1. Treating Earlier and Effectively with Combination Therapies
This slideset was developed with support from GlaxoSmithKline

2. Aim Provide practical guidance on improving diabetes care
through highlighting the need for:
a sense of urgency in treating to target
earlier introduction of combination therapy
consideration of patient profile
use of combinations of drugs with complementary mechanisms of action

3. Need for an early and intensive approach to type 2 diabetes management
At diagnosis of type 2 diabetes:
50% of patients already have complications1
up to 50% of -cell function has
already been lost2
Current management:
two-thirds of patients do not
achieve target HbA1c3,4
majority require polypharmacy
to meet glycemic goals over time5
Diagnosis of type 2 diabetes may occur years after its onset and, by the time of diagnosis, serious complications have often already developed.1
In addition, on average 50% of pancreatic β-cell function has already been lost by the time of diagnosis.2
Despite the need for intensive management strategies to delay further progression of the disease and to reduce loss of glycemic control, studies have shown that the majority of patients do not achieve HbA1c goals.3,4
Only approximately 25% of patients in the UKPDS treated with monotherapy achieved their glycemic goals after 9 years and required polypharmacy.5
1UKPDS Group. Diabetologia 1991; 34:877–890. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3Saydah SH, et al. JAMA 2004; 291:335–342. 4Liebl A, et al. Diabetologia 2002; 45:S23–S28. 5Turner RC, et al. JAMA 1999; 281:2005–2012.
1UKPDS Group. Diabetologia 1991; 34:877–890. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3Saydah SH, et al. JAMA 2004; 291:335–342.
4Liebl A, et al. Diabetologia 2002; 45:S23–S28. 5Turner RC, et al. JAMA 1999; 281:2005–2012.

4. Barriers to achieving good glycemic control
Limitations of reactive, stepwise treatment
Therapy not matched to the individual
Conservative prescribing of antidiabetic agents
A number of factors are likely to contribute to the complexities of controlling blood glucose levels in individuals with type 2 diabetes.
The Global Partnership has identified several key areas that will help the diabetes care team to increase the proportion of individuals achieving good glycemic control and thus decrease the risk of complications.
These include the need for:
a sense of urgency in treating to target, including earlier introduction of combination therapy
consideration of patient profile
use of combinations of drugs with complementary mechanisms of action.

5. Limitations of reactive, stepwise treatment

6. Conservative management of glycemia: traditional stepwise approach
OAD
monotherapy up-titration
OAD + multiple daily insulin injections
Diet and
exercise
OAD*
monotherapy
OAD
combination
OAD + basal insulin 10 9
HbA1c (%) 8
HbA1c = 7%
Diet and exercise are typically used as the first stage of stepwise management. However, although the benefits of lifestyle intervention are apparent, this strategy may be difficult to maintain over time.1
The next step usually involves introduction of a single oral antidiabetic agent in addition to diet and exercise.
If HbA1c levels start to rise, the oral antidiabetic agent is traditionally up-titrated to its maximal dose.
As the condition progresses and additional control is required, further oral antidiabetics are added in combination until, finally, introduction of insulin is required to maintain glycemic control.
A drawback of this approach is that there are often unacceptable delays in changing therapy, leading to long periods of hyperglycemia.
1Campbell IW. Br J Cardiol 2000; 7:625–631. 7
HbA1c = 6.5% 6
Duration of diabetes
*OAD = oral antidiabetic
Campbell IW. Br J Cardiol 2000; 7:625–631.

7. Drawbacks of the stepwise approach
Even short periods of hyperglycemia increase risk of complications1–3
A proactive approach is required to get patients to achieve their glycemic goals sooner
Microvascular complications 80
Normal HbA1c levels 60
Incidence per 1000 patient-years
Stepwise management is a reactive strategy that can involve significant delays before stepping up to the next level of treatment.
Even short periods of hyperglycemia increase the risk of microvascular and macrovascular complications1–3 and a more proactive approach is therefore required to achieve glycemic goals sooner.
More intensive strategies, involving earlier introduction of combination therapy in parallel with a diet and exercise program, have the potential to improve glycemic control over the long term. This in turn should reduce the substantial burden associated with diabetes-related complications.
1EDIC Group. JAMA 2003; 290:2159– EDIC Group. JAMA 2002; 287:2563– Nathan DM, et al. N Engl J Med 2003; 348:2294–2303. 40
Myocardial infarction 20 5 6 7 8 9 10 11
Updated mean HbA1c (%)
1EDIC Group. JAMA 2003; 290:2159– EDIC Group. JAMA 2002; 287:2563–2569.
3Nathan DM, et al. N Engl J Med 2003; 348:2294–2303.

