Many patients start on pills but end up on insulin. Why do pills tend to fail in the end and do they all fail at the same rate?

Pills for type 2 diabetes tend to fail after a period of time  because the  severity of  the  diabetes tends  to progress. Diabetes is a disorder associated with aging, reduction  in  physical activity, and  increasing body weight. Since all of these things tend to progress with time, it is not surprising that the severity of the dia- betes tends to progress and the response to pills that were previously effective tends to be diminished. Not only this, but  there appears to be a normal  aging- related decline in the ability of the pancreas to make insulin that  is steeper in those with diabetes. Since one  is  presently unable  to  prevent this  or  prevent aging from  occurring, the only factors that are con- trollable to prevent  progression of the  diabetes are weight and exercise, and these  are notoriously diffi- cult to manage with consistent success. Therefore, it is not surprising that many people with type 2 diabetes tend to require more and higher doses of pills over time and that many eventually fail to be controlled on pills alone. 

The pills do not all tend to fail at the same rate. The sulfonylurea drugs and metformintend to fail at a rate of about 5% of patients who were previously controlled on them per year. Thus, after 10 years, half of the patients tak- ing these drugs initially successfully will no longer be controlled  on  them.  However, there  is encouraging news from some of the newer  types of pills for dia- betes. It appears as if the medications of the TZD  class and possibly the DPP-IV  inhibitor  class (see Ques- tions 41 and 52 for a description) may actually modify the course of the diabetes itself and slow its progres- sion. The TZD type of drugs acts to improve the body’s response to the insulin it produces, while the DPP-IV  inhibitor  class may act to  restore  the  health  of the insulin-producing cells of the pancreas. Whether these types of drugs are able to achieve these improvements in a long-term manner, such that patients on them will not require insulin or other drugs by injection at all, remains to be shown by long-term studies.