Effects of Statin Therapy on Diagnoses of New-Onset Diabetes and Worsening Glycaemia
TAKE-HOME MESSAGE
- In this participant-level meta-analysis of 19 trials, statin therapy was associated with an increased incidence of new-onset diabetes and worsening glycaemia, with approximately two-thirds of the incident diabetes cases being among participants with glycaemic markers near the diabetes diagnostic threshold. The mean HbA1c increased by 0.06% to 0.08%, depending on the intensity of statin therapy.
- These findings reaffirm a dose-dependent association between statin therapy and new-onset diabetes, which may be of potential relevance for guidelines and shared decision–making. However, these glycaemic effects do not outweigh the benefits of statin therapy among individuals for whom they are recommended.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy.
METHODS
We conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy on new-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and on worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA1c increase of ≥0·5%). Standard inverse-variance-weighted meta-analyses of the effects on these outcomes were conducted according to a prespecified protocol.
FINDINGS
Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 25 701 [21%] with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes, median follow-up of 4·9 years). Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48). For each trial, the rate of new-onset diabetes among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials. Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy. In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06), and mean HbA1c increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins. Among those with a baseline measure of glycaemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution. The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time. Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo.
INTERPRETATION
Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes. Importantly, however, any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials. These findings should further inform clinical guidelines regarding clinical management of people taking statin therapy.
FUNDING
British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.
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Additional Info
Disclosure statements are available on the authors' profiles:
Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis
Lancet Diabetes Endocrinol 2024 Mar 26;[EPub Ahead of Print], Cholesterol Treatment Trialists’ (CTT) CollaborationFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Statins increase new-onset diabetes
This study is the new version of an old story. Statins being linked to an increase in new-onset diabetes came to a head when the JUPITER study1 reported a 25% increase in new-onset diabetes for rosuvastatin 20 mg compared with placebo. That was a shocking number, but what was the actual number of patients who were affected? JUPITER was a study of 17,802 participants. There were 270 new-onset diabetes cases on the rosuvastatin side and 216 on the placebo side. So the actual difference was 54 people. Although the 25% increase is shocking and accurate, the actual number of patients being 54 puts things into perspective.
After the JUPITER results came out, the Cholesterol Treatment Trialists’ collaboration looked at statin trials and published that there was a small increase in new-onset diabetes in the statin-treated arm. This current study is an extension of that study, and, here, they used patient-level data. Again, they saw a small increase in diabetes. This is to be expected, since essentially they included the same studies.
This time, they concluded that, for low- or moderate-intensity statins, there was a 10% increase in new-onset diabetes (RR, 1.10; 95% CI, 1.04–1.16). The actual difference was 1.3% per year for the statin users versus 1.2% per year for placebo. For high-intensity statin, there was a 36% increase in new-onset diabetes (RR, 1.36; 95% CI, 1.25–1.48). However, the authors were quick to point out that 62% of the patients who developed diabetes were at the top end of the metabolic parameters. In other words, they were already close to crossing over to diabetes to begin with.
The actual mean glucose measurements only went up by 0.04 mmol/L (95% CI, 0.03–0.05). This is a very small amount. HbA1c levels increased by just 0.06% (95% CI, 0.00–0.12) with low- or moderate-intensity statins and by 0.08% (95% CI, 0.07–0.09) with high-intensity statins. These were very small changes in the blood tests.
Perhaps our conclusion should be that there were increases in new-onset diabetes, but that those patients were already close to crossing over to begin with. Statins are good for reducing cardiovascular events; therefore, patients should still be on statins. We need to accept diabetes as a potential risk of this beneficial treatment, just like how antiplatelets are used for their benefits despite the increased risk of bleeding.
However, when I look at the HOPE-3 study,2 I actually have “hope.” This study looked over 12,705 intermediate-risk patients, with half receiving rosuvastatin 10 mg and the other half receiving placebo. After 5 years, there were cardiovascular benefits, but there was no increase in diabetes (RR, 1.02; 95% CI, 0.85–1.23; P = .82). One main difference in this study is that, during randomization, they made sure there was balance in the metabolic parameters between the two groups, resulting in equal numbers of participants with impaired fasting glucose, glucose intolerance, early diabetes, and elevated waist-to-hip ratio cases in both groups. Therefore, the metabolic patients were equally divided between the two groups. These were the patients who were most likely to cross over to diabetes. Once that was balanced at the beginning of the trial, there was no increase in new-onset diabetes out to 5 years. The older statin trials never looked at metabolic parameters; therefore, the metabolic patients may not have been equal in the two groups.
In conclusion, I think we should use statins, and perhaps the HOPE-3 study tells us that we are not doing harm to these patients in terms of diabetes. Perhaps in the next analysis of these data, we should divide the trials into those that separated metabolic syndrome patients evenly between the two groups and those that did not. That might give us more insight than just lumping all the studies together.
References