A 63-year-old Caucasian man presents to the outpatient cardiology clinic for a routine follow-up appointment. He has a history of hypertension, dyslipidemia and suffered a non ST segment myocardial infarction 2 years ago. The coronary angiogram at that time demonstrated diffuse coronary artery disease with an 80% stenosis of the proximal left circumflex artery identified as the culprit lesion. Primary percutaneous intervention was performed with placement of a drug eluting stent. Furthermore, non obstructive plaques (<40%) were visualized in the right coronary artery and left anterior descending coronary artery. Transthoracic echocardiography showed preserved left ventricular ejection fraction (57%) and the absence of significant valve disease. The patient reports no history of tobacco or illicit drug use, but drinks two glasses of beer on average each day. His family history is remarkable for type 2 diabetes and coronary artery disease in his father and elder brother. His current medications include aspirin, atorvastatin 80 mg OD, lisinopril 20 mg OD, metoprolol XL 50 mg OD and amlodipine.
The patient is single and works as a computer programmer. His lifestyle is sedentary. He admits not being engaged in any sports or physical activity during his leisure time and finds it difficult to adhere to a healthy diet. Upon evaluation in the clinic, he denies any complaints and the clinical examination is unremarkable. Blood pressure is 135/76 mmHg and heart rate 92 bpm. His length (181 cm) and weight (101.5 kg) yield a body mass index of 31 kg/m2. Laboratory results are notable for a glycated hemoglobin level of 8.1%, total and low density lipoprotein cholesterol of 163 mg/dL and 85 mg/dL, respectively, as well as a serum creatinine of 1.44 mg/dL corresponding to an estimated glomerular filtration rate (eGFR) of 51 mL/min/1.73m2 by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula.
Because of the new diagnosis of type 2 diabetes, fasting glucose is assessed and found to be elevated at 278 mg/dL. The albumin to creatinine ratio is 276 mg/g on a spot urinary sample. Eye examination shows early non proliferative diabetic retinopathy. The patient is very concerned about the diagnosis of type 2 diabetes as his father needed chronic ambulatory hemodialysis for end stage kidney disease when he was about the same age, which is a frightening prospect for the patient.
You discuss treatment options with the patient and propose to start metformin in addition to making healthy lifestyle recommendations. The patient is however reluctant to take metformin, as this medication made his brother feel sick all the time. He asks whether metformin gives him the best chance to prevent end stage kidney disease and recurrence of his heart problems.
The correct answer is: C. Risk reduction of heart failure hospitalizations with SGLT2 inhibitors is less pronounced in patients who do not have heart failure at baseline.
Answer options A and E are true. Metformin, because of its low cost and favorable safety profile with low risk of hypoglycemia episodes, is still endorsed as the first line agent in type 2 diabetes.1 However, it has not been studied through a randomized clinical trial. Yet, extended follow-up from patients treated with metformin in the United Kingdom Prospective Diabetes Study (UKPDS) indicates a 27% relative risk reduction in all-cause mortality over a cumulative follow up time of 20 years (p = 0.002).2 Furthermore, an all cause mortality benefit with metformin in type 2 diabetes is supported by abundant observational data, including a non-randomized prospective cohort study of 469,688 diabetes patients in primary care.3
The glucagon-like peptide-1 (GLP-1) agonist liraglutide was associated with a 15% reduction in all-cause mortality in the Liraglutide Effect and Action in Diabetes Evaluation of cardiovascular outcome Results (LEADER) trial (p = 0.02).4 This trial randomized 9340 patients with type 2 diabetes at high risk for cardiovascular events towards treatment with liraglutide versus placebo, administered through daily injections over a follow-up time of approximately 4 years. Kaplan-Meier curves for all cause mortality slowly diverged in favor of liraglutide after 18 months and continued to separate during the remainder of the trial. Other GLP-1 agonists including lixisenatide (HR, 95%CI = 0.94, 0.78-1.13) and semaglutide (HR, 95%CI = 1.05, 0.74-1.50) have not reproduced a reduced risk of all cause mortality in patients with type 2 diabetes.5,6 Exenatide was associated with a strong signal towards decreased mortality (HR, 95%CI = 0.86, 0.77-0.97) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).7 However, this finding was considered hypothesis-generating as the pre-specified primary outcome of EXSCEL, which was a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, failed to meet superiority.
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA REG OUTCOME) trial was the first randomized clinical trial showing a significant reduction in all-cause mortality with a glucose-lowering agent.8 In EMPA-REG OUTCOME, the SGLT2 inhibitor empagliflozin reduced all-cause mortality 32% over a follow-up time of only 3 years. Kaplan-Meier curves started to diverge within 1 month and continued to do so for the remainder of the trial. Patients in the EMPA-REG OUTCOME trial all had type 2 diabetes with established atherosclerotic disease and 75% had coronary artery disease. Canagliflozin, another SGLT2 inhibitor was studied in the Canagliflozin Cardiovascular Assessment Study (CANVAS) program including 10,142 patients.9 In CANVAS, patients in primary cardiovascular prevention were also recruited, resulting in a lower prevalence of coronary artery disease (56%) when compared to the EMPA-REG OUTCOME trial. Canagliflozin was associated with a non-significant trend towards lower all-cause mortality in the CANVAS program (HR, 95%CI = 0.87, 0.74-1.01).
