Sushil Jindal  ( Department of Medicine, People's College of Medical Sciences, Bhopal, India. )
Sanjay Kalra  ( Department of Endocrinology, Bharti Hospital, Karnal, India. )

Oral antidiabetic failure (OAD failure) is a term which is used frequently in clinical practice. There is no uniformly accepted definition, however, for this term. This communication describes the concept of OAD failure, and develops a working definition for the same. The definition uses resistant hypertension as an example, and assesses the relative role of various classes of OADs, lifestyle modification, secondary causes of hyperglycaemia, and symptomatology in diabetes praxis. It utilizes these concepts to build a definition of OAD failure which states: OAD failure is defined as a clinical situation where HbA1c remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be metformin and the second, preferably a sulfonylurea, provided adequate diet and exercise have been followed, and comorbid conditions causing hyperglycaemia ruled out. OAD failure may also be defined in patients who have symptoms suggestive of insulinopenia (osmotic symptoms, weight loss), and uncontrolled glycaemia (plasma glucose> 300mg %), in spite of using triple OAD therapy.

Keywords: Clinical inertia, diabetes, HbA1c, insulin, insulin initiation, metformin, sulfonylurea

 

Introduction

 

Diabetes management is a complex art, which entails not only the correct choice of glucose-lowering therapy, but the right timing of initiation as well. Appropriate treatment, started in a timely manner, is essential to prevent chronic and acute complications. However, this is easier said than done, especially for injectable drugs. There is significant inertia, on part of both patient and provider in the diabetes clinic. This prevents early prescription, and usage, of insulin therapy. In turn, this leads to an easily avoidable burden of hyperglycaemia, which translates into long term vascular and metabolic morbidity.

 

The need to define

 

Insulin is traditionally started when non-insulin drugs (oral antidiabetic drugs) (OADs) have "failed" or proven to be inadequate in achieving and maintaining glycaemic control.¹ Such a situation is known as OAD failure or OAD inadequacy. There is, however, no accepted definition of OAD failure in global scientific literature. Such a definition must be crafted, as it will delineate a phase in the natural history of type 2 diabetes (T2DM) when injectable therapy with insulin or/and GLP-1 receptor agonist should be strongly considered. This definition will help convince both physician, and patient, that there is no rationale in continuing to intensify OAD regimes. The definition will act as a bench mark for clinical practice and act as an aid to decision making. It will also harmonize treatment algorithms, and prevent confusing cross-talk between different diabetes care professionals. A precise and practical definition may reduce doctor shopping, clinical inertia, and iatrogenic errors of omission related to insulin initiation.

 

Early concepts

 

Decades ago, oral hypoglycaemic agent (OHA) failure was classified as primary and secondary.² Primary OHA failure implied inability to respond to oral drugs from the onset of therapy. It was usually seen in lean patients with low beta cell reserve, who may have been classified as having late onset auto immune diabetes (LADA). Secondary OHA failure included patients who stopped responding to OHA after years of good control on oral glucose lowering drugs. This implied gradual beta cell exhaustion, progressing through various stages of beta cell insufficiency. However, no precise definition of OHA failure was agreed upon.

 

Current confusion

 

The oral diabetes management coliseum has become even more crowded in the past two decades. This has led to lack of clarity in terms of defining OHA failure. Studies on DPP4 inhibitors have preferred to use the terms 'responder' and 'non-responder',^3,4 applying a linguistic smokescreen to hide the fact that these drugs are 'failures' in many persons. Other studies take arbitrary cutoffs of a 0.5% or 1.0% HbA1c reduction to define 'response', without mentioning that the drugs in question 'fail' to achieve HbA1c targets. The ADOPT study, which studied the glycaemic durability of monotherapy with rosiglitazone, as compared with metformin or glyburide, defined monotherapy failure as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter).⁵

 

Challenges and concerns

 

