Glucose-Lowering Drugs and Primary Prevention of Chronic Kidney Disease in Type 2 Diabetes Patients: A Real-World Primary Care Study

Abstract

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1-326.5) per 10,000 person-years. In the nested case-control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73-0.99 and AOR = 0.89; 95%CI: 0.74-1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56-0.94 and AOR = 0.64; 95%CI: 0.46-0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD.

Keywords: GLP-1 receptor agonists; SGLT-2 inhibitors; chronic kidney disease; glucose-lowering drugs; primary prevention; type 2 diabetes.

Figure 1

Flowchart of patient selection. eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease. * Controls were selected using an incidence-density sampling with replacement, which allows a subject to act as the control for more than one case. This explains that the sum of cases and controls exceeds the number of patients in the type 2 diabetes cohort (see Section 4.5, “Nested case-control study” in Section 4, “Methods”).

Figure 2

Incidence rates of chronic kidney disease by age and sex. p-y: person-years.

Figure 3

Trends in the incidence rates of chronic kidney disease by 10-year age bands. β_overall (95%CI) = −4.22 (−13.5, 5.07); β_18–30 (95%CI) = −0.47 (−4.75, 3.80); β_31–40 (95%CI) = −2.84 (−4.91, −0.77); β_41–50 (95%CI) = −3.65 (−6.96, −0.34); β_51–60 (95%CI) = −2.28 (−5.56, 0.99); β_61–70 (95%CI) = −1.72 (−8.68, 5.24); β_71–80 (95%CI) = −8.56 (−20.1, 2.96); β_>80 (95%CI) = −10.0 (−26.5, 6.52).

Figure 4

Incident chronic kidney disease overall and current use of glucose-lowering drugs by treatment duration. The reference comparison for each GLD is the non-use. Since all subjects are users of GLDs, the non-use category includes those users of any other GLD. IQR: interquartile range; CI: confidence interval; AOR: adjusted odds ratio. * Adjusted for all the variables in the Table 2, excepting CKD stage, plus the following comedication in the year before index date: antihypertensives (including alpha-adrenoreceptor antagonists, beta blocking agents, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and renin-inhibitors), diuretics (including high-ceiling, low-ceiling thiazides, low-ceiling excluding thiazides, direct potassium-sparing agents and, mineralocorticoid receptor antagonists), antiplatelet drugs (including COX-1 inhibitors, P2Y12 receptor blockers, others), oral anticoagulants (including vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors), heparins, class I and III antiarrhythmics, nonsteroidal anti-inflammatory drugs, paracetamol, metamizole, symptomatic slow-action drugs for osteoarthritis, opioids, glucocorticoids for systemic use, proton-pump inhibitors, H2-receptor antagonists, immunosuppressants, benzodiazepines, antidepressants, antiepileptics, anti-Parkinson drugs, antipsychotics, vitamin D and calcium (alone or in combination), and colchicine.

Figure 5

Incident chronic kidney insufficiency (G3–G5) and current use of glucose-lowering drugs by treatment duration. The reference comparison for each GLD is the non-use. Since all subjects are users of GLDs, the non-use category includes those users of any other GLD. IQR: interquartile range; CI: confidence interval; AOR: adjusted odds ratio. * Adjusted for all the variables in Table 2, excepting CKD stage, plus the following comedication in the year before index date: antihypertensives (including alpha-adrenoreceptor antagonists, beta blocking agents, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and renin-inhibitors), diuretics (including high-ceiling, low-ceiling thiazides, low-ceiling excluding thiazides, direct potassium-sparing agents and, mineralocorticoid receptor antagonists), antiplatelet drugs (including COX-1 inhibitors, P2Y12 receptor blockers, others), oral anticoagulants (including vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors), heparins, class I and III antiarrhythmics, nonsteroidal anti-inflammatory drugs, paracetamol, metamizole, symptomatic slow-action drugs for osteoarthritis, opioids, glucocorticoids for systemic use, proton-pump inhibitors, H2-receptor antagonists, immunosuppressants, benzodiazepines, antidepressants, antiepileptics, anti-Parkinson drugs, antipsychotics, vitamin D and calcium (alone or in combination), and colchicine.