Are We Hitting the Sweet Spot with Medications for Type 2 Diabetes? Part 2

Ian Jackson

Former National Health Service (NHS) Prescribing Adviser and Senior Lecturer in Clinical Pharmacology and Therapeutics at a UK Medical/Pharmacy School. Director Green Pill Training Ltd.

Contact: ian.pharmacist@gmail.com

In this article we look at the evidence for two categories of drugs used in the treatment of type 2 diabetes (thiazolidinediones and dipeptidylpeptidase-4 inhibitors).

Glitazones; In the Twilight Zone?

It was 2010 when rosiglitazone was withdrawn from the UK market. It was effective at lowering blood glucose but increased the risk of heart attacks and strokes. This leaves just one thiazolidinedione, pioglitazone, on the market, in the UK. (1)

A recent meta-analysis of 26 studies with 19 645 participants showed that pioglitazone reduced the risk of major adverse cardiovascular events (MACE)(RR, 0.8 [95% CI, 0.7–0.9]), with benefit only seen in patients with a history of established cardiovascular disease (0.8 [0.7–0.9]) and not in those without (1.0 [0.7–1.3]). No treatment effect was found on cardiovascular death (1.0 [0.7–1.2]) regardless of the presence of established CVDs. (2)

Pioglitazone treatment led to a higher risk of heart failure with a number needed to harm (NNH) of 34 and 44 for hospitalization for heart failure. For every 34 patients on pioglitazone we can expect one to develop heart failure. Pioglitazone can increase peripheral oedema, especially in combination with insulin. There is also a small increased risk of bladder cancer with pioglitazone. (3)

The National Institute for Health and Care Excellence (NICE) recommend that pioglitazone is not recommended or continued in patient’s with any of the following: heart failure or history of heart failure, hepatic impairment, diabetic ketoacidosis, current, or a history of, bladder cancer or uninvestigated macroscopic haematuria. (4)

Gliptins: Are They as Sweet as They Seem?

The dipeptidylpeptidase-4 inhibitors (gliptins), alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin have numerous benefits in that they are associated with far less weight gain and hypoglycaemia than the sulfonylureas. The main question is, do they reduce macrovascular events?

EXAMINE was a randomized, double-blinded study in 5,380 type 2 diabetic patients with a recent acute coronary syndrome event (ie. very high risk patients) comparing alogliptin vs. placebo. The primary outcome was 3-point MACE and the median follow-up was 18 months. The HbA1c was significantly lower in the alogliptin group but there was no significant reduction in cardiovascular events. (5)

CARMELINA is was a study for linagliptin involving 8,300 patients and TECOS was a similar study for sitagliptin involving 14,671 patients with type 2 diabetes and established CVD. Both linagliptin and sitagliptin did not show a clinically significant reduction in cardiovascular events when compared to placebo. (6)

SAVOR-TIMI was a double-blinded, randomised, placebo-controlled study in 16,492 type 2 diabetic patients with established CVD or multiple risk factors for CVD comparing saxagliptin vs. placebo. There was no reduction in the primary endpoints of 3 point MACE. (7) What was concerning was an increase in heart failure hospitalisation in the saxagliptin group. This led the U.S. Food and Drug Administration (FDA) to add warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. (8)

The FDA have also issued a warning that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain that can be severe and disabling. (9)

Discussion

The benefit of pioglitazone was consistently greater in secondary than primary prevention. The high risk of heart failure means that pioglitazone should be reserved for those patients at high risk of cardiovascular disease but with no history of heart failure and when other treatment strategies for type 2 diabetes have been tried.

Gliptins improve glycaemic control, but these studies have shown they have limited benefits in terms of reducing cardiovascular events even in very high-risk groups. This highlights the dangers of chasing surrogate markers to hit targets rather than focusing on outcomes.

References:

1) https://www.nursingtimes.net/news/behind-the-headlines-archive/avandia-diabetes-drug-suspended-27-09-2010[accessed 12 March 2023].

2) Zhou Y. et al. Pioglitazone for the Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Patients with or at High Risk of Type 2 Diabetes Mellitus: A Meta-Analysis, The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 5, May 2020, P1670–168.

3) Sinha, B. et al. Assessing the need for pioglitazone in the treatment of patients with type 2 diabetes: a meta-analysis of its risks and benefits from prospective trials. Sci Rep 10, 15781 (2020).

4)https://bnf.nice.org.uk/drugs/pioglitazone [accessed 12 March 2023]

5) White W, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369:1327-1335.

6) Green J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232-242.

7) Scirica B, el al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013; 369:1317-1326.

8) U.S. Department of Health and Human Services. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. February 2014. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-adds-warnings-about-heart-failure-risk-labels-type-2-diabetes [accessed 12 March 2023]

9) U.S. Department of Health and Human Services. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause joint pain. August 2015. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm [accessed 12 March 2023]