Yes, better outcomes happen when
doctors work with patients to intensify oral antidiabetic drugs
(OADs). Again, another article claiming that type 2 diabetes is a
progressive disease. The only time it is progressive is when the
patients with their doctors', refuse to aggressively treat type 2
diabetes and let it get out of control. Treated aggressively, type 2
diabetes can be managed and prevented from becoming progressive.
According to guidelines, antidiabetic
drugs (OADs) must be added three months after the failure of initial
therapy with metformin monotherapy and lifestyle modifications in
order to achieve glycemic goals. Many patients with T2D on OADs are
deprived of timely treatment intensification, regardless of
hemoglobin A1c (HbA1c) being above target range. The failure to
intensify treatment in a timely manner has been termed ‘Clinical
Inertia.’ According to Dr. H.J. Folse and colleagues, this delay
is associated with an inability to achieve target HbA1c in a timely
manner, increased risks of cardiovascular events, and amputations.
Previous studies have shown that poor
glycemic control due to clinical inertia can be improved by earlier
intensification with OADs. In a retrospective cohort, ‘the Inertia
study,’ a large United States claims database was used to estimate
time to intensification (TTI) with an additional OAD or injectable
medication for adults with type 2 diabetes and poor glycemic control
(HbA1c greater than or equal to 8%) after three or more months of
therapy that included metformin (index date), and no history of
injectable antidiabetic medications. The results showed that less
than 48% of subjects had received treatment intensification within 12
months after the index date. However, not much is known about
long-term consequences of clinical inertia. The primary outcome was
the time from index date to treatment intensification, defined as
patients filling a prescription for injectable or additional OADs.
The purpose of the study was to use the Archimedes Model in a cohort
of hypothetical patients with HbA1c greater than or equal to 48% on
metformin with no history of insulin use to examine the consequences
of delayed OAD treatment intensification on glycemic control and
long-term outcomes at 5 and 20 years in patients with T2D.
Using real world data, the study used a
cohort of hypothetical T2D patients with HbA1c greater than or equal
to 8%, and greater than or equal to 18 years old, on metformin, with
no history of insulin use. The cohort included three strata based on
the number of OADs taken at baseline. Treatment intensification
sequence included addition of a sulfonylurea, followed by a
dipeptidyl peptidase-4 inhibitor, and a thiazolidinedione. Based on
observed and extrapolated times to intensify the treatment, the
result included either ‘No Delay’ or ‘Delay.’ Treatment
failure was defined as HbA1c greater than or equal to 8% and patients
were followed for one year following the index date and when patients
filled a prescription for injectable or additional OADs. Subgroup
analyses were based on metformin monotherapy, metformin with one
other OAD, and metformin with two or more other OADs. Time to
treatment intensification was grouped as early intensified (within 6
months), late intensified (6 to 12 months), or never intensified
within 12 months.
The mean HbA1c at one year for patients
intensifying without delay vs. with delay was 6.8% and 8.2%,
respectively with an absolute reduction of 1.4%. Also, at five years
for no Delay vs. Delay, reductions in the risks of major adverse
cardiac events, myocardial infarction, heart failure, and amputations
were seen at 18.0%, 25.0%, 13.7%, and 20.4%, respectively. The
timing of intensification of OAD therapy per guideline
recommendations steered greater reductions in HbA1c and lower risks
of complications, but severe risk of hypoglycemia increased to 19%
for the no Delay group in comparison to 12.5% for the Delay group.
In general, the relative risk reduction (RRR) trend at five years was
similar to the results at 20 years. At five years, the incidence of
hypoglycemia was 51.7% higher and at 20 years, it was 18.0% higher in
the No Delay groups versus the Delay group.
Some of the limitations in this study
included lack of other adverse effects besides hypoglycemia, the
effects of hypoglycemia on costs, quality of life, and cardiovascular
risk. Also, the OAD add-ons selected were based on the U.S. OADs
prescribing patterns observed in the retrospective Inertia study from
2009-2013. However, the addition of following medications in the
treatment sequence was universally applied to everyone at an average
dose for each treatment. Future studies should expand the treatment
sequence with the addition of other classes of OADs.
In conclusion, this study supports the
timing of intensification of OAD therapy per guideline
recommendations, which leads to greater reductions in HbA1c and lower
risks of complications, but increases the risks of hypoglycemia
instead of delaying intensification. The differences in HbA1c between
patients delaying and not delaying have important long-term
consequences with substantial risk of complications of diabetes.
HbA1c has been found to be a relatively important risk factor for the
progression of diabetic retinopathy, but not so much for stroke and
ESRD. Overall, the results emphasized the potential impact of timely
treatment intensification on long-term outcomes.
- Intensifying OAD therapy at guideline-recommended time intervals results in greater reduction in HbA1c.
- Failure to intensify treatment in a timely manner results in a higher risk of complications, including adverse cardiac events, myocardial infarction, heart failure, and amputations.
- This study proves that intensifying OAD therapy results in a higher risk of hypoglycemia than delaying intensification.
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