8. Diet and exercise are beneficial to good glycemic control
Lifestyle changes can have beneficial outcomes1,2
Patients may require motivation to encourage them to follow a healthy diet and take exercise
Diet and exercise programs are essential components of diabetes care, and have been shown to:
provide initial improvements in glycemic control1
reduce weight2
improve insulin sensitivity in insulin-resistant individuals.2
However, many people find it difficult to maintain long-term changes in behaviour.3
Individuals may require considerable assistance and support in adopting and maintaining their diet and exercise programs. For example:
ensure that individuals are aware of the benefits of diet and exercise in controlling their blood glucose
ensure that they are involved in developing their diet and exercise program, and agree changes that suit their lifestyle
where possible, involve other members of the diabetes team, particularly friends and family, in addition to the dietician.
1Levy J, et al. Diabet Med 1998; 15:290– Macauley KA, et al. Diabetes Care 2002; 25:442–452. 3National Institutes of Health, Clinical Guidelines for the Identification, Evaluation and Treatment of Overweight and Obesity in Adults
1Levy J, et al. Diabet Med 1998; 15:290–296.
2Macauley KA, et al. Diabetes Care 2002; 25:442–452.

9. Benefits of diet and exercise may be difficult to maintain in the long term
Stepwise treatment may lead to delays
Pharmacological therapy should be introduced in tandem with lifestyle changes
Diet and exercise programs should be an integral component of diabetes care at all times.
However, in the real-life setting, without the careful monitoring and close management seen in clinical trials, compliance with diet and exercise – and therefore the effectiveness of glycemic control – is difficult to maintain.
There is, therefore, a strong rationale to introduce monotherapy with an oral antidiabetic agent at the same time as starting a diet and exercise program in many individuals.
Delaying the introduction of oral monotherapy (as in the stepwise approach) may expose patients to the risks of diabetes-related complications associated with hyperglycemia.

10. Delays often occur between stepping up from monotherapy to combination therapy
Length of time between first monotherapy HbA1c > 8.0% and switch/addition in therapy (months) 25
20.5 months 20
14.5 months 15
Months 10
Initial improvements in glycemic control seen with conventional antidiabetic agents in monotherapy are usually not maintained long term, and most patients ultimately require combination therapy to achieve good glycemic control.1
In practice, there is often a considerable delay between the loss of glycemic control with monotherapy and the introduction of another antidiabetic agent.
Analysis of data from the Kaiser Permanente Northwest database
(1994–2002)2 found that the average time from when the HbA1c action point of 8% was exceeded and the introduction of an additional or alternative oral antidiabetic agent was:
14.5 months for those on metformin monotherapy
20.5 months for those on sulfonylurea monotherapy.
Earlier introduction of combination therapy could reduce exposure of patients to the risk of diabetes-related complications associated with periods of hyperglycemia.2
1Turner RC, et al. JAMA 1999; 281:2005– Brown, JB et al. Diabetes Care 2004; 27:1535–1540. 5
Metformin only
Sulfonylurea only
n = 513
n = 3394
Brown, JB et al. Diabetes Care 2004; 27:1535–1540.

11. Up-titrating monotherapy to the maximum recommended dose may not provide benefit
HbA1c
Gastrointestinal side effects 10
-0.5 8 -1 6
Change in HbA1c from placebo (%)
Patients stopping treatment (%)
-1.5 4 -2 2
Using the traditional stepwise approach, for individuals inadequately controlled on sub-maximal doses of monotherapy, the next step was to up-titrate the dose of monotherapy.
However, up-titration to maximum recommended doses may provide little or no benefit in terms of improved glycemic control and may even be associated with a substantial increase in side effects.
For example, in a 14-week study of metformin monotherapy in 451 patients with type 2 diabetes:1
increasing the metformin dose from 2000 to 2500 mg/day gave no further improvement in glycemic control
the proportion of patients stopping treatment because of gastrointestinal side effects more than doubled (metformin 2000 mg/day = 4%; metformin 2500 mg/day = 10%).
Therefore, for patients inadequately controlled on sub-maximal doses of monotherapy, introduction of an additional agent in combination therapy may be preferable to up-titration to maximal doses of a single agent.
1Garber AJ, et al. Am J Med 1997; 103:491–497.
-2.5
500
1000
1500
2000
2500
500
1000
1500
2000
2500
Metformin dosage (mg)
Metformin dosage (mg)
Garber AJ, et al. Am J Med 1997; 103:491–497.

