Glycine and Heart Health: SGLT2 Drug Insights

meta-analysis PMID: 36161993

Glycine and Heart Health: SGLT2 Drug Insights

Quick Summary: A 2022 study used genetic analysis to explore how SGLT2 inhibitors—common drugs for type 2 diabetes—might lower risks of heart disease and diabetes. It found these drugs boost glycine levels in the blood, and glycine plays a small but real role in cutting heart disease risk. Other related compounds like choline also help with diabetes protection.

What the Research Found

This study looked at how SGLT2 inhibitors (medicines that help control blood sugar by blocking a kidney protein) affect heart disease and type 2 diabetes. Researchers used genetics to mimic the drugs' effects without giving them to people. Key discoveries include:

SGLT2 inhibition cut type 2 diabetes risk by about 75% and heart disease risk by 49% in the genetic model.
It raised blood levels of glycine (an amino acid your body uses for building proteins), total choline (a nutrient from foods like eggs and meat), and phosphatidylcholine (a fat-like molecule).
Glycine linked to a 6% lower heart disease risk per unit increase, but it didn't affect diabetes risk.
Choline and phosphatidylcholine lowered diabetes risk by 22% and 19%, respectively, but not heart disease.
Glycine explained just 2% of the heart benefits from SGLT2 drugs, while choline types explained 5-8% of diabetes benefits. This means other factors play bigger roles, but these molecules matter.

The findings held up when checked against extra data sets, showing reliable results.

Study Details

Who was studied: No real people took part directly. Instead, researchers analyzed genetic data from large groups, like 118,000 from UK Biobank for blood chemicals, 183,000 for heart disease (60,000 with it, 123,000 without), and 898,000 for diabetes (74,000 with it, 824,000 without). Most were of European background.
How long: This wasn't a time-based trial; it used one-time genetic snapshots from databases to predict lifelong effects.
What they took: No supplements or drugs were given. Genetic changes in the SLC5A2 gene (which codes for the SGLT2 protein) acted as stand-ins for the drugs, mimicking a blood sugar drop of about 1% and raising glycine by a small amount (0.34 standard units).

What This Means For You

If you have type 2 diabetes or heart concerns, SGLT2 inhibitors like empagliflozin (brand name Jardiance) are already prescribed to manage blood sugar and protect your heart. This study hints that part of their power comes from boosting glycine and choline levels naturally.

For heart health: Higher glycine might offer a tiny edge against coronary artery disease (blocked heart arteries). Foods rich in glycine—like bone broth, gelatin, or pork skin—could support this, but don't expect miracles from diet alone. Talk to your doctor before trying supplements, as this isn't proven for direct use.
For diabetes: Choline from diet (think liver, fish, or nuts) may help alongside meds. If you're on SGLT2 drugs, know they work through multiple paths, including these nutrients.
Actionable tip: Focus on proven steps like exercise, balanced eating, and following your doctor's advice. This research adds to why SGLT2 drugs are heart-smart choices, but glycine isn't a magic fix—its role is small.

Study Limitations

This genetic study has strengths like avoiding bias, but it's not perfect. Keep these in mind:

It assumes genes act only through SGLT2 paths, but they might influence other body processes (called pleiotropy), skewing results.
No one took glycine supplements, so we don't know if pills would help heart or diabetes risks the same way.
The 2% role for glycine in heart protection is minor—most benefits come from elsewhere, like better blood sugar control.
Results mainly apply to people of European descent; effects could differ in other groups.
It doesn't explain how glycine protects the heart, like through inflammation or blood flow—we need more studies for that.

Overall, this builds excitement for SGLT2 drugs but calls for trials on glycine itself to see real-world benefits.

Key Findings

This Mendelian randomization (MR) study identified that SGLT2 inhibition (mimicked by genetic variants in the SLC5A2 gene) is associated with reduced risks of coronary artery disease (CAD) and type 2 diabetes (T2D). SGLT2 inhibition increased circulating levels of glycine, total choline, and phosphatidylcholine. Glycine showed a direct inverse association with CAD risk (OR 0.94 [0.91–0.98]) but not T2D, while total choline and phosphatidylcholine were linked to lower T2D risk. Mediation analysis revealed glycine accounts for 2% of the protective effect of SGLT2 inhibition on CAD, whereas choline metabolites mediate 5–8% of its effect on T2D.

Study Design

The study employed a two-sample two-step MR design, leveraging genetic proxies for SGLT2 inhibition (variants in SLC5A2 gene) and metabolite levels. Summary statistics were derived from:
- SGLT2 inhibition: Gene expression and HbA1c data.
- Metabolites: UK Biobank (n ≈ 118,000).
- CAD: CARDIoGRAMplusC4D consortium (n ≈ 60,000 cases, 123,000 controls).
- T2D: DIAGRAM consortium and FinnGen (n ≈ 74,000 cases, 824,000 controls).
No direct supplementation or intervention was tested; effects were inferred through genetic associations.

Dosage & Administration

This study did not involve glycine supplementation or administration. Instead, genetic variants (e.g., SLC5A2 SNPs) served as proxies to mimic the biological effects of SGLT2 inhibition, which indirectly increased endogenous glycine levels (β 0.34 [0.05–0.63] SD per 1 SD of SGLT2 inhibition).

Results & Efficacy

SGLT2 inhibition:
Reduced T2D risk (OR 0.25 [0.12–0.54], p < 0.001).
Reduced CAD risk (OR 0.51 [0.28–0.94], p = 0.03).
Glycine:
Inversely associated with CAD (OR 0.94 [0.91–0.98], p = 0.002).
No significant association with T2D (OR 0.99 [0.95–1.03], p = 0.58).
Mediation:
Glycine mediated 2% of SGLT2 inhibition’s effect on CAD (OR 0.98 [0.96–1.00]).
Total choline and phosphatidylcholine mediated 5–8% of SGLT2 inhibition’s effect on T2D.

All associations were statistically significant, with 95% confidence intervals excluding null effects where noted.

Limitations

MR assumptions: Potential violations, such as pleiotropy (genetic variants affecting multiple pathways), were not fully addressed.
Indirect effects: Results reflect genetically predicted SGLT2 inhibition, not direct glycine supplementation.
Small mediation proportion: Glycine’s contribution to CAD risk reduction (2%) is modest, suggesting other metabolites or mechanisms are more impactful.
Population homogeneity: Most data came from European-ancestry populations, limiting generalizability.
No mechanistic insight: The study does not clarify how glycine might biologically influence CAD.

Clinical Relevance

This study suggests SGLT2 inhibitors (commonly used for T2D) may reduce CAD risk partly through elevating glycine levels, though glycine’s mediated effect is small (2%). However, the research does not support glycine supplementation as a standalone intervention for CAD or T2D, as the observed benefits were indirect and secondary to SGLT2 inhibition. Clinicians should focus on established SGLT2 inhibitor benefits rather than glycine itself, while researchers may explore whether glycine potentiates the effects of these drugs. For supplement users, the findings highlight glycine’s potential role in cardiometabolic health but emphasize the need for direct clinical trials to validate its efficacy.