Availability of multiple classes of drugs, and more than one drug in almost each class, confuses the situation further. Should OAD failure be defined for each class, or for each drug? Are all drugs of a particular class equivalent in glucose lowering efficacy? Should every class of OADs be tried before labeling a person as having OAD failure? If so, should we go up to 5 or 6 classes of OADs? Can drug failure be diagnosed without adequate focus on non-pharmacological therapy, including diet, physical activity and stress management? If a temporary phase of uncontrolled dysglycaemia occurs, as in acute medical, surgical, endocrine, obstetric or emotional emergency, are we justified in applying a label of OAD failure? Another confounding factor relates to choice of glycaemic parameters. If OAD failure is to be defined, should it be based on HbA1c, or on the glycaemic triad, pentad or hexad?⁵ Are fasting glucose, postprandial glucose, hypoglycaemia, glycaemic variability, and ketonuria/ketosis adequate to diagnose OAD failure? Yet another concern arises with regards to pharmacotherapeutic management of OAD failure. If we use the term 'OAD failure', and initiate insulin, should OADs be continued? If so, which ones and why? Should insulin be given only to OAD failed patients, or can it be prescribed in anticipation of failure?

 

Beta cell insufficiency

 

To answer these questions, we need to understand the concept of beta cell insufficiency.⁶ Weighing about 1 gram, the beta cell mass functions to maintain euglycaemia in the face of multiple counteregulatory mechanisms. By the time T2DM is diagnosed, about half of the beta cell functional mass is lost. A 4-7% annual attrition occurs thereafter, which is associated with progressive deposition of amyloid in the islets of Langerhans. The gradual reduction in beta cell mass and function is compounded by insulin resistance, which may worsen with weight gain. Comorbid conditions such as sleep apnoea, infections and stress, and lack of healthy lifestyle may precipitate beta cell insufficiency as well. Beta cell insufficiency is a gradual and progressive condition, which passes through well identified stages. The incidence increases with duration of diabetes, and reaches up to 50% at 6 years of diagnosis (UKPDS).⁷ Recent cohort studies have shown that treatment failure is very common. In ADOPT (A Diabetes Outcome Progression Trial), a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide was noted.⁵ When prescribed in addition to metformin, a 12%, 26% and 38% dual therapy failure rate was seen after 2 years with thiazolidinediones, sulfonylureas and DPP4 inhibitors respectively.⁸ According to guidelines, such a situation warrants addition of either a third drug or insulin. A composite definition of OAD failure, if available, will guide therapeutic strategy in such a dilemma. The definition will assist physicians in deciding whether to prescribe insulin or add a third (or fourth) OAD.

 

The hypertension exemplar

 

Hypertension is a medical condition which is similar to diabetes in many ways- Chronic, vasculo-metabolic, multifactorial, poly-etiologic, requiring patient self-care for control, with multiple classes of drugs and molecules, as well as multiple means of assessment. Hypertension management shares the same challenges that diabetes does. One such clinical challenge is that of resistant hypertension, similar to refractory diabetes. Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of optimum doses of three anti hypertensive agents of different classes, one of which should be a diuretic.⁹ This definition has served its users well, and has facilitated good clinical practice. It encourages screening and investigation to confirm the diagnosis of resistant hypertension, rule out secondary causes of high blood pressure, and assists in rational choice of antihypertensive drug combinations.

 

Definition in evolution

 

Keeping this as a precedent, we propose that: OAD failure is defined as a clinical situation where HbA1c remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be an insulin sensitizer (metformin).

 

Language and perception

 

There may be many criticisms of this definition, The need to use the term 'inadequacy', as opposed to failure,^10,11 has been raised for sulfonylureas and insulin: there is no reason why the same argument should not apply to all OADs. The phrase 'OAD inadequacy' or 'OAD refractoriness' avoids negative connotation associated with patient failure or physician failure, and may be preferred by some. We reason, however, that such semantic diplomacy may distract us from trying to overcome clinical inertia, and from ensuring timely insulin initiation. Hence, a firm name, along with an objective definition, must be crafted for this well-recognized clinical condition.

