In type 2 diabetes, intensive glucose control for 5.6 years did not differ from usual care for major CV events at 14 years

Abstract

Question In patients with type 2 diabetes, does intensive glucose control for a median 5.6 years reduce major cardiovascular (CV) events over 15 years compared with usual care? Methods Design Long-term observational follow-up of a randomized controlled trial (Veterans Affairs Diabetes Trial Follow-up [VADT-F] study). ClinicalTrials.gov NCT00032487. Allocation Unclear allocation concealment.* Blinding Blinded* (outcome adjudicators for patient-reported amputations and CV events). Follow-up period Median 13.6 years for CV events; median 15 years for all-cause mortality. Setting 20 centers in the USA. Patients 1791 military veterans >40 years of age (mean age 60 y, 97% men, mean diabetes duration 12 y) who had type 2 diabetes mellitus and an inadequate response (hemoglobin [HbA1c] level 7.5%) to maximum doses of 1 oral drug or insulin. Intervention Intensive glucose control targeted to a normal HbA1c level and median level >1.5% lower than the usual care group (n =892) or usual care targeted to an HbA1c level of 8% to 9% (n =899). Patients received randomized treatments for a median 5.6 years. Outcomes Primary outcome was a composite of major CV events (nonfatal myocardial infarction or stroke, CV death, new or worsening congestive heart failure, or amputation for ischemic gangrene). Secondary outcomes included all-cause and CV mortality and major diabetes outcomes (primary composite outcome, end-stage renal disease, or nontraumatic amputation). Patient follow-up 92% of patients were followed through linkage to national registries (Veterans Affairs central medical and death files, Centers for Medicare & Medicaid Services claims files, and National Death Index), and 78% provided additional data through annual surveys and chart reviews (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In type 2 diabetes, intensive glucose control for a median 5.6 years did not differ from usual care for major cardiovascular events at 13.6 years or all-cause mortality at 15 years. Intensive glucose control for a median 5.6 y vs usual care in type 2 diabetes Outcomes Events per 1000 patient-y RRR (95% CI) at a median 13.6 y Intensive glucose control Usual care Major cardiovascular event 47 52 6.5% (4 to 17) Major diabetes outcome 50 56 7.1% (3 to 16) Cardiovascular mortality 12 13 5.5% (18 to 25) RRI (CI) at a median 15 y All-cause mortality 37 36 1.5% (9 to 13) Abbreviations defined in Glossary. RRR, RRI, and CI calculated from usual care event rates and hazard ratios in article. Nonfatal myocardial infarction or stroke, cardiovascular death, new or worsening congestive heart failure, or amputation for ischemic gangrene. Major cardiovascular event, end-stage renal disease, or nontraumatic amputation. Commentary Whether the benefits of intensive blood glucose control extend beyond a finite period of intensive management (the so-called legacy effect) continues to be debated (1-3). Although a glycemic legacy effect was found in UKPDS (United Kingdom Prospective Diabetes Study) (3), the VADT-F study found no such effect for long-term rates of major CV events in patients with advanced type 2 diabetes. The 2 postintervention studies differed in diabetes stage at the time of intervention (new onset in UKPDS, advanced in VADT), which might partly explain the dissimilar outcomes and suggest a crucial role for tight glycemic control in the early phases of the disease (1, 3). What is the main take-home message for physicians? The findings of these studies support the importance of maintaining glycemic control over time and suggest that we should promote intensive dietary and lifestyle approaches, which hold promise for long-term remission (2). We also need to consider the availability of effective cardioprotective strategies, including statins, angiotensin-converting enzyme inhibitors, and antiplatelet agents, none of which were standard practice at the time of UKPDS. Moreover, glucagon-like peptide-1 receptor agonists and sodiumglucose cotransporter 2 inhibitors have recently been shown to improve CV outcomes independently of glycemic control (1, 4). Evidence for CV benefit in type 2 diabetes continues to evolve; hence, we should never lower our guard!