Editor's Note: Please see the associated Expert Analysis on the same topic here.
A 82-year-old male with hypertension, type 2 diabetes, coronary artery disease, chronic kidney disease stage 3 and a prior stroke comes to your office complaining of dizziness, palpitations and confusion occurring every morning for the past week. The symptoms are not related to exertion and resolve after eating breakfast. The patient lives at home and completes his acts of daily living independently, but his family notes memory problems recently. The patient was recently discharged from the hospital where he was treated for a urinary tract infection and urinary retention complicated by acute kidney injury. Due to his worsening kidney function, he was discharged with instructions to stop metformin and begin taking glyburide to manage his diabetes. The patient's finger stick blood glucose in your office was 48. Subsequent lab tests show elevated creatinine with and estimated GFR of 40 and a hemoglobin a1c of 7%.
Regarding optimal medical management of this patient's diabetes, which of the following statements is true?
The correct answer is: C. Metformin can be continued in patients tolerating the drug who experience a new drop in GFR, provided GFR remains above 30.
Answer A is false. Low a1c targets did not reduce risk of macrovascular complications in VADT (Veterans Affairs Diabetes Trial), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) and ACCORD (Action to Control Cardiovascular Risk in Diabetes).1-3 In fact, strict a1c targets put patients at higher risk of hypoglycemia, which was associated with significantly higher adjusted risk of major cardiovascular events, according to secondary analysis of ADVANCE data.4
Answer B is false. The American Geriatrics Society recommends a goal a1c of 7.5-8% in older patients with moderate comorbidities and life expectancy less than 10 years;5 the American Diabetes Association recommends a more relaxed goal of 8-8.5% for older patients with complex medical issues.6
Answer C is true and is the correct answer. Current US Food and Drug Administration guidelines contraindicate metformin at GFR <30, and do not recommend initiating the drug at GFR between 30-45.7 For patients tolerating the drug who experience a drop in GFR, new guidelines state reduced renal dosing is a safe option,8 provided their new GFR is >30.
Answer D is false. Although oral dipeptidyl peptidase 4 inhibitors have few side effects and low risk of hypoglycemia, a systemic review found these medications do not decrease risk of major cardiovascular events.9
Overview: According to US Veterans Affairs data, risk factors for hypoglycemia are present in as many as 50% of older patients being treated for diabetes. Risk factors for hypoglycemia include advanced age, renal impairment, memory problems and sulfonylurea use. Tight glycemic control increases risk of hypoglycemia, which puts patients at risk for adverse cardiovascular events. Unlike sulfonylureas, metformin is not associated with increased risk of hypoglycemia, and can be continued in patients with GFR >30. In this patient, continuing metformin to achieve a more lenient a1c goal of 7.5-8.5% is an optimal treatment strategy for mitigating his risk of an adverse cardiovascular event.
Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veteerans with type 2 diabetes. N Engl J Med 2009;360:129-39.
ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;328:2560-72.
Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410-8.
American Geriatrics Society Expert Panel on Care of Older Adults with Diabetes Mellitus, Moreno G, Mangione CM, Kimbro L, Vaisberg E. Guidelines abstracted from the American Geriatrics Society guidelines for improving the care of older adults with diabetes mellitus: 2013 update. J Am Geriatr Soc2013;61:2020-6.
American Diabetes Association. Improving care and promoting health in populations: standards of medical care in diabetes - 2018. Diabetes Care 2018;41:S7-12.
Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431-7.
Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014;312:2668-75.
Rotz M, Ganetsky VS, Sen S, Thomas TF. Implications of incretin-based therapies on cardiovascular disease. Int J Clin Pract 2015;69:531-49.