DPP-4 Inhibitors, Lipid-Lowering Agents & Risk of Serious Muscular Injury

5-year examine challenges alleged improve in threat for extreme muscular harm when combining DPP-4 inhibitors with lipid-lowering brokers.

The European Medicines Company issued a security warning for elevated muscular harm threat utilizing dipeptidyl peptidase-4 (DPP-4) inhibitors in 2012. The discover was based mostly on a number of instances reported to the European pharmacovigilance system. This warning was very regarding to those who have been taking DPP-4 together with statins and fibrates. To check this concept, a examine was carried out. Rhabdomyolysis was the muscle harm that the European Medicines Company was most involved about. Rhabdomyolysis is brought on by harm to the skeletal muscle. It additionally includes leakage of poisonous intracellular fluid into plasma. Reducing-lipid brokers resembling statins are identified for the danger of muscular accidents, resembling Rhabdomyolysis. There are a couple of theories on the mechanism behind the danger of muscular harm with statins. One view is that it outcomes from mitochondrial dysfunction as a consequence of statins inhibiting motion on HMG-CoA reductase exercise and ldl cholesterol synthesis. The mechanism for muscular toxicity resulting in harm is much less established for DPP-4 inhibitors. Fibrates, that are additionally a category of lipid-lowering medication, have been additionally utilized by sufferers in the course of the examine.  

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a comparatively new class of oral diabetes medication. Also referred to as gliptins, they’re normally prescribed for folks with sort 2 diabetes who haven’t responded nicely to metformin and different medicines. The medicines on this drug class include Januvia (Sitagliptin), Galvus (Vildagliptin), Onglyza (Saxagliptin), and Tradjenta (Linagliptin). These medicines work by blocking the motion of DPP-4, which is an enzyme that destroys a gaggle of gastrointestinal hormones often known as incretins. Incretins assist stimulate the manufacturing of insulin when it’s wanted.  

Statins are generally used to decrease ldl cholesterol by decreasing the manufacturing of ldl cholesterol by the liver. The enzyme within the liver answerable for making ldl cholesterol is named hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). The medicines on this drug class include Atorvastatin (Lipitor), Lovastatin (Altoprev), Pitavastatin (Livalo, Zypitamag), Pravastatin (Pravachol), Rosuvastatin (Crestor, Ezallor), Simvastatin (Zocor). To evaluate muscular harm threat utilizing DPP-4 inhibitors and lipid-lowering brokers resembling statins, a pharmacoepidemiologic strategy was used. Knowledge from a nationwide medico administrative database was additionally used.  

The usage of fibrates leads to a lower in plasma triglycerides and is normally related to a average discount in LDL ldl cholesterol and a rise in HDL ldl cholesterol concentrations. The medicines on this drug class embody Fenofibrate (Antara, Lipofen, Lofibra, Tricor), Fenofibric acids (Fibricor, Trilipix), Gemfibrozil (Lopid). Not like statins, fibrates usually don’t trigger muscular harm, except they’re paired with statins. Medical doctors typically keep away from combining a statin with fibrates due to concern over the upper threat of muscle harm with the mix. 

A nested case-control examine in a nationwide cohort of sufferers with type-2 diabetes mellitus was used. The examine interval ranged from January 1, 2009, to December 1, 2014. The examine included people with no historical past of DPP-4 inhibitor use earlier than cohort entry. Over 700,000 persons are registered within the database that was used for this examine. There have been 35,117 sufferers with sort 2 diabetes constituting the supply cohort. The subpopulation outcomes confirmed that the usage of DPP-4 inhibitor medicines was not considerably related to an elevated threat of muscular harm. Nevertheless, some sufferers have been concomitantly utilizing statins and fibrates and skilled an elevated threat of muscular harm as anticipated. The examine’s authors failed to seek out any proof of an affiliation between DPP-4 inhibitor use and the danger of extreme muscular harm in sufferers with diabetes utilizing lipid-lowering medicines.  

Observe Pearls: 

• The European Medicines Company issued a security warning for elevated muscular harm threat utilizing dipeptidyl peptidase-4 (DPP-4) inhibitors in 2012. 
• The outcomes confirmed that the usage of DPP-4 inhibitor medicines was not considerably related to an elevated threat of muscular harm. 
• Medical doctors typically keep away from combining a statin with fibrates due to concern over the upper threat of muscle harm with the mix, which was demonstrated on this examine.  

Pariente, A., Labat, V., et al. DPP-4 Inhibitors in Combination with Lipid-Lowering Agents and Risk of Serious Muscular Injury: A Nested Case-Management Examine in a Nationwide Cohort of Sufferers with Sort 2 Diabetes Mellitus. Drug Saf 43, 767–774 (2020).  

Future Funchess, PharmD Candidate, Tougaloo School, South School Faculty of Pharmacy