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What is the best way to treat a diabetic patient who has a metformin intolerance? Test your knowledge of alternative monotherapies, including SGLT2 inhibitors, GLP-1 agonists, and sulfonylureas.
How does your knowledge of metformin and alternative monotherapies, including SGLT2 inhibitors, GLP-1 receptor agonists, and sulfonylureas stack up? Take the following quiz to find out. 1.Fill in the blank: Up to ___ of patients develop gastrointestinal side effects related to metformin therapy, and about ____ of patients have GI side effects severe enough to cause treatment discontinuation.A. 15%, 1%B. 20%, 2%C. 25%, 3%D. 30%, 5%
Answer: D. 30%, 5%
Up to 30% of patients on metformin may experience gastrointestinal side effects, including nausea, diarrhea, vomiting, bloating, and abdominal pain. For the majority of patients, these symptoms improve after the initial titration period. About 5% of patients on metformin, however, may develop GI side effects that are severe enough to cause treatment discontinuation. Too rapid escalation of dosage may worsen these symptoms, though supporting evidence is lacking. Taking metformin after a meal can help alleviate symptoms.1
Contraindications to metformin use include all of the following, except:
Renal disease or renal dysfunction
Congestive heart failure
Acute or chronic metabolic acidosis
All of the above
Answer: E. All of the above
The FDA labeling states that metformin is contraindicated in patients with renal disease or dysfunction and suggests that women with serum creatinine >1.4 mg/dL and men with serum creatinine >1.5 mg/dL should not receive the drug. Metformin is also contraindicated in patients with acute renal injury, such as that resulting from myocardial infarction, septicemia, and shock. Patients who are on medication for congestive heart failure and with known hypersensitivity to metformin should also not receive the drug. Finally, patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, should not receive the drug. Metformin carries a black box warning because it can increase the risk for lactic acidosis, which can be fatal in up to 50% of cases.2
Which of the following are recommended by the American Association of Clinical Endocrinologists as monotherapy for treating type 2 diabetes (T2DM) when metformin cannot be used?
A and B
Answer: D. A and B
Recommendations vary about which agents to use as monotherapy when metformin cannot be used. The American Association of Clinical Endocrinologists (AACE) recommends GLP-1 agonists, DPP-4 inhibitors, and alpha-glucosidase inhibitors as alternatives to metformin. Due to adverse effects, the AACE advises caution when using thiazolidinediones, sulfonylureas, and meglinitides.3 On the other hand, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) recommends a sulonylurea, meglinitide, pioglitazone, or a DPP-4 inhibitor in lieu of metformin monotherapy, as well as a GLP-1 inhibitor when weight loss is desirable.4 Finally, the International Diabetes Federation recommends a sulfonylurea, meglinitide, or glucosidase inhibitor when metformin cannot be used.5
Advantages of using SGLT2 inhibitors as monotherapy include all of the following, except:
Significant reductions in HbA1c
Appropriate alternative for patients who cannot take metformin due to renal dysfunction
Low risk of hypoglycemia
Once daily oral administration
Answer: B. Appropriate alternative for patients who cannot take metformin due to renal dysfunction
Studies have suggested that monotherapy with SGLT2 inhibitors can significantly improve HbA1c. In a randomized, double-blind, placebo-controlled, phase 3 trial, participants on canagliflozin (cana) 100 and 300 mg once daily experienced significant reductions from baseline compared with placebo (-0.77%, -1.03%, 0.14%, respectively; P<0.001). Reductions were even greater among participants with baseline HbA1c 10.6% or higher (cana 100 mg:-2.13% and cana 300 mg: 2.56%).6 Due to their insulin-independent mechanism, SGLT2 inhibitors also carry low risk of hypoglycemia. Once daily oral administration may also be attractive to some patients. SGLT2 inhibitors act on the kidneys to reduce renal reabsorption of glucose, and their use is not recommended in patients with significant renal impairment (eGFR <60 mL/min per 1.73 m2). For this reason, SGLT2 inhibitors may not be the most appropriate alternative in patients for whom metformin is contraindicated due to renal dysfunction.
Which of the following is a drawback when choosing a sulfonylurea for monotherapy in lieu of metformin?
High risk for hypoglycemia
B and C
Answer: D. B and C
Sulfonylureas are used consistently as monotherapy, and have the advantage of low cost. The ADA/EASD recommends sulfonylureas as first-line in patients who cannot receive metformin, especially when cost is a concern.4 Sulfonylureas can be quite effective when used as monotherapy, reducing HbA1c by 1-2%, but these drugs can also result in progressive deterioration in glycemic control. In patients on sulfonylurea monotherapy, the A1c initially declines then increases after about 1.5 years, with about 34% of patients experiencing failure of monotherapy by 5 years. Sulfonylureas also carry a high risk for hypoglycemia and can result in weight gain of about 1-4 kg on average.7
Advantages of monotherapy with GLP-1 receptor agonists include:
Effective reduction in HbA1c
Beta cell preservation
All of the above
Answer: D. All of the above
GLP-1 receptor agonists used as monotherapy over 26 weeks have been shown to reduce HbA1c more than sitagliptin alone, and to have similar efficacy as metformin and pioglitazone therapy.8 Weight loss, low risk for hypoglycemia, and improved beta cell function are also advantages of GLP-1 therapy. Drawbacks include GI side effects, possible though unproven increased risk of pancreatitis, high cost, and the need for injections. The ADA/EASD recommends using GLP-1 agonists as monotherapy in patients who cannot tolerate metformin and for whom weight loss is desired.4
1. Bouchoucha M, et al. Metformin and digestive disorders. Diabetes Metab. 2011 Apr;37(2):90-96.
2. Food and Drug Administration. Metformin hydrochloride tablets. Accessed 1 July 2015 at http://www.fda.gov/ohrms/dockets/dailys/02/May02/053102/800471e6.pdf.
3. Garber AJ, et al. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement--executive summary. Endocr Pract. 2013 May-Jun;19(3):536-557.
4. Inzucchi SE, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012 Jun;55(6):1577-1596.
5. International Diabetes Federation. Global guideline for type 2 diabetes. Accessed 1 July 2015 at
6. StenlÃ¶f K, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013 Apr;15(4):372-382.
7. Irons BK, et al. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes Metab Syndr Obes. 2014 Jan 18;7:15-24.
8. Russell-Jones D, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012 Feb;35(2):252-258.