Metformin Withdrawal Symptoms in PCOS: What Happens

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Does metformin cause withdrawal symptoms?

The metformin prescribing information describes no withdrawal syndrome. The reactions it lists occur during treatment: diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort and headache as the common reactions, alongside lactic acidosis, vitamin B12 deficiency, and hypoglycemia when metformin is combined with insulin or an insulin secretagogue [1]. The extended-release label lists the same core profile and adds taste disturbance among reactions reported in 1% to 5% of patients [2].

What happens when metformin is stopped in PCOS?

Metformin is not a labeled treatment for PCOS. The immediate-release label covers type 2 diabetes in adults and children 10 years and older; the extended-release label covers adults with type 2 diabetes [1][2]. The label's stopping instructions are tied to kidney function and medical procedures rather than to a taper, and none of them is PCOS-specific [1].

The label does carry one PCOS-relevant note: metformin may result in ovulation in some anovulatory women, and it advises discussing the potential for unintended pregnancy with premenopausal women [1]. That note is about what can happen while taking metformin.

Vitamin B12 after stopping metformin

The label says a decrease to subnormal vitamin B12 levels was seen in approximately 7% of patients in 29-week trials, may be associated with anemia, and appears to be rapidly reversible with discontinuation of metformin or with vitamin B12 supplementation. It advises measuring hematologic parameters annually and vitamin B12 every 2 to 3 years [1].

In the Diabetes Prevention Program Outcomes Study, low B12 (203 pg/mL or less) occurred in 4.3% of metformin users versus 2.3% of placebo users at 5 years, and 7.4% versus 5.4% at 13 years, which was not statistically significant [3]. Combined low and borderline-low B12 (298 pg/mL or less) was 19.1% versus 9.5% at 5 years and 20.3% versus 15.6% at 13 years [3]. Each year of metformin use was associated with a 13% higher odds of B12 deficiency [3]. That study enrolled adults with prediabetes, not women with PCOS.

How common are metformin GI side effects?

In a U.S. trial of immediate-release metformin up to 2,550 mg per day, diarrhea occurred in 53% of 141 metformin patients versus 12% of 145 placebo patients; nausea/vomiting in 26% versus 8%; flatulence in 12% versus 6%; and diarrhea led to discontinuation in 6% [1]. In placebo-controlled extended-release trials including 781 metformin patients and 195 placebo patients, diarrhea occurred in 10% versus 3% and nausea/vomiting in 7% versus 2%; diarrhea led to discontinuation in 0.6% [2]. These are rates during treatment, not after stopping.

Does stopping metformin cause weight gain?

Whether stopping metformin causes weight gain in women with PCOS is not established. During the Diabetes Prevention Program, weight fell 2.06% with metformin versus 0.02% with placebo, and weight loss stayed greater over 7 to 8 years of open-label follow-up (2.0% versus 0.2%) [4]. In a later analysis of DPP participants who had lost at least 5% of body weight in the first year, continued metformin use was an independent predictor of long-term weight loss within the metformin group [5]. Metformin is not a labeled treatment for weight loss or for PCOS [1].

When the label says to hold or stop metformin

Metformin is contraindicated if eGFR is below 30 mL/min/1.73 m2, and starting is not recommended at eGFR 30 to 45; if eGFR later falls below 45, the label says to assess the benefit and risk of continuing, and to discontinue if it falls below 30 [1]. For iodinated contrast, the label says to stop metformin at the time of or before the procedure in patients with eGFR 30 to 60, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used; eGFR is rechecked 48 hours afterward and metformin restarted if renal function is stable [1]. It is also temporarily discontinued while food and fluid intake is restricted [1].