12. Proactive management of glycemia: early combination approach
Diet and exercise
OAD* monotherapy
OAD combinations
OAD
up-titration 10
OAD + basal insulin
OAD + multiple daily insulin injections 9
HbA1c (%) 8
ACTION POINT:
An early, intensive approach to type 2 diabetes management reduces the risk of early treatment failure by adopting an intensive therapeutic strategy immediately upon diagnosis.
Early use of combination therapy with oral antidiabetics provides better and more rapid glycemic control. 7
HbA1c = 7%
HbA1c = 6.5% 6
Duration of diabetes
*OAD = oral antidiabetic

13. Potential advantages of early combination therapy
Earlier achievement of therapeutic goals
Potential reduction in risk of side effects if you combine drugs at lower doses versus up-titration of single dose
Opportunity to combine oral antidiabetic drugs with complementary modes of action
Potential to delay disease progression
Given the drawbacks of the traditional stepwise approach, there is a strong rationale for earlier use of combination therapy.
Earlier introduction of combination therapy offers the potential for therapeutic goals to be achieved more rapidly than with conventional stepwise management, thus reducing the risks associated with extended periods of poor glycemic control.
Combination therapy with sub-maximal doses of oral antidiabetic agents may offer improved safety and tolerability compared with monotherapy with a single agent titrated to maximal doses.
Combination therapy with agents with complementary mechanisms of action is likely to have additional benefits for the long-term management of type 2 diabetes.
Combining agents that target the dual defects of insulin resistance and β-cell function that underlie type 2 diabetes has the potential to maintain good glycemic control in the long term and to delay or prevent disease progression.

14. Patients achieving HbA1c < 7% (%)
Benefits of adding TZD to sub-maximal sulfonylurea compared with up-titration 10 20 30 40 50 60
Patients achieving HbA1c < 7% (%)
Up-titrated SU + PBO
22%
RSG + SU
50%
The benefits of earlier use of combination therapy with a thiazolidinedione (rosiglitazone) plus a sulfonylurea have been demonstrated in the RESULT study.1
A total of 227 older individuals with type 2 diabetes (> 60 years) with inadequate glycemic control were randomized to treatment with either sulfonylurea + rosiglitazone 4 mg/day or sulfonylurea + placebo.
Treatment was individualized over 2 years, with up-titration of study medication to a maximum of 40 mg/day for sulfonylurea and 8 mg/day for rosiglitazone.
Combination therapy with rosiglitazone and a sulfonylurea provided superior glycemic control, with 50% of patients achieving the target HbA1c of < 7%, compared with only 22% of those taking up-titrated sulfonylurea.1
Combination therapy with rosiglitazone and a sulfonylurea was well tolerated, with no increase in the risk of hypoglycemia compared with the sulfonylurea group.1
1Rosenstock J, et al. Diabetes Obes Metab 2005; [In press].
Abbreviations: PBO, placebo; RSG, rosiglitazone; SU, sulfonylurea; TZD, thiazolidinediones.
Rosenstock J, et al. Diabetes Obes Metab 2005; [In press].

15. Benefits of adding TZD to sub-maximal metformin compared with up-titration
HbA1c
Gastrointestinal side effects 60
58% 12 50
48% 10 40 8 7%
Patients discontinuing due to GI disturbances (%)
Patients achieving HbA1c < 7% (%) 30 6 20 4 3% 10
The benefits of earlier use of combination therapy with a thiazolidinedione (rosiglitazone) plus metformin have been demonstrated in the EMPIRE study.1
Individuals were titrated to a dose of metformin 1 g/day over 4–7 weeks.
Those who did not achieve glycemic targets with sub-maximal metformin (1 g/day) were randomized to 24 weeks’ treatment with open-label metformin plus either rosiglitazone titrated to 8 mg/day (n = 296) or metformin up to an additional 1 g/day (n = 277).
More patients achieved HbA1c < 7% with rosiglitazone added to sub-maximal metformin compared with up-titrated metformin therapy (58% versus 48%, respectively).
Fewer individuals on combination therapy (n = 382) experienced gastrointestinal (GI) side effects compared with those taking up-titrated metformin (n = 384; 29% versus 39%) and there were fewer withdrawals as a result of GI side effects (3% versus 7%).
1Rosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A144. 2
MET 1 g/day
+ MET 1 g/day
MET 1 g/day + RSG 8 mg/day
MET 1 g/day
+ MET 1 g/day
MET 1 g/day + RSG 8 mg/day
Abbreviations: MET, metformin; RSG, rosiglitazone; TZD, thiazolidinediones.
Rosenstock J, et al. Diabetes 2004; 53 (Suppl. 2):A144.

