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Initial Combination Therapy for Type 2 Diabetes: Hit It Early and Hit It Hard?


Early use of combination therapy to treat type 2 diabetes is shown to limit glucose toxicity and preserve beta-cell function.

The advice to “hit early and hit hard,” perhaps whispered in the corner of an Olympic boxing ring in London during August, may also be a propos for clinicians seeking to deliver optimal therapy to patients with type 2 diabetes (T2D). While I have recently affirmed the tone and much of the content of the 2012 American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement on the treatment of T2D1 I find the therapeutic approach espoused in that document actually contrary to the more logical “hit early/hit hard” guidance. The ADA\EASD statement lays out, once again, the long-standing stepwise approach to intensifying diabetes therapy for most patients. What troubles me is that this methodology is at odds with another set of reputable guidelines, issued by the American Academy of Clinical Endocrinology (AACE),2 as well as with some new research that points to the benefit of early use of combination therapy.

Based on Ralph DeFronzo’s teaching about the “Ominous Octet,”3 we increasingly understand the etiology of T2D as multifactorial, the collective result of:

1. Neurologic malfunction (satiety)
2. Abnormal gastric emptying (rapid glycemic transit)
3. Insulin resistance (peripheral disposal of glucose)
4. Dysfunctional lipid metabolism
5. Excess hepatic glucose production 
6. Beta-cell failure (insulin production)
7. Poor alpha-cell regulation (inappropriate glucagon production), and
8. Altered role of the kidney in handling glucose

Each of these metabolic derangements results in increased free fatty acids or hyperglycemia, or both. These conditions, which are toxic to the beta cell, lead to beta-cell failure-the final common pathway of T2D development.

Against this background, I find it odd that optimal T2D therapy would address these contributing factors one-by-one in a sequential fashion, leaving other potentially toxic processes unaddressed until failure of therapy demands attention to them. If you will indulge my use of metaphor, this is certainly not how we approach responsible automotive repair. If failure to safely stop is attributed to worn brake pads, a leaky brake fluid line, and a bad master cylinder, it is unlikely the car owner would select the least expensive item to repair and leave other contributing elements unaddressed unless the car failed to stop again.

The current ADA/EASD position statement doesn’t suggest combination therapy until A1C is ≥ 9.0%1 while the AACE guidelines have long suggested initial combination therapy when the A1C is ≥7.5%.2 This difference may be the result of ADA/EASD consensus committee concerns over cost or potential adverse effects of therapy. The global savings from preserving beta-cell function, however, may be shown to trump medication cost.1 Also, we now have oral agents that in combination (ie, metformin and DPP-4 combinations) address many of the Ominous Octet defects with essentially no risk of weight gain or hypoglycemia.
Combine First to Help Conquer
The highly anticipated results of the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial4 released in June indicated that insulin initiated early after a diagnosis of T2D in combination with oral agents (not as a step-wise addition) resulted in a stable pattern of glycemic control over the approximately 6 years of study.4 This finding poses a strong challenge to our long-held understanding of the natural history of T2D, which has as its cornerstone the “inexorable decline of beta-cell function.” The stability of beta-cell function over such a long period was, to me, one of the truly remarkable findings from ORIGIN.

Two smaller studies5,6 on the initiation of T2D therapy combining oral agents and insulin also have shown beneficial beta-cell effects. Lingvay and colleagues5 treated patients with newly diagnosed T2D for 3 months with insulin injections plus metformin and then randomly assigned them to continue this regimen or to receive 3 oral antidiabetic agents. After 3.5 years, beta-cell function was preserved and glycemic control was maintained in both groups, supporting early and aggressive treatment of T2D following an initial insulin-based treatment period. The Joslin Diabetes Center’s Gordon Weir has demonstrated that early intensive therapy with insulin (for several weeks to months) to clear glucose toxicity seems to preserve (and even improve) beta-cell function over the course of the ensuing year.6 

What remains unknown is whether using combination oral therapy from the onset of T2D diagnosis will have a benefit on the natural history of beta-cell function in T2D similar to that seen with insulin plus oral agents. This is an important question, since we also don’t know how willing patients with newly diagnosed T2D will be to accept insulin therapy before other treatments have been tried, and have failed.

There are no studies that clearly address the comparative efficacy of initial oral combination therapy vs stepwise addition of therapy over time. What is known is that stepwise advancement of therapy too often moves too slowly (clinical inertia) and leaves patients exposed to prolonged periods of hyperglycemia. In a study of primary care clinicians, the average patient with T2D remained at an A1C >7% for more than 8 years while therapy was “intensified” in a stepwise manner.7 Intervals between adding or switching agents were much longer than the currently recommended 3 months (ADA/EASD and AACE).1,2

Where does this discussion lead us clinically? It seems obvious that our traditional step-therapy approach has not been working well. Patients are not controlled in a timely fashion and only slightly more than 50% are controlled at all.8 Even those who are controlled are subject to the beta cells’ inexorable decline. Studies (although with small sample sizes) are offering hope that aggressive initial use of multiple therapies, including insulin, may alter the natural history of beta-cell function in T2D.

So is there benefit from using early aggressive therapy with a combination of oral agents, either given as single agents administered simultaneously or as fixed-dose combination pills? While the jury is out yet, from a mechanistic standpoint this makes sense. Cost and lack of outcomes-trial data seem to be the only substantive barriers to considering initial combination therapy. 

For commercially insured patients, even the cost barrier has largely been overcome-out of pocket expense for combination metformin/DPP-4 therapy may be little more than metformin alone. And new legislation softening the financial impact of the Medicare prescription drug coverage “doughnut hole” may make branded combination drugs more affordable to some seniors.

Perhaps in no area of medicine are new therapies and treatment approaches appearing at such a rapid rate as in diabetes care.9 This means that clinicians will be faced with treatment decisions long before evidence-based guidance is available. We are going to have to think through to the most reasonable solution for our therapeutic problems. It seems untenable to deprive our patients of the newer, effective, well-tolerated therapies as we wait for years for data to accumulate. 

To me, “hit it early and hit it hard” with oral combination therapy in all but the most mild cases of T2D seems like a very attractive strategy that is supported by a recognized body of experts.2 Anything we can do to prevent progression of beta-cell failure and target organ damage seems like a viable option.


1. Inzucchi SE, Bergenstahl RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient centered approach. Diabetes Care. 2012 Apr 19; [Epub ahead of print].
2. Jellinger PS, Davidson JA, Blonde L, et al. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007;13:260-268.
3. DeFronzo R. From the triumvirate to the ominous octect: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-775.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661582/pdf/zdb773.pdf
4. Gerstein HC, Bosch J, Dagenais GR, et al; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-328.
5. Harrison LB, Adams-Huet B, Raskin P, Lingvay I. β-cell function preservation after 3.5 years of intensive diabetes therapy. Diabetes Care. 2012;35:1406-1412.
6. Winslow R. New strategies for treating diabetes. Wall Street Journal. July 10, 2012:D1.
7. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535-1540.
8. Cheung BMY, Ong LK, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999-2006. Am J Med. 2009;122:443-453.
9. Fonseca V. President, Medicine and Science Address, 72nd Scientific Session of the American Diabetes Association, Philadelphia. June 2012.

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