Better outcomes with HbA1c reduction associated with intensification of OADs in type 2 diabetes.
Type 2 diabetes (T2D) is a progressive disease that frequently requires stepwise treatment intensification to maintain good glycemic control. 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 oral 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 ≥8%) after three or more months of therapy that included metformin (index date), and no history of injectable antidiabetic medications. The results showed that <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 ≥8% 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 ≥8%, ≥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 ≥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.
Folse HJ, Mukherjee J, Sheehan JJ, Ward AJ, Pelkey RL, Dinh TA, et al. Delays in treatment intensification with oral antidiabetic drugs and risk of microvascular and macrovascular events in patients with poor glycemic control: An individual patient stimulation study. Diabetes, Obesity, and Metabolism: A journal of pharmacology and therapeutics. 2017, Feb 17. Accepted Author Manuscript. Doi:10:1111/dom.12913
Khunti K, Wolden ML, Thorsted BL, Anderson M, and Davies MJ. Clinical inertia in people with type 2 diabetes: A retrospective cohort study of more than 80,000 people. Diabetes Care. 2013 Nov; 36(11): 3411-3417.
Turner RC, Cull CA, Frighi V, Holman RR, UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA1999;281:2005–2012.
Tenzing Dolkar, BSc., PharmD Candidate 2017, Lake Erie College of Osteopathic Medicine, School of Pharmacy