16. Patients achieving HbA1c < 7% Patients achieving HbA1c < 7% (%)
Benefits of glyburide/metformin versus monotherapy as initial pharmacotherapy
Patients achieving HbA1c < 7% 80 70 60 50
Patients achieving HbA1c < 7% (%) 40 30 20
The benefits of early combination therapy with a sulfonylurea (glyburide) plus metformin have been demonstrated in individuals previously treated with diet and exercise alone.1
A total of 486 patients were randomized to 16 weeks’ treatment with glyburide/metformin (1.25/250 mg/day), metformin (500 mg/day) or glyburide (2.5 mg/day).
Compared with metformin or sulfonylurea monotherapy, the glyburide/metformin combination provided superior reductions in HbA1c, with more patients achieving the goal of HbA1c < 7.0%.
Combination therapy was generally well tolerated, with fewer gastrointestinal side effects than with metformin monotherapy.
1Garber AJ, et al. J Clin Endocrinol Metab 2003; 88:3598–3604. 10
GLY
MET
GLY/MET
Abbreviations: GLY, glyburide; MET, metformin.
Garber AJ, et al. J Clin Endocrinol Metab 2003; 88:3598–3604.

17. How quickly should patients be reaching HbA1c targets?
The Global Partnership recommends:
Treat patients intensively so as to achieve target HbA1c < 6.5%* within 6 months of diagnosis
< 6.5%
*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not possible
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

18. When should combination therapy be introduced?
The Global Partnership recommends:
After 3 months, if patients are not at target HbA1c < 6.5%,* consider combination therapy
*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not possible
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

19. Therapy not matched to the individual

20. Individuals with high baseline HbA1c require more intensive treatment
Risk of complications increases with HbA1c
Individuals with high baseline values require particularly urgent and intensive treatment
Monotherapy is often insufficient in these individuals and combination therapy should be initiated earlier
High HbA1c levels increase the risk of complications. This risk can be dramatically reduced through glycemic control; a 1% reduction in HbA1c reduces the risk of microvascular complications by 37% and myocardial infarction by 14%.1
Hence, individuals with high HbA1c levels at diagnosis are at particularly high risk of diabetes-related complications and early and intensive treatment to improve glycemic control as rapidly as possible is particularly important.
Monotherapy or late introduction of combination therapy is often inadequate in these individuals and so other approaches are required.
1Stratton IM, et al. BMJ 2000; 321:405–412.
Stratton IM, et al. BMJ 2000; 321:405–412.

21. How should patients with high baseline HbA1c be managed?
The Global Partnership recommends:
Initiate combination therapy or insulin immediately for all patients with HbA1c  9% at diagnosis
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

22. Inappropriate prescribing of antidiabetic agents

23. Reasons for conservative prescribing patterns
Familiarity with traditional agents
Concerns regarding safety of newer agents
Perceived lack of efficacy of antidiabetic agents
A number of factors may contribute to the reluctance of physicians to change the way they manage type 2 diabetes.
Physicians are familiar with traditional agents, such as sulfonylureas and metformin, that have been available for many years and are therefore more likely to prescribe them without considering newer options.
In addition, they may have greater concerns about the safety profiles of newer agents compared with conventional agents, of which they have experience of managing the risk and impact of adverse events.
Some physicians attribute the low proportion of patients achieving recommended glycemic targets to a lack of efficacy of available antidiabetic agents rather than recognizing the importance of when and how to use agents most effectively in order to optimize glycemic control.

