Results of an observational registry study of men with type 2 diabetes and hypogonadism (low testosterone) suggest that up to 12 years of testosterone injections every 3 months may improve glycemic control.
A second study in the same cohort hints that this treatment may lower the risk for cardiovascular events and improve survival ― but that study has inherent weaknesses and does not address safety concerns, experts caution.
Farid Saad, MD, who recently retired from Medical Affairs Andrology, Bayer, Berlin, Germany, and Karim S. Haider, MD, a urologist at a clinic in Bremerhaven, Germany, presented the latest results from the two observational studies in an oral session at the American Diabetes Association (ADA) 81st Scientific Sessions earlier in the summer.
Invited to comment, Maarten Albersen, MD, cautioned: “These are nonrandomized data; hence, any hard conclusions on the comparison between testosterone and control are impossible due to the fact that these groups are unadjusted for all potential confounders.”
Earlier this year, a randomized controlled trial (T4DM) that was published in Lancet Diabetes and Endocrinology showed that testosterone might prevent or revert type 2 diabetes in men enrolled in a lifestyle program, although there were safety concerns with this trial.
A large, ongoing randomized phase 4 trial, TRAVERSE, is expected to deliver results in a couple of years, noted Albersen, a member of the European Association of Urology Scientific Office, from Leuven University, Leuven, Belgium.
Glycemic Control, but at What Price?
Saad and Haider presented findings from 361 men with type 2 diabetes who underwent treatment in a urology clinic in Bremerhaven, Germany. Of those patients, 183 men opted to receive testosterone undecanoate (Nebido) 1000 mg, which was administered by injection every 3 months, and 178 men opted not to receive this treatment (control patients).
Saad presented the glycemic control findings.
“We previously published a study that showed that testosterone undecanoate injections were associated with prevention of progression from prediabetes to diabetes (Diabetes Care. 2019;42:1104-1111),” he told Medscape Medical News in an email.
This was followed by a study of 11 years of treatment in the patients in the current research, which was presented at the European and International Congress on Obesity (ECOICO 2020), as previously reported and subsequently published (Diabetes Obes Metab. 2020;22:2055-2068).
The current study showed that among men with hypogonadism and type 2 diabetes, from baseline to 12 years, mean A1c decreased from 9.4% to 5.6% in the group that received testosterone undecanoate injections (T-group) and increased from 7.8% to 10.4% in the control group.
“The randomized controlled trial [T4DM]…confirms the beneficial effects of testosterone plus exercise on glycemia and metabolic profile (with exercise only as a control group),” Albersen said.
But in the T4DM trial, a safety trigger for a hematocrit >54% was met by 22% of patients receiving testosterone, vs 1% of patients in the control group, “and it is known that an elevated hematocrit is a risk factor for thromboembolic events,” he pointed out.
Mortality, MACE, and Diabetic Complications
Haider reported findings regarding mortality, major adverse cardiovascular events (MACE; myocardial infarction [MI] or stroke), and diabetic complications.
At baseline, more than a third of patients (38%) in each group had a history of cardiovascular disease.
Compared to patients in the control group, those in the T-group were younger (mean age, 61 vs 63 years) but otherwise had a worse risk factor profile. They were more likely to smoke (41% vs 38%), they had higher mean body mass index (36 vs 33 kg/m2), higher systolic blood pressure (163 vs 145 mm Hg), higher LDL-cholesterol level (4.7 vs 4.1 mmol/L), and higher A1c (9.4% vs 7.8%; P < .0001 for all).
But during follow-up, fewer patients in the T-group than in the control group died (15 patients [8.2%] vs 61 patients [34%]).
None of the patients in the T-group had an MI or stroke, compared to 56 cases of MI (31.5%) and 56 cases of stroke (31.5%) in the control group.
Albersen says these results “do not make sense. No MI and stroke in the T-group seems somewhat bizarre (in a group with higher up-front risk).”
He wondered how strict the follow-up was and noted that the sample was too small to provide definitive conclusions about mortality.
With regard to microvascular complications, fewer patients in the T-group than in the control group developed retinopathy (3.3% vs 16.9%), nephropathy (0.01% vs 2.8%), or diabetic foot syndrome (0% vs 10.1%)
Waiting for TRAVERSE Trial Results for CV Safety of Testosterone
Albersen noted that the 5-year, AbbVie-sponsored phase 4 trial of testosterone gel in 6000 men, TRAVERSE, “is awaited to clarify cardiovascular effects of testosterone therapy in a randomized fashion…as there have been concerns on the cardiovascular safety.” That trial is expected to be completed in June 2022.
In a commentary that accompanied the publication of the T4DM study earlier this year, Naveed Sattar, MD, of the University of Glasgow, Glasgow, United Kingdom, and colleagues noted, “The US Food and Drug Administration agree [that caution is needed] and have mandated that any product for age-related hypogonadism should have a cardiovascular outcome trial.” This led to the TRAVERSE study.
“It is hoped the resulting data will at least show the cardiovascular safety of testosterone treatments in men with low serum testosterone (<10.4 nmol/L) and at least one symptom of hypogonadism,” the editorialists write.
Bayer AG (previously Schering AG) contributed partial funding for statistical analyses and data entry of the two studies. Haider is a speaker for and receives research and travel support from Bayer. Saad is a consultant for Bayer AG and owns shares for Bayer AG and AbbVie. Aboumarzouk and Albersen have disclosed no relevant financial relationships. Sattar has received personal fees and a research grant from Boehringer Ingelheim and personal fees from Amgen, AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. The disclosures of the other editorialists are with the editorial.
American Diabetes Association (ADA) 81st Scientific Sessions: Scientific Sessions. Presented on June 28, 2021. 238-OR, 240-OR.
Need Your Help Today. Your $1 can change life.