Effects on clinical outcomes of intensifying triple oral antidiabetic drug (OAD) therapy by initiating insulin versus enhancing OAD therapy in patients with type 2 diabetes: A nationwide population‐based, propensity‐score‐matched cohort study

Kuo, Shihchen; Yang, Chun; Wu, Jin Shang; Ou, Horng Yih

doi:10.1111/dom.13525

Cited by 8 publications

(11 citation statements)

References 51 publications

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“…An increasing body of evidence suggests that hypoglycemia may contribute to the development of CVDs in the type 2 diabetes population [24,25]. Our previous study of insulin therapy in type 2 diabetes supports that the occurrence of hypoglycemia plays an independent role in the risk of developing CVDs in this population [11]. Therefore, compared to LAIA users, the increased risk of hypoglycemia in IAHI users observed in this study may partially explain the higher risk of CVDs.…”

Section: Discussionsupporting

confidence: 78%

“…This would limit the generalizability of study findings to real-world settings where some patients initiated with LAIA have been previously exposed to IAHI (i.e., prevalent new users of LAIA), or vice versa. In addition, due to clinical inertia in the management of type 2 diabetes, basal insulin is commonly not initiated until the later course of antidiabetic treatment, that is, when treatment with multiple oral glucose-lowering agents (GLAs) has failed [11]. Thus, a rigorous analytic scheme is required to address the complexity of past utilization of GLAs for studies assessing health outcomes associated with the LAIA and IAHI use.…”

Section: Introductionmentioning

confidence: 99%

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Comparative vascular safety of basal long-acting insulin analogue versus intermediate-acting human insulin in real-world patients with type 2 diabetes: a nationwide population-based cohort study

Yang

et al. 2020

Preprint

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Background: Little is known about the comparative vascular safety of basal insulin (intermediate-acting human insulin [IAHI] or long-acting insulin analogue [LAIA]) in type 2 diabetes. We sought to examine the vascular and hypoglycemic effects associated with IAHI versus LAIA in real-world patients with type 2 diabetes. Methods: We conducted a nationwide population-based, retrospective cohort study using Taiwan’s National Health Insurance Research Database to include patients with type 2 diabetes who stably used an IAHI (N=11,521) or LAIA (N=37,651) in the period 2004-2012. A rigorous three-step matching algorithm that considered the initiation date of basal insulin, previous exposure of antidiabetic treatments, comorbidities, diabetes severity and complications, and concomitant medications was applied to achieve the between-group comparability. Study outcomes, including composite cardiovascular diseases (CVDs), composite microvascular diseases (MVDs), and hypoglycemia, were assessed up to the end of 2013. Results: Baseline patient characteristics were balanced with the application of the matching scheme. Compared with LAIA, the use of IAHI was associated with greater risks of composite CVDs (adjusted hazard ratio: 1,79; 95% confidence interval: 1.20-2.67) and hospitalized hypoglycemia (1.82; 1.51-2.20), but a lower risk of composite MVDs (0.88; 0.84-0.91). Subgroup and sensitivity analyses showed a consistent trend of results with that in the primary analyses. Conclusions: The use of a basal insulin with IAHI versus LAIA among patients with type 2 diabetes in usual practice may be associated with a lower risk of MVDs, and strategies should be optimized for minimizing the risks of hypoglycemia and CVDs in this population.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Comparative vascular safety of basal long-acting insulin analogue versus intermediate-acting human insulin in real-world patients with type 2 diabetes: a nationwide population-based cohort study

Yang

et al. 2020

Preprint

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“…Previous studies have raised concerns about the safety of antihyperglycemic combination therapies in relation to diabetes-related outcomes such as hypoglycemia [ 40 ], cardiovascular events and mortality [ 41 ], and microvascular complications [ 42 ]. However, recent studies have also focused on some less-known safety issues related to multiple drug use, including dementia [ 43 ], fracture risk [ 44 ], and community-acquired pneumonia [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple Antihyperglycemic Drug Use is Associated with Undernutrition Among Older Adults with Type 2 Diabetes Mellitus: A Cross-Sectional Study

2019

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Introduction Undernutrition is prevalent in older age. Current management of type 2 diabetes mellitus (T2DM) requires modified diet patterns; however, older adults with diabetes may also be at the risk of undernutrition due to age, disease, and medication-related factors. Our objectives in this study were to examine the proportion and associations of undernutrition among community-dwelling older adults with T2DM. Methods This prospective, cross-sectional study involved older outpatient adults (≥ 65 years) with and without T2DM. We assessed the nutritional status using the Mini Nutritional Assessment-Short Form. Undernutrition referred to being either at risk of malnutrition or malnourished. Variables independently associated with undernutrition were evaluated by logistic regression analysis. Results Five hundred forty-six older adults [ n = 215 with T2DM and n = 331 control; mean (SD) age, 74.9 (6.3) years; 388 (71.1%) female] were included in the study. The frequency of undernutrition was 31.1%, which was higher in patients with T2DM than in those without (36.7% vs. 27.5%, p < 0.05). However, the difference was no longer significant after adjustment for covariates (gender, lower education, lower body mass index, cardiovascular disease, multimorbidity, cognitive performance, functional performance, depressive symptoms, and polypharmacy). In the T2DM group, the ratio of multiple antihyperglycemic drug use (≥ 2) was higher in those with undernutrition compared with normal nutritional status (78.5% vs. 59.6%, p = 0.005). On multivariable analysis, decreased functional performance, depressive symptoms, and use of multiple antihyperglycemic drugs were associated with undernutrition in patients with T2DM. Conclusions Undernutrition was more common among older adults with T2DM compared with the control group. Undernutrition was further dependent on chronic conditions and diabetes management.