Only injectable liraglutide and oral empagliflozin have thus demonstrated a survival benefit in patients with type 2 diabetes inside the context of an adequately powered, randomized, placebo-controlled trial.10 There is reasonable evidence that metformin use is also associated with a mortality benefit in type 2 diabetes. While the effect is slow and steady in the case of liraglutide and metformin, it seems to occur much sooner with empagliflozin, which also showed the largest effect size in its randomized clinical trial (EMPA-REG OUTCOME).
Answer option B is true. In a pre specified analysis of microvascular outcomes from the EMPA REG OUTCOME trial, the risk for renal replacement therapy was significantly reduced (HR, 95%CI = 0.45, 0.21-0.97).11 This corroborates with results of the CANVAS program showing a highly significant risk reduction for its renal end-point which was the composite of renal death, need for renal replacement therapy, or a 40% decrease in eGFR (HR, 95%CI = 0.60, 0.47-0.77).9 Although better glycemic control itself is clearly associated with a lower incidence of microvascular events and specifically diabetic nephropathy,12 the relatively modest reduction in glycated hemoglobin levels of approximately 0.5-0.6% seen with empagliflozin in the EMPA-REG OUTCOME trial and canagliflozin in the CANVAS program cannot completely account for the pronounced benefits observed. Indeed, specific nephroprotective effects have been attributed to SGLT2 inhibitors.13
Answer option D is true. SGLT2 inhibitors promote the tubulo glomerular feedback mechanism, thereby inducing vasoconstriction of the afferent arteriole.13 This reduces hydrostatic pressure inside the glomerular capillaries, counteracting glomerular hypertension and hence hyper filtration that is characteristically present in diabetic nephropathy and reflected by albuminuria. It has been demonstrated that when glomerular hyper filtration is present in diabetes, renal plasma flow and the glomerular filtration rate decrease after administration of empagliflozin.14 Because glomerular hypertension drives the loss of functional nephrons over time and thus the progression of chronic kidney disease, SGLT2 inhibitors have the potential to slow down the progress of diabetic nephropathy at the cost of an initial drop in the glomerular filtration rate. This pattern of eGFR evolution is exactly what has been observed in the EMPA-REG OUTCOME trial and very similar to what has been shown with renin-angiotensin system inhibitors that reduce glomerular hypertension through vasodilation of the efferent arteriole.11,15 The nephroprotective effects of both medication classes is reflected by their significant effect on proteinuria in type 2 diabetes. Indeed, the risk for progression towards macro albuminuria was reduced with 38% in the EMPA-REG OUTCOME trial (p<0.001)11 with comparable results observed in the CANVAS program.9
Answer option C is false. It has been demonstrated in the EMPA REG OUTCOME trial that empagliflozin reduces the risk of heart failure hospitalization and cardiovascular death, with a consistent benefit observed in patients with versus without baseline heart failure.16 Heart failure was present in 10.1% of patients included in the EMPA-REG OUTCOME trial. Empagliflozin reduced the risk for heart failure hospitalizations in this group (HR, 95%CI = 0.72, 0.50-1.04) to a similar extent as in patients without heart failure at baseline (HR, 95% CI = 0.63, 0.51-0.78). Moreover, when assessing the risk for heart failure onset with the Health ABC Heart Failure risk score,17 even EMPA-REG OUTCOME patients at the lowest risk demonstrated a significant reduction in subsequent heart failure hospitalizations with empagliflozin (data have not published yet, but have communicated at the European Society of Cardiology Congress 2017 in Barcelona).
References
- American Diabetes Association. American Diabetes Association standards of medical care in diabetes. Approaches to glycemic treatment. Diabetes Care 2017;40: S1-129.
- Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
- Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. BMJ 2016;354:i3477.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
- Pfeffer M, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
- Verbrugge FH. Role of SGLT2 inhibitors in patients with diabetes mellitus and heart failure. Curr Heart Fail Rep 2017;14:275-83.
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34.
- Zoungas S, Arima H, Gerstein HC, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 2017;5:431-7.
- Verbrugge FH, Martens P, Mullens W. SGLT-2 inhibitors in heart failure: implications for the kidneys. Curr Heart Fail Rep 2017;14:331-7.
- Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-97.
- Holtkamp FA, de Zeeuw D, Thomas MC, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011;80:282-7.
- Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526-34.
- Kalogeropoulos A, Psaty BM, Vasan RS, et al. Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. Circ Heart Fail 2010;3:495-502.
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