Finding the Right Combination Therapy of Anti Diabetic Drugs

Sarwono Waspadji
Jakarta Diabetes and Lipid Center,
Division of Endocrinology and Metabolism,
Department of Medicine, FMUI
Diabetes Mellitus has become major public health problem all over the word. The
escalating prevalence is also occurring in Indonesia, which will be the 4 th greatest diabetic
population in 2030. The population study in Jakarta and its surroundings also showed this
tendency, proved by the increase of DM prevalence from 1.7% in 1981 to 5.7% in 1992 and 11.8
% in 2005. The National Health survey done in 2008 by the Ministry of Health Republic of
Indonesia, shows the national prevalence of Diabetes Mellitus of 5.8 %. However, in the rural
areas although increasing, the prevalence of DM is still relatively low. Our recent study in the
very rural area of Flores Island showed the prevalence of DM as 1.55 % and IGT 2.22% (on
OGTT).
Leave untreated DM will cause serious organ damage systematically, both macrovascular
and microvascular complications. To cope with the problems, strategies for reduction of diabetic
cardio-vascular complications have to be implemented. Glycemic control is one of the most
important strategies. There are ample evidences showed that the higher the A1c as a measures
of glycemic control is associated with higher cardiovascular events among diabetics. The United
Kingdom Prospective Diabetes Study (UKPDS) was established to definitively answer the
glycemic control controversy as well as an attempt to answer important questions about the class
of agents used to achieve control in conjunction with chronic diabetes vascular complications.
UKPDS resulted in many important aspects of diabetes management included a strong evidence
that hyperglycemia is a treatable, and better glycemic control can improve cardiovascular
outcomes. This conclusion was then reconfirmed by the UKPDS follow up study, showing the
legacy positive effects of early good glycemic control toward the cardiovascular outcomes.
Since then, the earlier the better is an important slogan for the prevention of vascular
complications of diabetes. This important finding was soon followed by some important studies
which unfortunately found an unexpected results.Accord and VADT studies taught us all a
sharp lesson. Taking high-risk patients and imposing very tight glycemic control led to the
perverse outcome of greater mortality in the intensive group. This shows that we need to use
more meticulous clinical care in those in whom hypoglycemia (the major suspect for the adverse
outcome) may pose a problem. Extra caution is also needed in those in whom established
pathology can be detected. Enthusiasm (over enthusiasm?) among in hospital patients, initiated
by van den Berg study, become also less popular. Intensive aggressive and too low target might
cause higher mortality as shown in Nice Sugar Study. Again in Nice Sugar study hypoglycemia
is the major culprit for the adverse outcomes. The newer guidelines set up the target at slightly
higher target: 7 % for outpatients as well 140 -180 mg/dL for critically ill in patients. However

this seemly higher target should be achieved earlier to prevent worse and higher incidence of
T2DM complications and its sequels, as can be seen in the latest guidelines of the management
of diabetes (e.g. AACE 2013 guidelines, Perkeni guidelines 2011).
How about the glycemic control and healthcare system in Indonesia? Data from
International Diabetes Management Prevention Study (IDMPS) Indonesia - Perkeni clearly show
the health care condition in Indonesia especially for Diabetes Mellitus. The percentage of
diabetics who achieve recommended glycemic target is not satisfactory (mean A1c 8.15 %, and
only about 30 % percent of total diabetic patient can achieve the recommended target of A1c < 7
%). But we are not alone. Glycemic control achievement in our neighbouring countries and
even in the developing countries are not satisfactory either. There are so many factors affecting
the poor achievement. Beside medical management problems, poor compliance is one of the
important problems especially for diabetics who needs long term, preventive treatment in
asymptomatic person. Patient compliance is influenced by several factors, not only patient
related factor, but also socioeconomic, healthcare team/system, condition related and last but not
least therapy related factors. Patient-related factors not necessarily the biggest barrier to
compliance. To support the patients needs in their efforts at self-management, more effective
interventions are essential. In the management of Type 2 DM, to achieve optimal blood glucose
control, many algorithms have been put forward to guide physician treated diabetics
rationally.The most important issue in the overall management of T2DM is individualization
treatment approach in the attempt to achieve the target glycemic control to prevent
cardiovascular complications. There are many algorithms available from many diabetes
organizations including ADA, EASD as well as Indonesian Society of Endocrinology.
It is well documented that using monotherapy alone, a large proportion of diabetics could
not achieve the recommended glycemic target to prevent the emergence of cardiovascular
complications, which even have been present at the time of diagnosis. In the UKPDS, 50%
patients at 3 years and 75% patients at 9 years needed combination therapy. Another evidence
supports the early use of combination therapy. Up-titrating monotherapy to the maximum
recommended dose may not provide benefit and delays often occur between stepping up from
monotherapy to combination therapy, rendering to a higher cardiovascular complications. There
are several possible rational combinations of hypoglycemic agents including Oral-oral
hypoglycemic agents combinations as well as Insulin-oral combinations. Both types of
combinations will be adressed below. Careful considerations should be implemented before
determining hypoglycemic agent(s) combinations. Principles in selecting hypoglycemic drug
interventions should always include: 1/ Effectiveness in lowering blood glucose, as well possible
side effects 2/ Extraglycemic effect that may reduce long-term complications, 3/ Safety profile,
4/ Tolerability,5/ Ease of use, and last but not the least 6/ Cost and the affordability of the
patients to be treated.

