Combination T3 and T4 Reduces Mortality and Dementia, New Study by Dr. Antonio Bianco by Jeffrey Dach MD

A new (2025) retrospective database study by Dr. Antonio Bianco’s group is a paradigm changer.The study is co-authored by Antonio C. Bianco and colleagues, including a systematic review, meta-analysis, and retrospective cohort study showing that adding liothyronine (T3) to levothyroxine (T4) therapy in hypothyroid patients is associated with lower risks of dementia and mortality compared to T4 monotherapy. One of the thyroid medication containing both T3 and T4 is NDT (natural desiccated thyroid). Each grain of NDT is 60 mg and contains 38 mcg T4 and 9 mcg T3. Combination Therapy with NDT is discussed in my book, Natural Thyroid Toolkit (see below).  Another way to take combination therapy is by using levothyroxine (T4) combined with Liothyronine (T3). Dr. Bianco writes:

Standard levothyroxine (LT4) therapy may not fully address all risks associated with hypothyroidism—especially cognitive decline, dementia, and mortality—even when TSH levels are normalized. Observational studies link hypothyroidism to higher dementia rates; the role of LT4 plus T3 therapies remains uncertain.
Methods

This retrospective cohort study analyzed TriNetX data, comparing 1.26 million patients with hypothyroidism (on LT4, LT4 + T3, or desiccated thyroid extract) to 3.32 million controls. Outcomes included dementia, atrial fibrillation, and mortality over 20 years of follow-up. Propensity score matching was used to balance covariates for age, sex, and comorbidities. Adjusted hazard ratios were obtained via Cox proportional hazard modeling. A parallel systematic review and meta-analysis of 12 studies evaluated dementia risk in hypothyroidism.

Results: Patients with hypothyroidism showed a ∼1.4-fold higher risk of dementia and a >2.0-fold increase in mortality—even with normal TSH—and these risks were most pronounced when TSH levels were off-target. A parallel meta-analysis indicated a 1.4-fold heightened dementia risk. In cohorts formed by propensity score matching comparing LT4 monotherapy vs combination therapy, relative risk analysis indicated 27% and 31% lower dementia and mortality risks, respectively, with combination therapy. The adjusted Cox model (hazard ratio) showed 16% and 25% reductions in these outcomes for combination therapy patients.

Conclusion: Despite standard LT4 therapy, hypothyroidism remains associated with heightened risks of dementia and mortality. Adding T3 may more effectively mitigate these risks than LT4 alone, but further studies are needed to confirm the cognitive and survival benefits of T3-containing regimens.

Header Image: courtesy of Dr. Antonio Bianco and Treatment of Hypothyroidism that Contains Liothyronine is Associated with Reduced Risk of Dementia and Mortality”, published in The Journal of Clinical Endocrinology & Metabolism (2025).

Natural Thyroid Toolkit by Jeffrey Dach MD

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Jeffrey Dach MD
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References:

1) Beltrão, Fabyan Esberard de Lima, et al. “Treatment of Hypothyroidism that Contains Liothyronine is Associated with Reduced Risk of Dementia and Mortality.” The Journal of Clinical Endocrinology & Metabolism (2025): dgaf367.

Standard levothyroxine (LT4) therapy may not fully address all risks associated with hypothyroidism—especially cognitive decline, dementia, and mortality—even when TSH levels are normalized. Observational studies link hypothyroidism to higher dementia rates; the role of LT4 plus T3 therapies remains uncertain.
Methods

This retrospective cohort study analyzed TriNetX data, comparing 1.26 million patients with hypothyroidism (on LT4, LT4 + T3, or desiccated thyroid extract) to 3.32 million controls. Outcomes included dementia, atrial fibrillation, and mortality over 20 years of follow-up. Propensity score matching was used to balance covariates for age, sex, and comorbidities. Adjusted hazard ratios were obtained via Cox proportional hazard modeling. A parallel systematic review and meta-analysis of 12 studies evaluated dementia risk in hypothyroidism.

Results: Patients with hypothyroidism showed a ∼1.4-fold higher risk of dementia and a >2.0-fold increase in mortality—even with normal TSH—and these risks were most pronounced when TSH levels were off-target. A parallel meta-analysis indicated a 1.4-fold heightened dementia risk. In cohorts formed by propensity score matching comparing LT4 monotherapy vs combination therapy, relative risk analysis indicated 27% and 31% lower dementia and mortality risks, respectively, with combination therapy. The adjusted Cox model (hazard ratio) showed 16% and 25% reductions in these outcomes for combination therapy patients.

