Type 2 diabetes patients with metformin intolerance

Type 2 diabetes mellitus (T2DM) is a global disease that currently affects more than 300 million individuals worldwide and is projected to increase by 55% over the next 20 years.1 By and large most patients diagnosed with T2DM are initially started on metformin as it is considered the optimal first-line therapy by clinical guidelines and consensus recommendations.2–4 Additionally, it is widely accepted to continue metformin throughout the progression of this chronic disease, even when other therapies are added. With the increasing number of diabetic patients in the world, it can be expected that many patients, for various reasons might be unable to tolerate or have contraindications to metformin use. Major issues of intolerability are usually related to gastrointestinal (GI) side effects or the presence of chronic kidney disease (CKD). This brief review will recommend appropriate treatment options when metformin cannot be used in these two scenarios, taking into account efficacy, adverse effect profiles, comorbid conditions and patient preference.

One common cause for metformin intolerability is the GI side effects experienced by many patients. According to the package insert for one brand of metformin commonly available in the US, one study showed that more than 25% of patients experienced nausea and vomiting, and more than 50% of patients experienced diarrhoea. Other less common GI side effects include flatulence, indigestion, and abdominal discomfort.5

Many patients who experience GI side effects will find that they are self-limiting in nature and do not require discontinuation from metformin.6 Additionally, these adverse events may be reduced in frequency and/or severity by starting at a lower dosage and titrating up slowly to the maximum tolerated dosage as well as taking with larger meals.6 Finally some patients will experience relief from GI side effects by changing to an extended release formulation of metformin.6,7 One study found that switching from immediate release metformin to extended release metformin reduced the incidence of diarrhoea from 58% to 14% and nausea from 18% to 6% at 6 months.7,8

Despite proper titration, administration with food and use of the extended release formulation, some patients will continue to experience intolerable GI side effects. For these patients with true metformin intolerance, use of another agent should be considered, and there are a wide variety of options for these patients.

Patients who have experienced GI side effects with metformin are not precluded from using other antidiabetic drugs with GI side effects, such as glucagon-like peptide-1 (GLP-1) agonists and alpha-glucosidase inhibitors. However, patients with intolerable GI side effects with metformin may be hesitant to start another agent with a similar side effect profile. It would therefore be reasonable to try GI neutral agents first (Table 1).

Sulfonylureas (SUs) and thiazolidinediones (TZDs) followed by sodium-glucose linked transporter (SGLT)-2 inhibitors are the most effective GI neutral oral agents for A1c lowering. Sulfonylureas, which are usually added to metformin in the patient who has not gained glycaemic control on metformin monotherapy, would seem the most likely candidate for the intolerant patient; however the risk of hypoglycaemia and weight gain might preclude the use of this class. TZDs, such as pioglitazone, do not confer as great a risk for hypoglycaemia, but do carry a risk of weight gain. For patients with questionable or reduced beta-cell function and sufficient renal function (generally eGFR >45ml/min), SGLT-2 inhibitors may be preferable, as their mechanism of action is insulin independent and relies on increased urinary glucose excretion rather than increasing insulin secretion.10–12 Meglitinides and dipeptidyl peptidase-IV inhibitors (DPP-IV) may also be considered, as they are also GI neutral. However, these agents lack the ability to target fasting plasma glucose to the same degree as the agents listed above.

Insulin is undoubtedly the most effective agent for A1c lowering, but many patients are unwilling to start insulin very early in their disease progression. In the case of a patient who is early on in their disease and has fair baseline glycaemic control (within 1–2% of A1c goal), insulin may not be the most preferable option given the other non-insulin medications currently available. However, for the patient with extremely poor glycaemic control (>2–3% above A1c goal) who cannot tolerate metformin, insulin may be the only antidiabetic agent that will effectively reduce blood sugars.

While metformin can be used in patients with varying levels of renal dysfunction, albeit at lowered doses, the general consensus is to discontinue therapy when eGFR falls below 30ml/min.2,4,5,13 Concern for lactic acidosis heightens when metformin cannot be appropriately excreted by the kidneys. Thus, providers are compelled to discontinue therapy before eGFR is <30ml/min in patients with coexisting risk factors for lactic acidosis such as heart failure exacerbation, alcoholism, old age, or hepatic disease.5

In CKD patients there are a variety of medication options available. In terms of efficacy, sulfonylureas, meglitinides, thiazolidinediones, GLP-1 agonists, and insulin will provide the most A1c reduction. In patients with longer history of diabetes, SUs may not be as effective depending on endogenous insulin production. Similar in mechanism of action but with less hypoglycaemia compared to SUs, the meglitinides may be preferred, as they do not undergo extensive renal elimination. When choosing an agent from either class, glibenclamide and tolbutamide should be used conservatively to avoid possible accumulation of active metabolites.

Pioglitazone may provide reduction in albuminuria in patients with CKD.14 It does not require dose-adjustment in renal failure; however, the common adverse effect of fluid retention may be accentuated in patients with other comorbidities such as heart failure or CKD.

GLP-1 agonists are a favourable option, particularly in patients with newly diagnosed diabetes. These agents provide good efficacy as well as lead to substantial weight loss (2.8kg).15 Yet injectable formulations and noted gastrointestinal side effects with the GLP-1 agonists are troublesome for some patients, possibly making them less desirable options when taking into account patient preferences. Of the available GLP-1 agonists, exenatide should be avoided when CrCl <30ml/min.16 In patients closer to glycaemic goal (SMBGs within 1.7–2.8mmol/l of goal), DPP-IV inhibitors may be an attractive option. They provide modest A1c reduction, are generally well tolerated and are available in oral formulation. When choosing a DPP-IV inhibitor, it should be noted that most DPP-IV inhibitors require dose reduction once eGFR <50–60ml/min.17–19 Linagliptin, however, does not need to be dose-adjusted in renal dysfunction, and thus, might be the preferred DPP-IV in this scenario.

A newer class of antidiabetic mediations, the SGLT-2 inhibitors, have increasingly gained favour. These agents have a low risk of hypoglycaemia, are fairly well tolerated, provide moderate A1c-lowering, and are available via oral formulation. Common adverse effects include genital mycotic infections and urinary tract infections. Unfortunately, their use is limited in renal dysfunction. Dapagliflozin and canagliflozin should be discontinued when eGFR <60ml/min and <45ml/min, respectively.20,21

In patients nearing glycaemic control with mild renal dysfunction, the clinician may choose an alpha-glucosidase inhibitor. They are generally safe, however, gastrointestinal intolerances, dosing frequency and discontinuation cut-off of SCr >2mg/dl make their use restricted in patients with CKD.

Naturally, insulin therapy should be considered for patients with CKD unable to take metformin. Doses are titrated to targeted blood glucose levels and A1c; thus the efficacy of insulin therapy has no ceiling. As insulin is eliminated via the renal system, it should be dose-adjusted more conservatively in patients with CKD to avoid hypoglycaemia given alterations in pharmacodynamics.

From the above discussion it is quite apparent that there is not one agent that stands out as the singular therapeutic option for the patient intolerant to metformin for either GI or renal reasons. Each section highlights scenarios in which one medication class might be preferred over another depending on the intolerance and patient specific factors such as concomitant diseases or specific side effects. While it may be frustrating to providers that a single answer to this dilemma has not emerged, it should be comforting to know there are several viable options available for nearly any type of patient. As the incidence of diabetes continues to increase, providers must recognise the importance of individualised medication therapies and take into consideration the overall health, dysglycaemia and specific factors for each patient and make treatment decisions accordingly.