Old Malaria Drug as Good as Blockbuster Type 2 Diabetes Agent

LOS ANGELES — The old generic malaria drug hydroxychloroquine appears to have beneficial effects in patients with type 2 diabetes, new research suggests.

The findings were presented April 26 here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by Amit Gupta, MD, of the GD Diabetes Institute, Kolkata, India.

Hydroxychloroquine is an immunomodulatory drug traditionally used to treat malaria and is also a disease-modifying anti-rheumatic drug used for rheumatoid arthritis and lupus.

Data also suggest that it increases intercellular insulin availability by inhibiting insulin-degrading enzymes and has anti-inflammatory properties.

Since 2014, hydroxychloroquine has been approved in India as an add-on for patients with type 2 diabetes who don't achieve glycemic targets with two other oral glucose-lowering drugs, "which is quite a common scenario," Gupta commented during his presentation.

In a 24-week study involving 87 patients not reaching glycemic targets using maximal doses of both metformin and the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin (Galvus, Novartis), adding 400 mg hydroxychloroquine reduced HbA_1c to the same degree as adding 300 mg canagliflozin (Invokana, Janssen), a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, with a bit more weight loss and similar safety profiles.

"Hydroxychloroquine can be an alternative for patients who cannot afford canagliflozin [because of] high cost," Gupta said.

Asked to comment, session moderator Lance Sloan, MD, medical director of the Texas Institute for Kidney and Endocrine Disorders, Lufkin, Texas, told Medscape Medical News: "I think it's really fascinating that they've approved it for the treatment of diabetes in India. It's really not on the radar here in this country."

He noted that although hydroxychloroquine does appear to safely lower glucose, "Obviously we have much more cardio-renal information about canagliflozin that we don't have with this. It's not just about glucose-lowering any more. We'd like to have drugs that affect other aspects of the disease process."

And, Sloan said, "It's generic, so there's not a big pharma company that's going to spend a lot of money trying to do the cardiovascular outcome trials."

But at least one such trial with hydroxychloroquine is now being conducted in India, Gupta noted.

An internet check of US chain pharmacies revealed that prices for 60 x 200 mg tablets of hydroxychloroquine ranged from $25.54 to $59.25. For 30 x 300 mg tablets of canagliflozin, the range is $497.76 to $526.06.

Hydroxychloroquine Lowers HbA1c, BMI, and CRP

In the 24-week, multicenter, open-label study, the 87 patients with relatively recently diagnosed type 2 diabetes (average duration 6.1 years) and mean HbA_1c of 8.4% who were taking metformin 2000 mg and vildagliptin 100 mg daily were randomized to add-on hydroxychloroquine 400 mg or canagliflozin 300 mg daily.

The primary outcome, change in HbA_1c from baseline to week 24, decreased from 8.32% to 7.11% (P = .001) with hydroxychloroquine and from 8.63% to 7.44% with canagliflozin (P = .001), with an insignificant difference between the two groups (P = .29).

Fasting plasma glucose dropped from 143 to 112 mg/dL (P = .001) and 147 to 117 mg/dL (P = .001) with hydroxychloroquine and canagliflozin, respectively (P = .31 between groups). Values for post-prandial glucose were 210 to 142 mg/dL (P = .001) and 219 to 153 mg/dL (P = .001), respectively (P = .05 between groups).

Interestingly, body mass index (BMI) dropped significantly with hydroxychloroquine (from 27.2 to 25.7 kg/m²; P = .003), but remained unchanged with canagliflozin (27.9 to 27.5 kg/m²; P = .312).

"We were very surprised with the weight loss," Gupta said, noting that some patients reported an increased appetite with canagliflozin and that weight loss with hydroxychloroquine might also be because of the drug's anti-inflammatory effect.

Sloan commented, "I'm still a little perplexed about what the mechanism is for the weight loss [with hydroxychloroquine]. I'm not aware of that in the rheumatology literature."

Rates of reported hypoglycemia were 5.4% with hydroxychloroquine versus 8.2% with canagliflozin. Confirmed hypoglycemia, however, defined as symptoms plus measured glucose < 50 mg/dL, occurred in 0% versus 2.3%, respectively.

There were no cases of new-onset or worsening retinopathy, a known adverse event associated with both hydroxychloroquine and diabetes, Gupta said in response to a question from the audience.

High-sensitivity C-reactive protein (hsCRP) levels dropped from 2.8 to 1.9 mg/dL with hydroxychloroquine (P = .001) but did not significantly change with canagliflozin (2.7 to 2.5 mg/dL; P = .38), with a significant difference between groups (P = .001).

According to Gupta, "The state of the art of diabetic treatment is beyond glycemic control. It's to address the residual risk that we are often neglecting, that is the state of low-grade chronic inflammation which acts as a connect between diabetes, obesity, and cardiovascular mortality and morbidity. The time has come to break this connect so that the progress and the morbidity of diabetes can be arrested."

"Hydroxychloroquine, with its dual property of reducing blood sugar and as an anti-inflammatory drug, can emerge out as an important drug in the arsenal in the anti-diabetic regimen."

Sloan commented, "It might be something to consider if cost is a problem." But he also pointed out that "canagliflozin has great renal data with CREDENCE that we don't have with this medication...I think it's an interesting medication with regard to glucose lowering...but until they show me the data with regard to the cardiorenal stuff, I think I'll still go with an SGLT2 inhibitor."

Gupta has reported no relevant financial relationships. Sloan has disclosed being a consultant and/or speaker for AstraZeneca, Janssen, Merck, Pfizer, Boehringer Ingelheim, Lilly, and Novo Nordisk.

AACE 2019. Presented April 26, 2019.

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