 

Metformin is mandatory

 

Metformin is the unanimous first line choice for management of type 2 diabetes. Unless contraindicated or poorly tolerated, its use is recommended by current international guidelines.^12,13 In spite of over 60 years of use, this mature drug continues to exude maiden charm.¹⁴ Thus, a diagnosis of OAD failure must specify that metformin has been used in optimal or maximally tolerated doses. The other class of directly acting insulin sensitizers, the thiazolidinediones, is linked with various limitations and side effects. These prevent their use as routine drugs in a vast proportion of persons with type 2 diabetes. We can therefore delete reference to the drug class of sensitizers, and make the definition more concise: OAD failure is defined as a clinical situation where HbA1c remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be metformin.

 

Sulfonylureas: old is gold

 

As already mentioned, the classification of non-insulin antidiabetic drugs has become complex. A simple taxonomic model divides these drugs into three: insulin sensitizers, insulin secretagogues, and nutrient off-loaders. Sensitizer and secretagogues are further classified as directly acting and indirectly acting.¹⁵ Of all these classes, metformin (direct sensitizer) and sulfonylureas (direct secretagogues) are the most potent glucose lowering drugs. If a patient experiences 'failure' with directly acting drugs, there is minimal chance of the indirectly acting drugs acting efficiently. While the most potent sensitizer is metformin, sulfonylureas are acknowledged to be effective secretagogues. The HbA1c lowering effect of metformin and sulfonylureas is more than that of other OADs. Modern sulfonylureas are considered "safe and smart" choices for the management of type 2 diabetes.¹⁶ Hence, our working definition of OAD failure may be improved, to include the two most potent glucoselowering drugs. OAD failure is defined as a clinical situation where HbA1c remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be metformin, and the second, preferably a sulfonylurea.

 

Role of lifestyle modification

 

The definition we have proposed does not take non pharmacological therapy into account, however. Adequate focus on nutrition, exercise and stress is essential for glycaemic control. At the same time, there may be temporary medical, surgical, endocrine or emotional f ac tors wh i ch may re du ce re spons e to OADs. A similar situation is seen in the description of resistant hypertension, which mandates exclusion of pseudo resistance, masked hypertension and white coat hypertension.⁹ Secondary causes of hyperglycaemia, such as acromegaly, Cushing's syndrome, or steroid intake, need to be ruled out before labelling OAD failure. "Pseudofailure of OADs" is a term we may apply to patients who do not adhere to prescribed lifestyle modification or medical therapy; this too needs to be excluded. A better definition of OAD failure, then, would be: OAD failure is defined as a clinical situation where HbA1c that remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be metformin, and the second, preferably a sulfonylurea, provided adequate diet and exercise have been followed, and comorbid conditions causing hyperglycaemia ruled out.

 

Glycaemia and symptoms

 

We have taken HbA1c as the sole glycaemic parameter to define OAD effect or failure, as it is considered the gold standard. HbA1c is used as primary outcome in clinical trials, and for therapeutic stratification and goal-setting in modern treatment guidelines. There may be patients, however, in whom HbA1c cannot be estimated, due to lack of availability, or accuracy. In such patients, plasma glucose values and symptomatology may guide us to a diagnosis of OAD failure. Such a definition is concordant with recommendations to initiate insulin therapy in symptomatic patients.¹² There may exist clinical situations where a three month wait for labeling OAD failure is not warranted. These are encountered in patients with symptoms, signs and laboratory abnormalities suggestive of extreme insulinopenia, where it is clear that insulin therapy will be required. A delay in starting insulin will be counterproductive, and go against the tenets of good clinical sense. The definition thus expands to OAD failure to be defined as a clinical situation where HbA1c remains above goal, despite concurrent use of optimum dose of three oral glucose lowering drugs of different classes, one of which should be metformin and the second, preferably a sulfonylurea, provided adequate diet and exercise have been followed, and comorbid conditions causing hyperglycaemia are ruled out. OAD failure may also be defined in patients who have symptoms suggestive of insulinopenia (osmotic symptoms, weight loss), and uncontrolled glycaemia (plasma glucose> 300mg %), in spite of using triple OAD therapy.

