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Type 2 diabetes is rapidly increasing worldwide, and there have been many advances in the care of diabetic patients. Nevertheless, less than half of the patients are achieving the glycemic goal of HbA1c < 7%. This shows that current therapeutic modalities have limitations, and the need for continued development of new antidiabetic drugs is clear. In 2007, a meta-analysis focusing on the thiazolidinedione drug rosiglitazone suggested an unacceptably high cardiovascular risk for this newly approved drug, prompting changes in regulations for antidiabetic drug development. The FDA guidance for Diabetes Mellitus-Evaluation of Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes was released as a draft in Feb 2008, and the final form was published in December 2008. The guidance, though not a regulation, requires developers to demonstrate that all new antidiabetic agents have an acceptable cardiovascular risk. The European Medicine Agency (EMA) also published a draft guideline in January 2010 on the clinical investigation of medicinal products for the treatment of diabetes mellitus which included a cardiovascular safety assessment component. Considering the increased CV risk in type 2 diabetic patients, antidiabetic drugs should not result in an unacceptable increase in cardiovascular risk. The FDA has offered guidelines for the assessment of cardiovascular safety for antidiabetic drugs. Careful prospective planning of clinical trials (choice of study type, subject selection, and meta-analysis) and thorough preclinical safety assessment (choice of cardiovascular endpoints: MACE, endpoint adjudication) are needed to assess possible cardiovascular risk.
Diabetes Mellitus ; Humans ; Hypoglycemic Agents ; Social Control, Formal ; Thiazolidinediones

10.Optimized mixture of hops rho iso-alpha acids-rich extract and acacia proanthocyanidins-rich extract reduces insulin resistance in 3T3-L1 adipocytes and improves glucose and insulin control in db/db mice.

Matthew L TRIPP ; Gary DARLAND ; Veera Reddy KONDA ; Linda M PACIORETTY ; Jyh Lurn CHANG ; Jeffrey S BLAND ; John G BABISH

Nutrition Research and Practice 2012;6(5):405-413

Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 (6.25 microg/mL) exhibited the greatest reductions in TNFalpha-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to 5 microg/mL troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination (5 microg/mL) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to 5 microg/mL pioglitazone or 901 microg/mL aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.
Acacia ; Adipocytes ; Animals ; Aspirin ; Chromans ; Glucose ; Humulus ; Insulin ; Insulin Resistance ; Interleukin-6 ; Lipolysis ; Metformin ; Mice ; Thiazolidinediones

1.Troglitazone and tumor inhibition: an evolving concept in the management of systemic malignancies.

2.Response: Effects of Rosiglitazone on Inflammation in Otsuka Long-Evans Tokushima Fatty Rats (Korean Diabetes J 2010;34:191-9).

3.Letter: Effects of Rosiglitazone on Inflammation in Otsuka Long-Evans Tokushima Fatty Rats (Korean Diabetes J 2010;34:191-9).

4.Response: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8).

5.Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8).

6.Response: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8).

7.Letter: The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone (Diabetes Metab J 2012;36:371-8).

8.The Effect of Rosiglitazone and Metformin Therapy, as an Initial Therapy, in Patients with Type 2 Diabetes Mellitus.

9.Clinical Trial for Antidiabetic Drugs: FDA Guidance for Diabetes Mellitus-Evaluation of Cardiovascular Risk in New Antidiabetic Therapies.

10.Optimized mixture of hops rho iso-alpha acids-rich extract and acacia proanthocyanidins-rich extract reduces insulin resistance in 3T3-L1 adipocytes and improves glucose and insulin control in db/db mice.

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