Is Combination Antihyperglycemic Therapy Superior to Monotherapy as an Initial Type 2 Diabetes Treatment?
Q. What is the rationale behind starting initial combination therapy in patients with type 2 diabetes?
A. Since type 2 diabetes is associated with multiple physiologic abnormalities, combination therapy may help address many of these concerns concomitantly so as to minimize side effects and provide rapid metabolic balance. Understanding the mechanisms of action of the differing agents will help the clinician choose the optimal regimen for any given patient.
Q. What are the most common oral hypoglycemic agents used in the initial therapy of type 2 diabetes?
A. The American Diabetes Association (ADA) recommends biguanides (eg, metformin in the United States), if not contraindicated, as the initial agent for treatment of type 2 diabetes.1 Metformin works by decreasing glucose production by the liver and increasing glucose uptake into the muscles. It can decrease hemoglobin A1c (HbA1c) values by 1.5% to 2%. It is contraindicated in patients with renal insufficiency (creatinine levels >1.4 mg/dL in females and >1.5 mg/dL in males).
Metformin does not cause hypoglycemia, but patients frequently experience nausea and diarrhea. Side effects can be minimized or avoided by starting the medication at a low dose and gradually increasing it, taking it with food, and/or using time-release formulations. Metformin is safe, inexpensive, and may reduce cardiovascular risks.
Other oral hypoglycemic agents that can be considered as first-line therapy include:
• Sulfonylureas. These are the most widely used antihyperglycemic medications. Some examples include glyburide, glipizide, and glimiperide. They can lower HbA1c by 1.5% to 2%. Side effects include hypoglycemia and weight gain.
• Meglitinides. These medications are taken with or shortly before meals to increase the insulin response to each meal. Examples include repaglinide and nateglinide. Typical reductions in HbA1c values are between 0.5% to 1%. Side effects include hypoglycemia and weight gain.
• Dipeptidyl peptidase-4 (DPP-4) inhibitors. These agents work by increasing the endogenous incretin glucagon-like peptide-1 (GLP-1), which increases meal-stimulated insulin release and decreases glucagon made by the pancreas. Examples are sitagliptin, linagliptin, saxagliptin, and alogliptin. They lower HbA1c by 0.5% to 1%. These drugs have not been found to cause weight gain or significant hypoglycemia.
• Thiazolidinediones (TZDs). These drugs work by decreasing glucose production by the liver and increasing glucose uptake into the muscles and fat. The 2 FDA-approved examples are pioglitazone and rosiglitazone. Typical reductions in HbA1c values are between 1.5% to 2%. They are not associated with hypoglycemia but can cause weight gain. Patients with advanced congestive heart failure should avoid these medications.
• Alpha-glucosidase inhibitors. These work by decreasing the digestion of starches in the small intestine so that glucose enters the bloodstream more slowly. The 2 FDA-approved drugs for use in the United States are acarbose and miglitol. They are usually used in combination with other agents and have a typical HbA1c reduction between 0.5% and 1%.
• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors. These newer agents work by blocking the reabsorption of glucose from the kidneys, thus promoting loss of glucose in the urine. The 3 FDA approved drugs are canagliflozin, dapagliflozin, and empaglifolzin. They can help with weight loss and cause mild reduction in blood sugar levels with little risk of hypoglycemia. The main side effects are urinary tract and genital mycotic infections.
• Colesevelam. This drug is actually a lipid-lowering medication, but it has been found to also lower blood sugars by an unknown mechanism.2 It is currently used in addition to other hypoglycemic agents (eg, metformin, sulfonylureas, and insulin) for the treatment of type 2 diabetes.
• Bromocriptine QR. This drug is usually used in the treatment of Parkinson’s disease but the QR formulation has been found to have beneficial glucose-lowering effects in type 2 diabetes.3 Given once a day in the morning, it resets the body’s circadian clock, decreasing blood sugar levels.
Q. What are the injectable non-insulin hypoglycemic agents?
A. There are 2 classes of injectable hypoglycemic agents available in the United States.
• GLP-1 receptor agonists. These agents work by increasing the blood concentration of the incretin GLP-1, which increases insulin release from the pancreas. The drugs that are available in the United States include twice-daily exenatide, daily liraglutide, once-weekly extended-release exenatide, albiglutide, and dulaglutide. They are associated with 0.5% to 1.5% reductions in HbA1c, weight loss, and low risk of hypoglycemia.
• Pramlintide. This is a derivative of a natural hormone called amylin, which is released by the pancreas after a meal to slow the emptying of the stomach. It helps keep after-meal glucose levels from rising too high and can suppress the appetite and cause weight loss.
Q. When should combination therapy be considered at the onset of treatment in type 2 diabetes?
A. The 2013 American Association of Clinical Endocrinologists algorithm recommends dual therapy if the initial HbA1c is ≥7.5% and progression to triple therapy if the goal is not achieved within 3 months.4 If the HbA1c is higher than 9.5% at the time of diagnosis, a combination therapy should be started or insulin therapy can be considered.5 Starting insulin as the initial therapy is strongly recommended by the ADA if the HbA1c is above 10%.1
Insulin can be used in combination with multiple oral hypoglycemic agents, such as metformin, DPP-4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, and also with injectable hypoglycemic agents (eg, GLP-1 receptor agonists and pramlintide). Insulin should be avoided in combination with sulfonylureas so as to minimize the risk of hypoglycemia.
Triple therapy combinations, such as metformin + sulfonylurea + thiazolidinediones, can be used in patients reluctant to start insulin but studies have shown that insulin-based therapy did not result in greater weight gain nor did it decrease patient satisfaction.6 The patients using the triple oral therapy experienced more adverse effects.
Q. Do some combination therapies work better than others?
A. A 2011 study compared the effectiveness of different combination therapies.7 Although metformin caused the greatest reduction in HbA1c levels when used in monotherapy, combination therapies reduced HbA1c levels even more. There was weak evidence suggesting that metformin plus GLP-1 agonists decrease the HbA1c levels more than metformin plus DPP-4 inhibitors. There were no significant differences between all the other combinations, such as metformin plus sulfonylureas or metformin plus thiazolidinediones. The combination of metformin and sulfonylurea had an increased risk of hypoglycemia and weight gain compared to metformin plus other hypoglycemics or sulfonylurea plus other hypoglycemics.
A 2014 systematic review of 15 randomized controlled trials looked at early combination therapy in type 2 diabetes patients with a mean baseline HbA1c between 7.2% and 9.9%.8 Drugs combined with metformin included thiazolidinediones, insulin secretagogues, as well as DPP-4 or SGLT-2 inhibitors. Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in HbA1c.
Karin Sterl, MD, is a clinical fellow in the division of endocrinology, metabolism, and lipid research at Washington University School of Medicine in St Louis, MO.
Kim A. Carmichael, MD, is an associate professor of medicine in the department of internal medicine, division of endocrinology, diabetes, and lipid research at Washington University School of Medicine in St Louis, MO.
References:
1.American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(1):S14-S80.
2.Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab. 2010;12(5):384-392.
3.Shivaprasad C, Kalra S. Bromocriptine in type 2 diabetes mellitus. Indian J Endocrinol Metab. 2011;15(Suppl 1):S17-S24.
4.Handelsman Y, Mechanick J, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(Suppl 2):1-53.
5.Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35(6):1364-1379.
6.Lingvay I, Legendre JL, Kaloyanova PF, et al. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes: which is better? Diabetes Care. 2009;
32(10):1789-1795.
7.Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613.
8.Phung OJ, Sobieraj DM, Engel SS, Rajpathak SN. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(5):410-417.