Approximately 30 million adults have diabetes (DM) in the United States and DM confers a risk for cardiovascular disease (CVD). Whether CVD is prevented by antidiabetic therapies which target glycemic control remains relatively unknown. Between 2013-2017 there were multiple pivotal trials of newer agent called sodium?glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP1RA) vs placebo. These newer agents demonstrated reduction in CVD and kidney outcomes. These new medications demonstrated lower risk of major adverse cardiovascular events (MACE) versus placebo with a pronounced effect among those with pre-existing CVD, and less data for those without CVD. But the trials also demonstrated increased risks of adverse events including a two-fold risk of amputations. There were both trial and post-marketing reports of fractures with SGLT2 because of impaired bone metabolite excretion. These medications are high cost; $300-$500 per month of treatment under VHA contracting. Use of these high cost medications if they prevented CVD would provide a return on investment. However, their efficacy is demonstrated vs placebo; their effectiveness relative to other commonly used medications remains unknown because data from real world cohorts is methodologically limited. Methodologically strong comparative effectiveness observational studies are necessary to determine the relative benefits We propose to conduct a National longitudinal study using administrative, clinical and laboratory data to quantify the relative risks/ benefits of DM agents among Veterans in two cohorts with and without CVD. This proposal will answer the question: Among patients with DM, what are the absolute risks of adverse events and potential cardiovascular and renal benefits for those who add on SGLT2 or GLP1RA compared to dipeptidyl peptidase 4 inhibitors (DPP4)? We will expand the cohort through FY2020 of Veterans with diabetes: utilizing national Veterans Health Administration (VHA) data (corporate data warehouse-vital signs; pharmacy, medical datasets, Medicare/ Medicaid data and vital status files), national death index and additional data on ankle brachial index and echocardiograms. Eligible veterans will be new users of SGLT2, GLP1RA or DPP4 aged >18 years who utilize VHA from 10/1/2000 through 09/30/2020. The current data (through FY 2016) has 35,799 SGLT2 new users; 68,876 new users of GLP1RA; and 203,030 new users of DPP4 (reference). We propose to evaluate the risks and benefits in 2 cohorts, those with and without CVD. The proposed study follows this cohort from new drug initiation until an outcome or censoring event (leave VHA, change therapy or death). The comparisons of interest will be: SGLT2 or GLP1RA vs. DPP4.
Aim 1 will test the hypothesis that the risk of MACE (4 component- AMI/ Stroke/ CV death/ Heart failure) in patients treated with SGLT2 or GLP1RA is lower than the risk in patients treated with DPP4.
Aim 2 will test the hypothesis that CKD progression and all-cause mortality is lower in patients treated with SGLT2 or GLP1RA vs. DPP4.
Aim 3 will test the hypothesis that amputation and peripheral artery disease (PAD) revascularization is higher for patients treated with SGLT2 vs. DPP4.
Aim 4 will test the hypothesis that risk of fracture is higher for patients treated with SGLT2 vs. DPP4. Propensity score weighting will be used to achieve similar groups. We will compare event rates accounting for baseline and time-varying covariates with marginal structural Cox proportional hazards models (MSM) with ?stabilized? inverse probability treatment weights (IPTW). The execution of the proposed research will provide actionable evidence for patients with DM, would impact VHA policy and results would add to the oversight and costs of purchased community care for DM. Our team has been extremely productive over the last 7 years and is poised to conduct a rigorous and necessary evaluation of the effectiveness of newer DM regimens. Our publication record attests to our ability to use VHA data for accurate and impactful measurememnt of the safety and effectiveness of DM medications.
Approximately 30 million adults have diabetes (DM) in the United States and DM confers a risk for cardiovascular disease (CVD). Between 2013-2017 multiple clinical trials of newer agents (SGLT2 or GLP1RA) were conducted versus placebo that demonstrated cardiovascular or renal benefit with a pronounced effect among those with pre-existing CVD. There is less data available among those without CVD. Evidence on the advantages and risks of these newer agents relative to other commonly used medications remains unknown because data from real world cohorts is methodologically limited for many reasons. We propose to conduct a large longitudinal national study using administrative, clinical and laboratory data to quantify the relative risks and benefits of newer antidiabetic agents among Veterans. We will include cardiovascular and renal outcomes and risks of amputations and fractures in 2 distinct cohorts, those with and without CVD. This study would be the largest methodologically rigorous evaluation of newer antidiabetic medications in Veterans to date.
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