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Optimal Treatment In T2D For CV Protection  

Nov 21, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Destiny Funchess, PharmD Candidate, Tougaloo College, South College School of Pharmacy 

How triple therapy can lead to optimal CV and renal protection.  

Type 2 diabetes carries a specific risk for cardiovascular and chronic kidney disease. Diabetic nephropathy, kidney damage that results from having diabetes, is the most common cause of chronic kidney disease. Patients with diabetic kidney disease have exceptionally high rates of cardiovascular morbidity and mortality. The mortality rate in patients with diabetes appears to be limited mainly to the subgroup with kidney disease and is a result of their high cardiovascular disease burden. The mechanisms behind the strong association between diabetic kidney disease and different forms of cardiovascular disease are not entirely understood. Patients with diabetes are more than twice as likely to die from vascular causes as those without diabetes. Cardiovascular disease accounts for approximately 60% of the life-years lost from diabetes. Triple therapy combination for cardiovascular and renal protection includes sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists, and pioglitazone.  


Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the transporter molecules available in the proximal tubule. Sodium-glucose cotransporter 2 inhibitors influence the majority of glucose reabsorption by the kidneys. SGLT2 inhibitors act by limiting glucose reabsorption in the kidney at a lower threshold by inhibiting Sodium-glucose cotransporter 2 in the distal nephron. This causes renal glucosuria, resulting in lower blood glucose. Currently, available drugs in this class include canagliflozin, dapagliflozin, and empagliflozin. Both the monotherapy of SGLT2 inhibitors and the combination with other agents are effective in controlling hyperglycemia. Not only are they useful in controlling hyperglycemia, but they are also effective in cardiovascular and renal protection. In a large randomized controlled trial, empagliflozin has decreased major adverse cardiovascular events. Studies examining the effect of dapagliflozin and canagliflozin on renal outcomes are underway. Treatment of adults with type 2 diabetes with empagliflozin has already been shown to reduce nephropathy risk. 

Glucagon-like peptide-1 (GLP-1) receptor agonists represent a class of medications used to treat type 2 diabetes mellitus in adults. Glucagon-like peptide-1 and glucose-dependent insulin tropic polypeptide (GIP) are both incretin hormones. These hormones are inactivated by dipeptidyl peptidase-4 (DPP-4), which stimulates insulin secretion after an oral glucose load. In patients with type 2 diabetes, this process doesn’t occur. The benefit of Glucagon-like peptide-1 (GLP-1) receptor agonists includes delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells if blood sugar levels are high. In terms of cardiovascular effects, GLP-1 agonists can improve left ventricular ejection fraction, myocardial contractility, coronary blood flow, cardiac output, and endothelial function while reducing infarction size and overall risks for a cardiovascular event. Drugs in this class include exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, and semaglutide.  There were four trials of cardiovascular outcomes of GLP-1 receptor agonists. Findings from the four trials showed that compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome.  

Pioglitazone is a glucose-lowering medication that works as an agonist of peroxisome proliferator-activated receptor-gamma. The Prospective Pioglitazone Clinical Trial in Macrovascular Events reported in 2005 that pioglitazone had a beneficial effect on cardiovascular disease.  This included reducing all-cause mortality and nonfatal myocardial infarction and stroke in patients with type 2 diabetes with a macrovascular disease history. There was also a randomized control trial that provided evidence of renal protection with pioglitazone in diabetic nephropathy.  

Ralph A. Defronzo, MD, who is the diabetes research unit director at the University of Texas Health Science Center at San Antonio, suggested the triple therapy combination of these three drugs during an online presentation. He also recommended other possible combination options for adults with type 2 diabetes. For patients with a prior stroke, he recommends pioglitazone plus GLP-1 receptor agonist. For patients with previous myocardial infarction, he recommends pioglitazone plus SGLT2 inhibitor plus GLP-1 receptor agonist. For renal outcomes prevention, he recommends SGLT2 inhibitor plus GLP-1 receptor agonist. Dr. Defronzo stated, “My prediction is we will be using individualized therapy for individualized people for CV risk reduction.” 

Practice Pearls: 

  • Triple therapy combination could serve as an optimal solution for cardiovascular and renal protection in type 2 diabetes 
  • According to Dr. DeFronzo, individualized therapy is needed for CV protection in the setting of type 2 diabetes 
  • In order to reduce the risk for cardiovascular diseases we need to look at those antidiabetic medications that have documented cardiovascular benefit, which are the SGLT2 inhibitors, pioglitazone and GLP-1 receptor agonists. 


References for “Optimal Treatment In T2D For CV Protection”:

2020 Robert E J Ryder, Ralph A DeFronzo, 10.15277/bjd.2020.250, British Journal of Diabetes https://bjd-abcd.com/index.php/bjd/article/view/551/741 

Destiny Funchess, PharmD Candidate, Tougaloo College, South College School of Pharmacy  


See our exclusive interview with Dr. Ralph DeFronzo.