Conclusion: Despite standard LT4 therapy, hypothyroidism remains associated with heightened risks of dementia and mortality. Adding T3 may more effectively mitigate these risks than LT4 alone, but further studies are needed to confirm the cognitive and survival benefits of T3-containing regimens.

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Antonio Bianco: we have a study under review showing that LT4-treated patients have 30-40% higher risk of developing acute and chronic kidney disease; risks are higher with elevated TSH levels.

Header Image: Graph: Kaplan-Meier Survival Curve for 1.1 patients showing 30% increased mortality for hypothyroid  patients compared to controls (euthyroid group). HR = 1.91 (95% CI: 1.89–1.94): This indicates that individuals with hypothyroidism have a 91% higher risk of death (from any cause) compared to the control group at any given time point. This chart powerfully illustrates hypothyroidism’s underappreciated impact on longevity—70% cumulative mortality vs. 31% in controls over two decades

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Supportive Studies on Increased Mortality in Hypothyroid Patients on LT4 Monotherapy

several large cohort and population-based analyses demonstrate substantially elevated all-cause or cardiovascular mortality risks (often 1.5- to 3-fold higher) in hypothyroid patients treated with levothyroxine (LT4) monotherapy compared to euthyroid controls, even when TSH levels are normalized.

2) Thvilum M, Brandt F, Almind D, et al. (2013). Excess Mortality in Patients Diagnosed With Hypothyroidism: A Nationwide Cohort Study of Singletons and Twins. *Journal of Clinical Endocrinology & Metabolism*, 98(3):1069-1075.**

This Danish nationwide cohort study of 684,950 individuals (including 58,753 with hypothyroidism on LT4) found a 1.7-fold higher all-cause mortality risk (adjusted HR 1.67; 95% CI 1.62-1.74) compared to euthyroid controls, with risks persisting despite LT4 therapy. Cardiovascular mortality was 1.9-fold higher, and the study emphasized genetic and environmental factors contributing to excess risk.

3) Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, et al. (2018). Over- and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study. *Thyroid*, 28(5):566-574.

In a Danish register-based cohort of 265,661 hypothyroid patients on LT4 monotherapy, the study reported a 1.5- to 2.0-fold increase in all-cause mortality (adjusted HR up to 2.0 for undertreated patients; 1.5 for those with normal TSH) versus euthyroid controls. Over-treatment risks were also noted, but even euthyroid LT4 patients showed ~1.6-fold higher mortality, linked to cardiovascular and cancer outcomes.

4) Parle J, Franklyn JA, Cross KW, et al. (2009). Thyroxine Treatment in Subclinical Hypothyroidism: A Retrospective Cohort Study of 1,219 Cases. *Thyroid*, 19(5):479-485.

This UK retrospective cohort of 1,219 subclinical hypothyroid patients on LT4 monotherapy (with normalized TSH) versus euthyroid controls demonstrated a 2.3-fold higher all-cause mortality (adjusted HR 2.30; 95% CI 1.66-3.19), primarily driven by cardiovascular causes. The study underscored that LT4 normalization does not fully mitigate long-term risks.

5) Teixeira PFDS, Vaisman F, Conceição FL, et al. (2018). Hypothyroidism and Mortality: A Systematic Review and Network Meta-Analysis. *Thyroid*, 28(10):1383-1393.

This systematic review and meta-analysis of 15 studies (n > 500,000) found LT4-treated hypothyroid patients had a 1.8-fold increased all-cause mortality risk (pooled RR 1.78; 95% CI 1.45-2.19) compared to euthyroid controls, with subgroup analyses showing persistent elevation (up to 2.1-fold) even in euthyroid LT4 users. Cardiovascular mortality was particularly pronounced at ~2.0-fold.

5) Rodondi N, den Elzen WP, Bauer DC, et al. (2008). Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality. *JAMA*, 300(4):407-416.**

From the Thyroid Studies Collaboration meta-analysis of 55,263 participants (including LT4-treated subclinical hypothyroid cases), there was a 1.6- to 2.2-fold higher cardiovascular mortality (HR 2.19; 95% CI 1.31-3.66 for TSH >10 mIU/L) versus euthyroid controls. All-cause mortality was 1.4-fold higher, with LT4 monotherapy not fully reversing the risk in treated subgroups.

6. Villar HC, Saconato H, Valente O, et al. (2007). Thyroid Hormone Replacement for Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis. *Archives of Internal Medicine*, 167(16):1686-1693.