24. Treatment options for type 2 diabetes
Sulfonylureas
1st generation e.g. chlorpropamide, tolbutamide
2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone
3rd generation e.g. glimepiride
Modified release
Glinides/meglitinides
Non-sulfonylureic e.g. repaglinide
Amino acid derivatives e.g. nateglinide
Biguanides
e.g. metformin
Thiazolidinediones
e.g. rosiglitazone, pioglitazone
-glucosidase inhibitors
e.g. acarbose
Insulin
regular
intermediate/long acting
pre-mixed
analogs
rapid acting
long acting
Fixed-dose oral antidiabetic drug combinations
e.g. glyburide/metformin, glipizide/metformin, rosiglitazone/metformin
There are currently a wide range of treatment options available for the management of type 2 diabetes.
Over time, the choice of agents has evolved significantly, with introduction of new generations of sulfonylureas as well as novel classes of agents, such as the thiazolidinediones and meglitinides.
There is also increasing choice in the types of insulin available.
With growing interest in the earlier introduction of combination therapy, combining agents from different antidiabetic classes may be of benefit because of their complementary mechanisms of action.
In addition, the increasing availability of fixed-dose oral antidiabetic combinations may increase convenience for both physician and patient.

25. Choosing antidiabetic agents: efficacy
Insulin
Metformin
α-glucosidase
TZDs*
Insulin
secretagogues
inhibitors
Effect on FPG/HbA1c1
Effect on plasma
insulin1,2 –
Effect on insulin
resistance3 –
Effect on insulin secretion4
These data represent an abbreviated summary; please consult current prescribing information for these agents to obtain complete information. –
= reduced levels
= increased levels
= no significant effect
*TZDs = thiazolidinediones
1DeFronzo RA. Ann Intern Med 1999; 131:281–303. 2Lebovitz HE. Endocrinol Metab Clin North Am 2001; 30:909– Matthaei S, et al. Endocrine Reviews 2000; 21:585–618. 4Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol; 2001; 109 (Suppl. 2):S265–S287.

26. Choosing antidiabetic agents: safety and tolerability
Insulin
Metformin
α-glucosidase
TZDs*
Insulin
secretagogues
inhibitors
Risk of
hypoglycemia1,2
Weight gain1,2
Gastrointestinal side effects1
Lactic acidosis1
These data represent an abbreviated summary; please consult current prescribing information for these agents to obtain complete information.
Edema3
= treatment-related adverse event
= not commonly seen in monotherapy
*TZDs = thiazolidinediones
1DeFronzo RA. Ann Intern Med 1999; 131:281–303. 2UKPDS. Lancet 1998; 352:837–853.
3Nesto RW, et al. Circulation 2003; 108:2941–2948.

27. Choosing oral antidiabetic agents: mechanism of action
 Carbohydrate breakdown/ absorption
-glucosidase inhibitors
 Insulin secretion
Sulfonylureas/ meglitinides
 Glucose output
 Insulin resistance
Biguanides
Thiazolidinediones
-glucosidase inhibitors (e.g. acarbose) – delay digestion and absorption of carbohydrates in the gastrointestinal tract.1,2
Sulfonylureas and meglitinides – stimulate insulin secretion from the pancreas.1,2
Biguanides (e.g. metformin) – suppress liver glucose output, enhance insulin sensitivity in the liver and stimulate insulin-mediated glucose disposal. They do not stimulate insulin secretion.1,2
Thiazolidinediones – decrease insulin resistance in fat, muscle and liver. In addition, they have a beneficial effect on β-cell function.1,2
When selecting agents for combination therapy, combining agents from different classes will give the best effects due to their complementary mechanisms of action.
1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
 Insulin resistance
1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

28. What are the ideal components for combination therapy?
The Global Partnership recommends:
Use combinations of oral antidiabetic agents with complementary mechanisms of action
Improved glycemic control
Agent B
Agent A
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

29. Paradigm for early combination treatment
If HbA1c  9% at diagnosis
Initiate combination therapy† or insulin in parallel with diet/exercise
Treat to goal of HbA1c < 6.5%* by 6 months
If HbA1c < 9% at diagnosis
Initiate monotherapy in parallel with diet/exercise
If HbA1c > 6.5%* at 3 months
Initiate combination therapy† in parallel with diet/exercise
The Global Partnership recommends a new paradigm for early combination treatment that incorporates the following recommendations:1
treat patients intensively so as to achieve target HbA1c < 6.5%* within 6 months of diagnosis
after 3 months, if patients are not at target HbA1c < 6.5%,* consider combination therapy
initiate combination therapy or insulin immediately for all patients with HbA1c  9% at diagnosis
use combinations of oral antidiabetic agents with complementary mechanisms of action.
*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not possible.
1Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355. 1 2 3 4 5 6
Months from diagnosis
*Or fasting/preprandial plasma glucose < 110 mg/dL (6.0 mmol/L) where assessment of HbA1c is not possible †Combination therapy should include agents with complementary mechanisms of action
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.