For several reasons, Sulphonylurea and Metformin combinations are the most popular
oral-oral combinations, as it is cheaper and show the highest benefit in terms of lowering A1c as
compared to the other combinations possible. Moreover, theoretically Sulphonylurea and
Metformin combination might have effects which are beneficial to ameliorate the dual defects in
Type 2 DM namely insulin resistance (Metformin) and Beta cell secretion defecency
(Sulphonylurea). There are different opinions concerning the actions of each type of
sulphonylurea on cardiovascular outcomes. However there remain conflicting results as for
beneficial cardiovascular effects of the Metformin and Sulphonylurea combination therapy.
Furthermore there are so many other possible combinations of oral-oral combinations. Each
combination will give their own benefit. In choosing Oral-oral combinations we should be
rational, which means sensible, can be tested by reasoning, and having logical basis. What is
rational always changes with time, with the current accepted concept, with evidence based.
Based on diabetes pathogenetic concept of insulin resistance and decreasing insulin secretion,
combination of Metformin-sulphonylurea and TZD-sulphonylurea as well as SulphonylureaDPP-4 inhibitor are rational as is also the case for combination of Metformin- DPP-4 inhibitor.
Metformin-DPP-4 inhibitor combination, beside concordance to the basic pathogenetic concepts
is theoretically more suitable for obese diabetics as both component have no weight gain effect.
The new non insulin dependen drug(s) is potensial also as component of hypoglycemic
combinations. As has been mentioned before, in choosing the right combinations, basic
principles in choosing the appropriate hypoglycemic agents should always be applied.
Knowledge on the benefit and risk of hypoglycemic agents medications should be mastered to
have the rational combination which will be most beneficial to the patients. It is also true as for
the results of End-Point Studies with different classes of antidiabetic drugs for the treatment of
patients with Type 2 Diabetes Mellitus.
Insulin is needed whenever there is insufficient endogenous insulin production.
Insulinopenia is suggested by clinical findings such as thinner patient, weight loss, marked
hyperglycemia, ketonuria and unstable glucose pattern. As for Insulin-Oral combinations,
theoretically Insulin can be combined with any oral hypoglycemic agents (Sulphonylurea,
Metformin, AGI, TZD, DPP-4 inhibitor as well as SGLT-2 inhibitor) with certain individual
benefits and precautions. Metaanalysis showed that Insulin-oral combinations might help reduce
the amount of insulin needed by 32 % for metformin, 42 % for sulphonylurea, 53 % for TZD,
and up to 62 % for metformin +sulphonylurea.
There are so many possible different configurations of combinations of Oral-oral
hypoglycemic agents as well as Insulin-oral hypoglycemic agents combinations. Treating T2DM
to achieve optimal blood glucose control is real medicine; the ART of treatment is very delicate,
meticulous and should be finely tuned for each individual patient. There are potential advantages
of having FCD (fixed dose combination) which is considered as having greater efficacy as
compared to monotherapy, decrease risk of side effects relative to higher dose monotherapy, and
also might improve medication adherence as well as lower cost. Not all Fixed Dose

Combinations are the same off course, depend on the type as well the doses of the drug
combined. Combination of all kinds of hypoglycemic agents are potentially rational, although
each combination might give different results and efficacy as well potensial side effects. Poor
compliance is an important medical problems especially for diabetics who needs long term,
preventive treatment in asymptomatic person, evenmore if the treatment is associated with
significant fearing side effects such as severe hypoglycemia and also weight gain. For ease of
use and practicality, fixed dose combination (sulphonylurea and metformin) might have
beneficial effect in terms of higher compliance although evidence showed that the effectiveness
of free and fixed dose combination were not different. The facts are also true for the
hypoglycemic effect of free and fixed dose combination. However with FDC, the treating
physicians loose the flexibility in optimizing individualization treatment for their specific
patients.
Conclusion and Recommendation
The latest recommendation as can be seen from the latest AACE guidelines (2013)
however strongly suggest for individualization therapy both in choosing monotherapy and
combination therapy. Likewise the choice of types of hypoglycemic agent(s) used. For
Indonesia as developing country with limited resources and affordability, the choice of
medications for the management of Type 2 DM to prevent the emergence of cardiovascular
complication will even be having more limitation. It is the treating physician who have to be
knowledgeable concerning the rational and proper management of type 2 DM as well as the
patients overall condition bio-psycho-economico-socially, to be able to choose the best
combinations of hypoglycemic agents to get the utmost benefit in manageing type 2 diabetes to
prevent the emergence of chronic cardiovascular complications.

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