FDA has approved a new treatment of Invokana for diabetic kidney disease, which affects one in three patients with type 2 diabetes.
Unfortunately, chronic kidney disease (CKD) affects one in three patients with type 2 diabetes. CKD increases the risk for serious cardiovascular events and end-stage renal disease in patients with type 2 diabetes. A common complication of diabetic kidney disease is heart failure, the leading cause of hospitalization in this population. About 30 percent of patients with Type 1 diabetes and 10 to 40 percent of those with Type 2 diabetes eventually will experience kidney failure. The approval of Invokana meets a 20 year need for therapy to improve outcomes in patients with type 2 diabetes, diabetic kidney disease. Moreover, the FDA indication further approved for a reduction in heart failure hospitalization and reduction in associated mortality in CKD, one of the highest risk groups for heart failure.
This drug has the potential to not only be a game changer in the battle with diabetes but to also save a lot of American lives, where diabetes is considered a serious health epidemic.
A major development and life altering news arrived on September 30th, 2019 for patients suffering from Diabetic Kidney Disease and type 2 diabetes. Right now, Invokana is the first and only medication that can reduce progression of Diabetic Kidney Disease and lower the risk of heart failure for many patients suffering from this disease and type 2 diabetes. Aside from reducing the risk of heart failure, Invokana can also reduce the risk of end-stage kidney disease, which is primarily caused by type 2 diabetes, and cardiovascular death.
Invokana approval in this population is founded on the phase 3 CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study. This landmark study indicated that Invokana significantly lowered the risk of cardiovascular events and the progression to end stage renal disease in patients with type 2 diabetes and diabetic kidney disease. In addition, this is the first study to show a significant reduction in cardiovascular events in patients without preexisting cardiovascular disease. These findings have been published in The New England Journal of Medicine and added to the standards of medical care by the American Diabetes Association.
CREDENCE is the first SGLT2 inhibitor study with primary renal outcomes in this population. This study is a randomized, double blind, parallel, placebo, multicenter study that evaluated 4,402 type 2 diabetes patients with diabetic kidney disease from 34 countries. The patients received the standard of care to include an ACE (angiotensin-converting enzyme) or ARB (angiotensin II receptor blocker). The primary outcomes were as follows: diagnosis of end-stage renal disease, doubling of serum creatinine level, renal death, or cardiovascular related death. Secondary outcomes included heart attack, stroke, and hospitalization due to heart failure. Exclusion criterion as follows, type 1 diabetes, history of diabetic ketoacidosis, liver disease, NYHA class IV heart failure, primary renal glucosuria, and renal disease treated with immunosuppressive therapy.
Results show that a 100 mg dose of Invokana reduced the risk of heart attack, stroke, and cardiovascular related deaths by 20% compared to placebo. In addition, cardiovascular death and hospitalizations related to heart failure were reduced by 31% and 39% among subgroups. Overall, Invokana had a composite risk reduction of stroke, heart attack, and cardiovascular related deaths by 32%. The renal results indicated similar positive outcomes with a 30% reduction in the composite endpoint including end-stage renal disease, doubling of serum creatine, and renal or cardiovascular death. Specifically, the risk of progression to end-stage renal disease was reduced by 31% and 33% in the subgroups with Invokana. Although all medications carry some risk, adverse and serious events were low for Invokana, rendering positive safety outcomes. CREDENCE was adequately powered to detect risk reduction and was overseen by seventeen academics and two trial sponsors.
Adverse events associated with SGLT2 inhibitors include urinary-genital tract infections that are seen particularly in women and uncircumcised men. Increased urination does occur with the use of Invokana, but only 350-450 ml of extra urine is excreted and luckily it does not cause frequent urination at night. Hypoglycemia is seen as a major side effect with many glucose lowering medications, but rarely with this one since it has a non-insulin-based mechanism of action. If this medication was being prescribed alongside other diabetes medications, specifically, insulin or a sulfonylurea like glipizide, then the risk of hypoglycemia would increase. Invokana may contribute to dehydration when used with a diuretic. While Invokana was originally thought to be associated with increased risk of lower-limb amputation, i.e., removal of the toe or part of the foot, this was not confirmed in the CREDENCE trial in an even higher risk group. Moreover, the risk for amputation in CREDENCE was widely divergent, with certain countries having a much higher risk than others, the US, Japan and Taiwan having the lowest risks. Genital infections are a very rare occurrence in people taking Invokana with an incidence of <0.00001%. Women tend toward vaginal yeast infections, while men may develop a yeast infection of the skin around the penis.This is avoided however, by keeping the area clean and using drying agents such as corn starch. In CREDENCE no genital infections were reported in Japan. Another rare side effect that can be prevented is diabetic ketoacidosis which is also very rare, 12/4401 people in CREDENCE. It occurs again in people on insulin or sulfonylureas that have volume depleting illness like diarrhea and reduce insulin dose but continue the SGLT2 inhibitor. This can be prevented with a little patient education to stop the SGLT2 until recovered from illness.
Diabetic kidney disease is a silent killer and many type 2 diabetes patients do not realize they developed this complication until it is too late. Once patients are diagnosed with end-stage renal disease they have a five-year survival rate of less than 40%. Invokana proves to reduce the risk of serious type 2 diabetic complications and is set to improve the health trajectory for this population.
As a healthcare professional, it is very important to come to realization on how technology is quickly changing and evolving indications for medications used for those with type 2 diabetes. Invokana has been around as a major diabetes medication for many years. The simple fact that now we can use this medication as an asset in reducing the risk of diabetic kidney disease on top of reducing hospitalizations due to heart failure is a significant accomplishment for so many people across the world. The new indication provides patients with a far vaster spectrum of options that are available to them.
- A 100 mg dose of Invokana reduced the risk of heart attack, stroke, and cardiovascular related deaths by 20% compared to placebo.
- This is the first study to show a significant reduction in cardiovascular events in patients without preexisting cardiovascular disease.
- The risk of progression to end-stage renal disease was reduced by 31% and 33% in the subgroups with the use of Invokana.
Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy -Retrieved from https://clinicaltrials.gov/ct2/show/NCT02065791.
Jardine, M. J., Mahaffey, K. W., Neal, B., Agarwal, R., Bakris, G. L., Brenner, B. M., … Perkovic, V. (2017). The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. American Journal of Nephrology, 46(6), 462–472. doi: 10.1159/000484633
Bakris GL. Major Advancements in Slowing Diabetic Kidney Disease Progression: Focus on SGLT2 Inhibitors. Am J Kidney Dis. 2019.-Online