With respect to prostate cancer mortality, metformin plus a statin was associated with a 36% reduction in risk of death.— Grace Lu-Yao, PhD, MPH
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A population-based retrospective cohort study involving 12,700 patients found that men with high-risk prostate cancer who took a statin alone or in combination with metformin had reduced all-cause and prostate cancer–specific mortality. The associations between the medications and reduced mortality were significant and “more pronounced in postdiagnostic users,” the authors wrote in Cancer Medicine.1
“With respect to prostate cancer mortality, metformin plus a statin was associated with a 36% reduction in risk of death,” said senior author Grace Lu-Yao, PhD, MPH, Associate Director of Population Science, Sidney Kimmel Cancer Center–Jefferson Health, and Vice Chair of Medical Oncology, Sidney Kimmel Medical College, Philadelphia. Among study participants whose first documented prescription for a study medication occurred after their diagnosis of prostate cancer, the combination of metformin plus a statin was associated with a 54% reduction in prostate cancer mortality, as well as a 32% reduction in all-cause mortality, compared with those who used neither drug.
Users of a statin alone in the postdiagnostic setting had a 42% reduction in prostate cancer mortality and a 27% reduction in all-cause mortality. “Metformin alone did not show any significant effects on all-cause mortality and [prostate cancer] mortality among either prediagnostic or postdiagnostic users,” the authors wrote.
“Based on Cox models, metformin plus a statin (hazard ratio [HR] = 0.75; 95% confidence interval [CI] = 0.67–0.83) and a statin alone (HR = 0.89; 95% CI = 0.83–0.96) were significantly associated with a lower all-cause mortality, after adjusting for potential confounders,” the researchers reported.
Improved Median Survival
Median survival was the same—3.1 years—for patients with high-risk prostate cancer who took metformin alone or who took neither metformin nor a statin. Median survival was higher—3.6 years—for those who took a statin alone and highest—3.9 years—for men who took both drugs.
“Among patients with stage IV [prostate cancer], data suggest there might be some synergistic effect between statins and metformin (HR = 0.93 for metformin alone, 0.82 for statin alone, and 0.66 for metformin plus a statin), although this interaction did not reach statistical significance (P for interaction = .18),” the authors noted.
“While the pattern found in stage IV prostate cancer is consistent with the findings from a preclinical study, the interaction did not reach statistical significance…. It could be because our sample size wasn’t sufficient.” Dr. Lu-Yao said.
Focused on High-Risk Patients
The study used data from the Surveillance, Epidemiology, and End Results (SEER) database and Medicare files to identify patients with high-risk prostate cancer diagnosed from 2008 through 2011. “We selectively focused on high-risk [prostate cancer] (T category ≥ T2c or prostate-specific antigen level ≥ 20 ng/mL or Gleason score ≥ 8; equivalent to overall cancer stage ≥ IIB), because evidence regarding statin effects are most consistent for advanced [prostate cancer],” the authors explained.
The study was restricted to those who survived at least 6 months. As Dr. Lu-Yao explained in an interview with The ASCO Post, “The recommendation for statins is for long-term maintenance to prevent cardiovascular disease, but growing evidence supports discontinuing statins for patients who have a limited life expectancy.” Without the exclusion of those patients, “the nonuser group could end up having sicker patients with a shorter life expectancy. When we included patients with less than 6 months of survival in the analysis, the results were similar.”
“The majority of patients with [prostate cancer] who later develop lethal metastatic disease have high-risk localized disease at presentation, also emphasizing the importance of effective treatment strategies at this stage,” the researchers noted. “Identifying or developing additional therapies with low toxicity and cost is important to improve longevity and quality of life of men diagnosed with high-risk [prostate cancer].”
Higher Comorbidities
Among the 12,700 patients included, 4,568 took neither a statin nor metformin. A total of 435 took metformin alone; 5,786 took a statin alone; and 1,911 took both drugs. Among men who took metformin, 81% also took statins. “Very few men took metformin alone, and we couldn’t get a very precise estimate of the effect,” Dr. Lu-Yao said.