 

Primary and secondary time frames

 

This definition can also be modified to include the concepts of primary and secondary failure. HbA1c reflects control over a period of three months, and changes in therapy are usually advised at three month intervals.

 

Therefore, the definition may state:

Primary OAD failure is diagnosed when this occurs within six months of diagnosis of diabetes and after three months of initiation of triple oral therapy. Secondary OAD failure is labeled if glycaemic control is lost, after adequate response to OADs has been documented for at least six months duration.

 

Chaos to consensus

 

For any definition to be widely accepted and use, consensus is necessary. Therefore, broad agreement is needed for this description of OAD failure as well. Our commentary goes beyond mere words: it has firm therapeutic implication. The concept of OAD failure strongly discourages use of more than 3 OADs to manage diabetes. It encourages metformin as a first line treatment, and supports sulfonylurea prescription, in a 'safe and smart' manner. The framework facilitates timely motivation and initiation of insulin, so as to control diabetes and avoid unnecessary complications. By preventing use of unnecessary OADs, saving precious time, and promoting good glycaemic control, it follows the tenets of quaternary prevention and good clinical sense.^17,18 At the same time, it encourages earlier use of insulin in symptomatic and severely hyperglycaemic patients. While this exposition will certainly stimulate further debate and discussion, having a working definition of OAD failure should help us in our aim to achieve efficient glycaemic control.

 

References

 

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2. Pontiroli AE, Caiderara A, Pozza G. Secondary failure of oral hypoglycaemic agents: frequenc y, possible causes, and management. DIABETES-METAB RES REV. 1994; 10:31-43.

3. Halimi S. DPP-4 inhibitors and GLP-1 analogues: for whom? Which place for incretins in the management of type 2 diabetic patients? Diabetes Metab. 2008; 34:S91-5.

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5. Kahn SE, Haffner SM, Heise MA, et al. ; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443

6. Kalra S, Gupta Y. Beta-cell Insufficiency. Eur. Endocrinol. 2017;13:51- 3

7. 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). JAMA 1999;281:2005-12.

8. Eriksson JW, Bodegard J, Nathanson D, Thuresson M, Nyström T, Norhammar A. Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality. Diabetes Res Clin Pract 2016;117:39-47.

9. de Boer IH, Bangalore S, Benetos A, Davis AM, Michos ED, Muntner P, Rossing P, Zoungas S, Bakris G. Diabetes and Hypertension: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40:1273-84.

10. Wright A, Burden AF, Paisey RB, Cull CA, Holman RR. Sulfonylurea inadequacy. Diabetes care. 2002;25:330-6.

11. Kalra S, Gupta Y. Basal Insulin Inadequacy versus Failure-Using Appropriate Terminology. Eur. Endocrinol; 2015;11: 79-80.

12. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149

13. International Diabetes Federation. Global guideline for type 2 d i a betes. Available from https://www.idf.org/e–library/guidelines/79-global-guideline-for-type-2-diabetes.html. Accessed 6 October 2017

14. Kalra S, Dhamija P, Das AK. Metformin: Midlife maturity, maiden c ha rm. I n di a n J En d oc r i n ol Me t a b. 2 0 1 2 ; 1 6 : 1 0 1 5.

15. Kalra S. Classification of non-insulin glucose lowering drugs. J Pak Med Assoc. 2016;66:1497-8.

16. Kalra S, Aamir AH, Raza A, Das AK, Khan AA, Shrestha D, Qureshi MF, Fariduddin M, Pathan MF, Jawad F, Bhattarai J. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab 2015;19:577.

17. Kalra S, Sreedevi A, Unnikrishnan AG. Quaternary prevention and diabetes. J Pak Med Assoc. 2014;64:1324-6.

18. Kalra S, Gupta Y. Good clinical sense in diabetology.J Pak Med Assoc. 2015;65:904-6.