Why was Human Mixtard (human insulin) withdrawn from the market?

Why Human Mixtard Was Withdrawn

Human Mixtard (premixed human insulin 30/70) has not been formally "withdrawn" from the market globally, but its use has been significantly de-emphasized and phased out in many healthcare settings due to superior safety profiles of insulin analogs, particularly the substantially higher risk of hypoglycemia with premixed human insulin formulations in hospitalized and elderly patients.

Evidence for Reduced Use in Clinical Practice

Hospital Setting Safety Concerns

The most compelling evidence against premixed human insulin comes from inpatient studies:

• A study in elderly patients (mean age ~70 years) demonstrated that premixed human insulin resulted in a threefold higher rate of hypoglycemia compared with basal-bolus regimens using insulin analogs 1
• This finding specifically indicated that premixed formulations should be avoided in the hospital setting due to unacceptable hypoglycemia risk 1

Pharmacokinetic Limitations

The fundamental problem with premixed human insulin like Mixtard 30 (30% regular, 70% NPH) relates to NPH's pharmacokinetics:

• NPH insulin has a pronounced peak of action approximately 8-12 hours after injection, creating significant hypoglycemia risk in patients with poor or variable oral intake 1
• This contrasts with modern basal insulin analogs that have flatter, more constant plasma concentrations and activity profiles 1

Transition to Insulin Analogs

Superior Safety Profile

Multiple guidelines now preferentially recommend insulin analogs over human insulins:

• In people with type 1 diabetes, treatment with analog insulins is associated with less hypoglycemia and weight gain as well as lower A1C compared with human insulins 1
• Long-acting insulin analogs (U-300 glargine or degludec) confer lower hypoglycemia risk compared with U-100 glargine 1
• Newer-generation basal analogs may reduce hypoglycemia risk in patients with type 1 diabetes 1

Clinical Trial Evidence

• Two controlled trials comparing NPH/regular insulin with basal-bolus analog regimens showed that while glycemic control was similar, the number of severe hypoglycemic episodes was higher in patients receiving human insulin 1
• The DCCT trial, while demonstrating microvascular benefits with intensive therapy using human insulins (regular and NPH), also showed intensive therapy was associated with a higher rate of severe hypoglycemia (62 vs 19 episodes per 100 patient-years) 1

Current Guideline Recommendations

Preferred Insulin Formulations

Modern diabetes management guidelines consistently favor analogs:

• Basal insulin analogs have longer duration of action with flatter, more constant plasma concentrations and activity profiles than NPH insulin 1, 2
• Rapid-acting analogs have a quicker onset and peak and shorter duration of action than regular human insulin 1
• For basal insulin, options include once-daily administration of glargine (U100 or U300) or degludec (U100 or U200), which are preferred over NPH 1

Limited Role for Human Insulins

Guidelines acknowledge human insulins primarily as cost-saving alternatives:

• Human insulins (NPH, regular, and premixed combinations) are recombinant DNA-derived human insulin, while insulin analogs have been designed to change the onset or duration of action 1
• Despite advantages of insulin analogs, for some patients the expense and/or intensity of treatment required for their use is prohibitive 1
• Human insulins, separately, self-mixed, or as premixed NPH/regular (70/30) formulations, are less costly alternatives to insulin analogs 1

Resource-Limited Settings

The WHO maintains human insulin as an option primarily for cost reasons:

• The WHO recommends using human insulin to manage blood glucose in adults with type 1 and type 2 diabetes 1
• However, long-acting insulin analogues should be considered for adults with frequent severe hypoglycemia 1
• The price of newer agents is currently several times higher than human insulin in most markets 1

Clinical Implications

When Human Insulin Might Still Be Used

• In resource-limited settings where cost is prohibitive 1
• When analog insulin expense is not feasible for individual patients 1
• The central precept is that some form of insulin be given in a planned regimen tailored to the individual patient 1

Key Safety Considerations

• Greatest caution is warranted for people at high risk of hypoglycemia, such as older patients and those with chronic kidney disease 1
• Patient education and use of low or variable dosing may be used to mitigate hypoglycemia risk 1
• Premixed formulations should specifically be avoided in hospital settings 1

Human Mixtard's decline reflects the evolution toward safer insulin formulations with more predictable pharmacokinetics, rather than a formal market withdrawal due to regulatory action.