Module 3: Pharmacologic Management of Diabetes

Most of the metformin-insulin studies that I am aware of have added metformin to insulin in T2DM. These show that the combination reduces HgbA1c better than insulin alone (although it is not clear how aggressively the insulin was titrated), weight gain is mitigated, and the insulin dose is typically lower than with insulin alone. Because metformin is felt to have some potential CV benefits as well, and some studies now suggest a potential anticancer effect, many experts endorse continuing metformin in insulin-treated patients.

Lower the dose, titrate the dose slowly, take with food, and try the long-acting formulations. Most patients resolve their GI side effects within 2-3 weeks, but some individuals simply cannot take the drug.

I think it may be the safest drug overall. Several studies have shown that the incidence of lactic acidosis is negligible and probably no different from that seen in diabetes in general, when metformin is used in those with mild-moderate CKD. I think the UK guidelines, which are based on eGFR and not serum creatinine, make a lot more sense. In the UK, metformin is continued when GFR <60 mL/min. At 45, the dose is reduced by half, and the drug is stopped when the GFR <30 mL/min. Of course, any use of metformin at these levels of renal function should only occur when the patient is reliable and appears regularly for follow-up examinations. Careful follow-up of renal function is mandatory.

Insulin resistance is the physiological state where insulin does not exert its usual effects at normal concentrations. The defect appears to be inside the insulin-responsive cell (eg, skeletal muscle cell), beyond activation of the insulin receptor by the hormone. In the example of glucose being taken up by a cell, a higher insulin concentration is required. The pancreas is usually up to the task, producing more insulin. However, when pancreatic insulin secretion begins to falter, glucose levels climb and hyperglycemia develops.

Not necessarily, but since insulin is renally cleared, when kidney function is progressively reduced, hypoglycemia may occur. In that circumstance the dose should be aggressively lowered, and the A1c target should be increased. Note that those with uremia have other factors that may predispose to hypoglycemia, including reduced appetite and decreased contribution of renal gluconeogenesis to endogenous glucose production.

We know from clinical trials that adding metformin, a TZD, or even a DPP-4 inhibitor can improve glycemic control and sometimes allow for a lowering of the dose of insulin. Metformin also attenuates body weight gain from insulin. Whether combining orals with insulin has a long-term benefit is not clear. I usually continue metformin (barring any contraindications), continue pioglitazone but at a lower dose, and stop the sulfonylurea, although continuing the latter when only basal insulin is being used is not unreasonable.

This combination is not approved, and most studies show few benefits. In my practice, I use it sparingly in those T1DM patients who are gaining weight with ever-increasing insulin doses. In select patients, I find that metformin sometimes stops a vicious cycle, allowing for weight loss or at least weight stabilization and a curtailing of the need for a higher insulin dose. Caution is advisable in metabolically unstable patients; adding lactic acidosis to a person at risk for DKA would be risky.

The main benefit with GLP-1 receptor agonists is weight loss, which does not occur with oral agents or certainly with insulin. There may be a benefit on beta-cell function as well, but data in humans are not yet clear. Of course, the disadvantages include GI side effects, the need for an injection, and some reports of pancreatitis, although it is still not clear if that is truly a side effect of this drug class.

Most available oral antidiabetic agents appear similarly effective for glycemic control (Level 3 Evidence), but there is limited evidence for clinical outcomes.

The American Diabetes Association (ADA) recommends administering pneumococcal polysaccharide vaccine to all patients ≥2 years old with diabetes, with a 1-time revaccination recommended for previously immunized persons >64 years old if the vaccine was administered more than 5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immunocompromised states.

American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care. 2011 Jan;34 Suppl 1:S11-61.