, MD, FACP
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References

1. Brunton L, Hilal-Dandan R, Knollmann BC, et al. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 13th Edition. McGraw-Hill Education, 2018.
2. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017; 40(Suppl 1):S64–S74.
3. Qaseem A, Barry MJ, Humphrey LL, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017; 166(4):279–90.
4. Maruthur NM, Tseng E, Hutfless S, et al. Dia-betes medications as monotherapy or metformin based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016; 164(11):740–51.

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