Is oral combination contraception suitable for patients with elevated C-peptide (Connecting Peptide) levels?

From the Guidelines

Oral combination contraceptives can be used in individuals with high C-peptide levels, but careful consideration and monitoring are necessary, especially if the high C-peptide is associated with significant metabolic issues. C-peptide is a marker that indicates insulin production, and elevated levels typically suggest insulin resistance rather than a contraindication to hormonal contraception. For patients with high C-peptide who need contraception, standard combination oral contraceptives containing ethinyl estradiol (20-35 mcg) with progestins like levonorgestrel, norethindrone, or newer options like drospirenone can be prescribed following routine screening 1. However, if the high C-peptide is associated with significant metabolic issues like diabetes, polycystic ovary syndrome (PCOS), or metabolic syndrome, certain formulations may be preferred. For instance, pills containing drospirenone (like Yaz or Yasmin) might offer additional benefits for patients with PCOS. Monitoring is important, with follow-up recommended after 3 months to assess tolerance and metabolic parameters. The estrogen component in combination contraceptives can potentially affect insulin sensitivity, but modern low-dose formulations minimize this effect. If concerns persist about metabolic impact, progestin-only methods like the mini-pill, implant, or hormonal IUD could be considered as alternatives with less potential impact on glucose metabolism.

Some key points to consider when prescribing oral combination contraceptives to individuals with high C-peptide levels include:

• The risk of cardiovascular disease associated with the use of combined oral contraceptives, although low, should be discussed with patients 1
• The levonorgestrel-releasing intrauterine device is a safe and effective contraceptive option for women with certain medical conditions, including cyanotic congenital heart disease and pulmonary vascular disease 1
• Monthly injectables that contain medroxyprogesterone acetate are not recommended for patients with heart failure due to the risk of fluid retention 1
• Low-dose oral contraceptives containing 20 mg of ethinyl estradiol are safe in women with a low thrombogenic potential, but not in women with complex valvular disease 1

In terms of specific guidance, the U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, provides classifications for combined hormonal contraceptives, including oral contraceptives, the combined hormonal patch, and the combined vaginal ring 1. However, the most recent and highest quality study on this topic is the 2020 umbrella review published in the BMJ, which found that the use of combined oral contraceptives is associated with an increased risk of cardiovascular disease, although the absolute risk is low 1. Therefore, the use of oral combination contraceptives in individuals with high C-peptide levels should be carefully considered and monitored, taking into account the individual's medical history and risk factors.

From the Research

Oral Combination Contraception and High C-Peptide

• The relationship between oral combination contraception and high C-peptide levels is complex and influenced by various factors, including the type and dose of estrogen and progestin used in the contraceptive 2, 3.
• Studies have shown that combined oral contraceptives (COCs) may increase insulin resistance, which can lead to higher C-peptide levels 3, 4.
• However, the effect of COCs on insulin resistance and C-peptide levels may vary depending on the specific formulation and dose of the contraceptive 3, 4.
• Some studies have found that COCs containing low doses of estrogen and anti-androgenic progestins may not negatively impact cardiovascular risk factors, including insulin resistance and C-peptide levels 2.
• C-peptide levels have been shown to be positively correlated with body mass index (BMI), triglyceride levels, and the triglyceride/high-density lipoprotein ratio, which are all components of metabolic syndrome 5.

Insulin Resistance and C-Peptide

• Insulin resistance is a key factor in the development of metabolic syndrome and cardiovascular disease, and C-peptide levels can be used as a marker of insulin resistance 5.
• Studies have found that COCs can increase insulin resistance, particularly those containing high doses of estrogen 4.
• However, the addition of progestin to estrogen-only COCs may attenuate the negative effects on insulin sensitivity 4.
• The effects of COCs on insulin resistance and C-peptide levels may also depend on the specific type and dose of progestin used 3, 6.

Clinical Implications

• The use of COCs in women with high C-peptide levels should be carefully considered, taking into account the potential risks and benefits of the contraceptive 2, 3.
• Women with high C-peptide levels may be at increased risk of cardiovascular disease and metabolic syndrome, and the use of COCs may exacerbate these risks 5.
• Healthcare providers should carefully monitor women using COCs, particularly those with high C-peptide levels, for signs of insulin resistance and cardiovascular disease 2, 3.