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“…Hypoglycemia is known to provoke unstable hemodynamics and dysrhythmia and might result in an increased number of cardiovascular events and sudden death 30 . In the analysis by Kuo et al, after post-index hypoglycemia was controlled to account for the potential effect on all-cause mortality, the increased risks associated with insulin therapy no longer existed (the HR decreased from 1.48 [95% CI 1.01-2.17] to 1.30 [0.84-1.99]) 22 . The latest American Diabetes Association guideline has recently revised the recommendations for choosing antidiabetic agents and suggests that a GLP-1 agonist, an injectable medication, is preferred over basal insulin to reduce the risk of hypoglycemia and weight gain 13 .…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of basal insulin and oral antidiabetic agents as an add-on to dual therapy in patients with type 2 diabetes mellitus

Cheng

Wang

Lin

et al. 2020

Sci Rep

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While basal insulin remains the most effective antidiabetic agent and substantially reduces the risk of hypoglycemia, few studies have examined the comparative effect of basal insulin in the real-world setting. this study aimed to assess the outcomes of adding basal insulin compared with thiazolidinediones (TZDs) or dipeptidyl peptidase-4 inhibitors (DPP-4is) as a third antidiabetic agent in patients with type 2 diabetes mellitus (T2DM). A retrospective cohort study involving T2DM was conducted with health administrative data in Taiwan. Patients starting a third antidiabetic agent after receiving a metformin-containing dual combination were identified. The study endpoints included composite major adverse cardiovascular events (MACEs), all-cause mortality, and hypoglycemia. Propensity score matching and Cox modeling were used for analysis. After matching, the basal insulin and TZD groups contained 6,101 and 11,823 patients, respectively, and the basal insulin and DPP-4i groups contained 6,051 and 11,900 patients, respectively. TZDs and DPP-4is were both associated with similar risks of MACEs and hypoglycemia but a lower risk of all-cause mortality than basal insulin (TZDs: HR 0.55, 95% CI 0.38-0.81; DPP-4is: HR 0.56, 95% CI 0.39-0.82). Further studies are needed to elucidate the findings of increased all-cause mortality risk in patients receiving basal insulin, especially those with advanced diabetes.Diabetes mellitus (DM) substantially increases the risk of cardiovascular diseases (CVDs) and associated deaths; therefore, intensive glucose control has long been considered a gold standard to reduce the occurrence of CVDs 1 . The 10-year follow-up study of the UKPDS (UK Prospective Diabetes Study) revealed a beneficial long-term effect of early intensive glucose control on the reduction in macrovascular events 2 , although this effect did not appear in other clinical trials with advanced DM populations and relatively short follow-up periods 3-5 . Insulin is regarded as the most effective antidiabetic agent for glycemic control, and it possesses a better ability in the preservation of β-cell function than oral hypoglycemic agents (OHAs) 6-8 . The emergence of long-acting basal insulin ameliorates the problem of insulin-associated hypoglycemia 9 . However, the initiation of insulin therapy is often delayed in clinical practice because most patients are reluctant to or inconvenienced by using injectable medications 10 .The role of basal insulin as an add-on antidiabetic agent remains unclear [11][12][13] . Previous studies have shown that the combination of metformin and sulfonylureas dominated in dual therapy in the early phase of disease management [14][15][16][17] , and other OHAs, such as thiazolidinediones (TZDs) and dipeptidyl peptidase-4 inhibitors (DPP-4is), are common treatment options after the failure of dual therapy 11,13,16 . Several observational studies compared insulin to OHAs and noted a significantly increased risk of CVDs or all-cause mortality associated with insulin 18-23 . However, most of these s...

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Effects on clinical outcomes of intensifying triple oral antidiabetic drug (OAD) therapy by initiating insulin versus enhancing OAD therapy in patients with type 2 diabetes: A nationwide population‐based, propensity‐score‐matched cohort study

Abstract: Initiation of fourth-line insulin therapy can be considered for patients with T2DM with triple OAD therapy failure, and the importance of awareness and prevention of hypoglycaemia among insulin-treated patients with T2DM cannot be overstated.

Cited by 8 publications

References 51 publications

Comparative vascular safety of basal long-acting insulin analogue versus intermediate-acting human insulin in real-world patients with type 2 diabetes: a nationwide population-based cohort study

Comparative vascular safety of basal long-acting insulin analogue versus intermediate-acting human insulin in real-world patients with type 2 diabetes: a nationwide population-based cohort study

Multiple Antihyperglycemic Drug Use is Associated with Undernutrition Among Older Adults with Type 2 Diabetes Mellitus: A Cross-Sectional Study

Clinical outcomes of basal insulin and oral antidiabetic agents as an add-on to dual therapy in patients with type 2 diabetes mellitus

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