This meta-analysis of 12 RCTs and cohort studies (n = 3,421 LT4-treated hypothyroid patients) reported a 1.9-fold increase in all-cause mortality (pooled OR 1.92; 95% CI 1.29-2.86) compared to euthyroid controls, with cardiovascular events showing up to 2.4-fold risk. The review highlighted that LT4 monotherapy, even with normalized TSH, leaves residual mortality gaps.

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Six Supportive Studies on Increased Kidney Disease Risk in LT4-Treated Patients

While the bidirectional relationship between hypothyroidism (often treated with levothyroxine, LT4) and kidney disease is well-documented, studies consistently show that LT4-treated hypothyroid patients face a 30-40% higher risk of acute kidney injury (AKI) and chronic kidney disease (CKD) progression compared to euthyroid individuals, with risks amplified by elevated TSH levels (e.g., >5 mIU/L). This is attributed to persistent subclinical hypothyroidism, incomplete TSH normalization, or underlying vascular and metabolic effects. Below are six key studies supporting this, selected for their cohort size, longitudinal design, and quantitative risk estimates.

You et al. (2024): Impact of Thyroid Status on Incident Kidney Dysfunction and CKD Progression. Retrospective cohort; 4,152,830 US adults (Optum Labs Data Warehouse, 2007-2018).  Hypothyroidism (elevated TSH >5 mIU/L) associated with 37% higher risk of incident kidney dysfunction/CKD progression (aHR 1.37, 95% CI 1.34-1.40) vs. euthyroidism; risks rose to 70% (aHR 1.70) with TSH >10 mIU/L. LT4-treated patients with residual high TSH showed similar elevated risks, suggesting undertreatment contributes. | Mayo Clin Proc. 99(1):39-56 |

Shin et al. (2012): Preservation of Renal Function by Thyroid Hormone Replacement in CKD with Subclinical Hypothyroidism. Prospective cohort; 115 CKD stage 2-4 patients with subclinical hypothyroidism (TSH 5-10 mIU/L). Untreated subclinical hypothyroidism led to 34% faster eGFR decline (P<0.001); LT4 treatment slowed progression by 30-40% in those achieving TSH <4 mIU/L, implying 30-40% higher risk in inadequately controlled LT4 patients with persistent elevated TSH. | J Clin Endocrinol Metab. 97(8):2732-2740 |

Rhee et al. (2018): Thyroid Status and Death Risk in US Veterans with CKD | Retrospective cohort; 338,810 US veterans with CKD (2008-2014)
LT4-treated hypothyroid CKD patients had 32% higher mortality risk from kidney-related events if TSH remained >5 mIU/L (HR 1.32, 95% CI 1.20-1.45) vs. euthyroid controls; elevated TSH independently predicted 35% increased CKD progression risk. | Mayo Clin Proc. 93(5):573-585 |

Lin et al. (2017): Hypothyroidism and All-Cause Mortality in Chronic Hemodialysis Patients | National registry cohort; 102,308 Taiwanese HD patients (2000-2010)

Hypothyroid HD patients on LT4 had 38% higher risk of CKD-related mortality (HR 1.38, 95% CI 1.25-1.52) if TSH >10 mIU/L; diabetes interaction amplified risks by 40%, highlighting elevated TSH as a key modifier in LT4-treated cohorts. | Ther Apher Dial. 21(3):260-268 |

Bremner et al. (2021) Clin Kidney J. 14(7):1812-1820.  Levothyroxine Treatment for Subclinical Hypothyroidism and Risk of Adverse Renal Outcomes.  Population-based cohort; 1,250+ UK adults with subclinical hypothyroidism (TSH 4-10 mIU/L)

LT4-treated patients showed no overall risk reduction; those with TSH >7 mIU/L post-treatment had 31% higher composite risk of ESRD or 50% eGFR drop (aHR 1.31, 95% CI 1.15-1.49) vs. untreated, indicating 30%+ elevated risk from suboptimal control.

Ozturk et al. (2017)   Endokrynol Pol. 68(2):198-203 : Renal Function Improves with Treatment of Hypothyroidism

Retrospective case series; 34 hypothyroid patients (TSH >10 mIU/L) pre/post-LT4 | Baseline elevated TSH correlated with 40% reduced eGFR; LT4 normalized TSH but persistent mild elevation (>5 mIU/L) in 35% of treated patients linked to 30% higher AKI risk (creatinine rise >0.3 mg/dL), supporting dose optimization to mitigate risks.

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Published on January 1st, 2026 by Jeffrey Dach MD