Statins either alone or in combination hold high promise for high-risk prostate cancer.— Grace Lu-Yao, PhD, MPH
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The median age of patients at diagnosis was 74 years. Users of statins and metformin alone or in combination “were significantly younger and more likely to have diabetes, obesity or metabolic syndrome, and hyperlipidemia, and they had a higher Charlson [Comorbidity Index] score with less advanced-stage cancer,” the authors noted. Although 13% of patients who did not use metformin or statins had a Charlson score of 2+, 26% of those who used metformin alone, 22% of those who used a statin alone, and 39% of those who used both drugs had a Charlson score of 2+.
“Those patients with a Charlson score of 2+ usually do a lot worse,” Dr. Lu-Yao said. “They have multiple comorbidities, so their mortality is even higher, but we actually showed they have a much lower mortality. At baseline, they may not be better off, but in terms of outcomes, they are doing pretty well on two medications.”
The authors also said it was “worth noting,” that the higher comorbidity scores at baseline of those who used both metformin and a statin vs nonusers “might have led to underestimated treatment benefits.”
Building on Previous Studies
“Statins either alone or in combination hold high promise for high-risk prostate cancer,” Dr. Lu-Yao said. “That is what our data show—and not just our data.” The study report cited several other studies that “show similar patterns but less effect” of statins in reducing mortality among patients with prostate cancer,” Dr. Lu-Yao stated. “But those studies were not limited to high-risk patients. Our study is focusing on high-risk patients.”
Dr. Lu-Yao singled out a 2015 study by Harshman et al,2 which found that statin use at the start of androgen-deprivation therapy was associated with a longer time to disease progression in prostate cancer cell line in vitro studies that “showed the potential mechanism by which statins may reduce tumor progression,” she noted.
According to Harshman et al: “Our in vitro finding that statins competitively reduce [dehydroepiandrosterone sulfate], thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged [time to disease progression] in statin users.”2
“The major motivation for the current study was the finding from preclinical animal studies that a combination of statins and metformin is better than either one alone for inhibiting disease progression or metastases,” Dr. Lu-Yao said. A literature review revealed that late-stage disease is where the potential benefits of statins are most consistently apparent.3
Findings Widely Applicable
“Our findings likely apply to most [patients with prostate cancer] because of the broad representation of various racial/ethnic groups in this study,” the authors wrote.
“This is not a single-institution study, and it is not limited to a specific group of patients,” Dr. Lu-Yao added. “It did include patients in all settings. It is a population-based study, so anyone at high risk in the geographic area covered by SEER in the registry is included. Given that the SEER area now covers about 30% of the U.S. population, a large population was included.”
“Although the data are promising,” Dr. Lu-Yao said, “I would love to see a randomized trial sponsored by the government,” including patients with high-risk prostate cancer randomly assigned to receive a statin alone, a statin plus metformin, or neither drug. “Metformin and statins in general are very inexpensive, so there is not a lot of profit margin, and it is hard to get industry sponsors for such studies. That is why I think the government sponsoring a randomized trial would be crucial.”
Dr. Lu-Yao acknowledged that obtaining government funding would be “particularly challenging given that current situation, but millions of patients could benefit from the results.”
DISCLOSURE: Dr. Lu-Yao has an immediate family member who has been employed by and has served in a leadership role for Sun Pharma Advanced Research Company and has an immediate family member who holds stock or other ownership interests in Merck.
REFERENCES
1. Tan X-L, E J-Y, Lin Y, et al: Individual and joint effects of metformin and statins on mortality among patients with high-risk prostate cancer. Cancer Med 9:2379-2389, 2020.
2. Harshman LC, Wang X, Nakabayashi M, et al: Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. JAMA Oncol 1:495-504, 2015.
3. Platz EA: Epidemiologic musing on statin drugs in the prevention of advanced prostate cancer. Cancer Epidemiol Biomarkers Prev 16:2175-2180, 2007.
