Two birds, one stone

Two birds, one stone

By: James LeFevre

Diabetes and hypertension are like a dynamic duo. Through numerous pathophysiological mechanisms, diabetes and hypertension are strongly linked. Diabetes increases the risk of hypertension, while simultaneously, hypertension increases the risk of diabetes. A match made in heaven? Unfortunately so.

Due to the strong linkage between diabetes and hypertension, identifying drugs that treat both conditions is incredibly important. Currently we have a few weapons in our arsenal—angiotensin II receptor blockers (ARBs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. 

ARBs are antihypertensive drugs that several clinical studies have shown to decrease the incidence of new-onset diabetes in patients with hypertension and heart failure. Subsequently, ARBs have been highly recommended as treatments for patients with both diabetes and hypertension by the American Diabetes Association. Likewise, recent studies have shown that antidiabetics drugs, SGLT2 inhibitors, possess cardioprotective effects that reduce the risk of cardiomyopathy for diabetic patients. So, you may ask, are these drugs treating diabetes or heart issues? Yes.

Improving diabetes with antihypertensive drugs

In a study performed by Liu and colleagues, three ARBs—telmisartan, valsartan, and irbesartan—were applied to evaluate their effects on insulin secretion and the underlying electrophysiological mechanism. The study involved using rat islets for in vitro experimentation and db/db mice for in vivo experimentation. Here’s what they learned:

  • Telmisartan enhances glucose-stimulated insulin secretion, but valsartan and irbesartan do not.
    • This effect was found to be independent of AT1 receptors.
  • Telmisartan increases intracellular calcium levels in β-cells, but valsartan and irbesartan do not.
  • Telmisartan activates voltage-gated calcium channels independent of AT1 receptors and Peroxisome proliferator-activated receptor gamma.
  • Telmisartan inhibits voltage-gated potassium (Kv) channels and prolongs action potential durations in β-cells.
    • Telmisartan directly inhibits Kv2.1 channels.
  • In vivo experimentation showed that Telmisartan improves hyperglycemia by increasing insulin secretion and amplifies glucose-stimulated insulin secretion in db/db mice.

Notably, Telmisartan was found to induce insulinotropic effects only at high concentrations of glucose, even with high concentrations of Telmisartan. This glucose-dependent effect indicates that Telmisartan may be useful in treating hyperglycemia without the risk of causing hypoglycemia. Additionally, this approach may prevent excessive insulin secretion and accelerated β-cell decline that is observed with glucose-independent insulinotropic agents.

Improving heart issues with antidiabetics drugs

In a separate class of drugs, SGLT2 inhibitors have shown to improve cardiovascular outcomes in diabetic patients. In a review on SGLT2 inhibitors, Brown and colleagues report three long-term outcomes trials (EMPA-REG OUTCOME trial, CANVAS program, and DECLARE TIMI-58 trial) that have shown a reduction in hospitalization due to heart failure in patients treated with SGLT2 inhibitors. This was seen in patients without pre-existing heart failure and pre-existing cardiovascular disease. Significant reductions in cardiovascular mortality were also found in two of the trials. Brown and colleagues report several mechanisms that have been proposed to explain the cardioprotective effects of SGLT2 inhibitors:

  • Glucosuric effect: SGLT inhibition increases glucose excretion and, therefore, osmotic diuresis. Subsequently, the intravascular volume decreases, ventricular preload decreases, and myocardial oxygen consumption decreases.
  • Depletion of sodium levels: Lower concentrations of sodium in the skin may lower blood pressure and improve heart function.
  • NHE inhibition: NHE1 inhibition increases mitochondrial ATP generation and antioxidant enzyme defenses which, in turn, may prevent heart failure.
  • SGLT2 inhibitors may prevent cardiac heart failure by increasing overall cardiac energy production through an increase in glucose and fatty acid oxidation.

Where does this lead us? ARBs and SGLT2 inhibitors may serve as effective strategies to combat patients with both diabetes and heart issues. Although SGLT2 inhibitors are normally indicated for type 2 diabetics, their cardioprotective effects may provide benefits for type 1 diabetics as well. Likewise, future research on ARBs may paint a clearer picture on how they benefit type 1 diabetics. The unintended benefits of SGLT2 inhibitors and ARBs may pave a way towards novel drugs through drug repurposing. Additionally, more research may lead to new drug combination therapies for diabetic patients with heart problems. 

Sources

  • American Diabetes Association. (2015). Standards of medical care in diabetes-2015 abridged for primary care providers. Clinical diabetes: a publication of the American Diabetes Association, 33(2), 97–111. doi: 10.2337/diaclin.33.2.97
  • Brown, E., Rajeev, S. P., Cuthbertson, D. J., & Wilding, J. (2019). A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors. Diabetes, obesity & metabolism, 21(2), 9–18. https://doi.org/10.1111/dom.13650
  • Liu, T., Cui, L., Xue, H., Zhi, L., Yang, X., Yang, H., … Zhang, Y. (2020, January 1). Telmisartan potentiates insulin secretion via ion channels, independent of the AT1 receptor and PPARγ. bioRxiv. https://doi.org/10.1101/2020.09.20.305334.
  • Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., … Matthews, D. R. (2017). Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine, 377(7), 644–657. doi:10.1056/nejmoa1611925 
  • Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., … Sabatine, M. S. (2018). Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. doi:10.1056/nejmoa1812389 
  • Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., … Inzucchi, S. E. (2015). Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine, 373(22), 2117–2128. doi:10.1056/nejmoa1504720

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